Section 12: Pregnancy

INTRODUCTION AND EPIDEMIOLOGY

Pregnancy and delivery require amazing maternal adaptation, with nearly every organ system altered by hormonal and/or mechanical means. Physiologic changes begin at conception and continue throughout pregnancy and the postpartum period. Such changes may impact the manifestation and course of a disease process as well as have implications for treatment. Maternal vulnerabilities, such as increased risk of thrombosis, hypertension, or diabetes, may also be revealed during pregnancy. Since any woman of reproductive age has the potential to be pregnant, their care must occur in the context of an understanding of normal and abnormal pregnancy physiology.

PHYSIOLOGY BY SYSTEM

CARDIOVASCULAR

A healthy heart adapts well to the marked demands of pregnancy, but congenital or acquired heart disease may present or worsen in the gravid woman due to the cardiovascular changes associated with increased cardiac workload. Estrogen mediates an increase in cardiac output (CO) by 6-week gestation via increased preload and stroke volume. Blood volume rises by 30% to 40% during pregnancy, peaking at the end of the second trimester. Cardiac output peaks in the third trimester, typically 30% to 50% above baseline. Total peripheral resistance declines by 20%. Systolic and diastolic blood pressures drop by 10 to 15 mm Hg in the first trimester then return to baseline in the second half of pregnancy; diastolic blood pressure declines more than systolic, so pulse pressure widens. The cardiac axis is shifted leftward, anterior and cephalad.

Blood flow distribution changes during pregnancy such that up to 25% of CO is directed to the uteroplacental unit (a new “end-organ”) and up to 20% to the kidneys. An increased proportion of CO supplies breast tissue, but cerebral blood flow remains at baseline proportions.

Cardiovascular adaptations lead to common complaints in pregnant women: palpitations, decreased exercise tolerance, and dizziness. A shift of the heart toward the chest wall may contribute to the experience of palpitations by the gravida, but palpitations may also represent increased sensitivity to mild sinus tachycardia, premature atrial or ventricular systoles, or, less likely, supraventricular tachycardia. It is postulated that the increase in blood volume may be associated with stretching of the myocardium, thereby potentially increasing myocardial irritability and predisposing to arrhythmias. While this is not clearly proven, both atrial and ventricular arrhythmias may occur in pregnancy just as they occur in the nonpregnant patient. By late pregnancy there is attenuated ability to increase cardiac output with exercise, and this combined with normal weight gain of pregnancy can lead to decreased exercise tolerance. Beyond midpregnancy the gravid uterus causes aortocaval compression in the supine position, decreasing CO by 30%, and venous return, leading to dizziness and dyspnea (termed supine hypotensive ­syndrome) in some women. Pertinent exam findings include systolic flow murmur by midpregnancy, mammary soufflé, point of maximal impulse displaced leftward and cephalad, and mild bilateral lower-extremity edema. Heart rate increases but is not generally above 100 beats/min. While the neck veins may appear full, jugular venous pulsation is not elevated. Electrocardiograms of pregnant women often will show left axis deviation, atrial enlargement and nonspecific ST-T wave changes, but such findings should be carefully interpreted within clinical context. The cardiac silhouette may be generous on chest radiograph. Increased cardiac output and volume of distribution in pregnant women necessitate careful attention to timing of intravenous contrast dye bolus for computed tomography pulmonary angiography, in order to avoid radiation exposure for an inconclusive study. Care should be taken to position pregnant woman in the left lateral decubitus (or at least with hip elevation to displace the pregnant uterus off the vena cava) when performing medical investigations or treating ill pregnant women to minimize such adverse hemodynamic effects.

RESPIRATORY

Pregnancy contributes to mechanical changes as well as progesterone-mediated physiologic adaptations in the respiratory system. In the upper airway, hyperemia, glandular hyperactivity, increased edema, and friability occur, related to elevated plasma volume and estrogen. Chest wall circumference increases by 5 to 7 cm due to elevated relaxin levels, and, eventually, the uterus elevates the diaphragm by about 4 cm though diaphragmatic excursion remains unchanged or even increased.

During pregnancy, oxygen consumption increases by 30% to 60% due to increased metabolic demands. Elevating progesterone levels increase respiratory drive early in pregnancy with continued effect throughout. Minute ventilation (tidal volume multiplied by breaths/min) increases by up to 50% through increased tidal volume; respiratory rate should remain unchanged. Vital capacity remains unchanged while functional residual capacity declines by up to 25%. Overall, pulmonary function testing interpretation remains unchanged, as forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity ratio, and peak expiratory flows remain stable.

Compensated respiratory alkalosis is expected on arterial blood gas testing, with PaO₂ elevated to 100 to 105 mm Hg, and PaCO₂ expected at 28 to 32 mm Hg. Clinically, pregnant women may complain of mild exertional dyspnea because of increased respiratory drive and physiologic anemia; however, this should not limit activities of daily living nor worsen with progressing pregnancy. Pertinent chest radiographic findings include generous cardiac silhouette, increased anteroposterior diameter, and prominent pulmonary vasculature.

RENAL/URINARY

Anatomic changes in the genitourinary system begin early in pregnancy, with kidneys increasing in size by about 1 cm in length and 30% in volume by midpregnancy, related to elevated blood volume and enlarging vasculature. The renal collecting system dilates due to progesterone- and prostaglandin-mediated smooth muscle relaxation initially and mechanical obstruction by the uterus later, so that mild to moderate hydronephrosis is expected on imaging. As a standard ultrasound parameter, ultrasound imaging should visualize ureteral jets in the absence of true obstruction. Ureteral peristalsis decreases, increasing the risk for ascending infection.

Early pregnancy vasodilatation due to surging progesterone and relaxin lead to increased glomerular filtration rate and renal plasma flow by 6 weeks. Glomerular filtration rate increases by 50%, and renal plasma flow increased by an even greater percentage. Medication metabolism is therefore accelerated, such that medications may require more frequent dosing (eg, twice daily rather than once daily) and higher doses (eg, when using antimicrobials with dosing ranges) for efficacy. Creatinine clearance rapidly increases by 25%, so that serum creatinine values average 0.5 mg/dL and blood urea nitrogen and uric acid levels decline. Bicarbonate excretion is accelerated, related to respiratory changes; pregnant women therefore have decreased buffering capacity and increased susceptibility to acidosis.

Altered glomerular membrane charge selectivity increases excretion of protein, albumin, and glucose. Up to 300 mg of protein on 24-hour urine collection is considered normal during pregnancy. Correlation between spot urine protein-to-creatinine ratios and 24-hour urine protein collection values has been variable, therefore only very low or very high urine protein-to-creatinine values are useful; and, although cumbersome, 24-hour urine protein collection remains the gold standard.

Progesterone markedly stimulates the renin-angiotensin system. Renin is produced by the placenta, thus there is an increase in maternal sodium absorption and potassium excretion. Between 6 and 8 L of water are retained to sustain normal pregnancy. Erythropoietin levels also increase, in order to meet red blood cell demands.

See Chapter 219 (Medication Management for a discussion of the implications of medication prescribing).

GASTROINTESTINAL

Progesterone mediates gastrointestinal (GI) smooth muscle relaxation, decreasing motility. As pregnancy progresses, the mechanical impact of the gravid uterus alters GI function. The majority of pregnant women experience nausea and vomiting early in pregnancy, attributed to high human chorionic gonadotropin (hCG) levels plus estrogen and progesterone. Constipation is common, related to decreased motility and delayed gastric emptying; absorption may be delayed. Not surprisingly, gastroesophageal reflux is reported by up to half of pregnant women and is related to progressive uterine enlargement, decreased lower esophageal sphincter tone and increased intra-abdominal pressure.

Hepatic physiology is generally stable during pregnancy. The high estrogen state of pregnancy may mimic liver disease findings, with palmar erythema and telangiectasias, in the absence of hepatic pathology. Alkaline phosphatase levels rise due to placental production. Dilution causes serum albumin and total protein levels to decline, which may impact pharmacokinetics of protein-bound medications. It is therefore preferable to obtain free drug levels rather than total levels when clinically indicated.

The gallbladder increases in size, although emptying capacity declines. Bile is more lithogenic during pregnancy and more saturated with cholesterol. Biliary sludge is common and may spontaneously resolve after delivery. Gallstones are more likely to be symptomatic than sludge and less likely to resolve spontaneously. Thus, there is an increased incidence of symptomatic gallstones both during pregnancy and postpartum.

HEMATOLOGIC

Marked adaptation allows increased blood flow to the uterus and developing placenta and preparation for delivery’s hemostatic challenge. Blood volume increases by 50% to 100% beginning by the 6th week of gestation. Plasma volume increases by 50% with an initial rapid rise, then gradual increase to peak at the 30th week. Erythrocyte mass rises less significantly, leading to the physiologic anemia of pregnancy, with typical Hgb levels of 10 to 12 g/dL by term. Neutrophilic leukocytosis may be seen, typically not beyond 16 × 10⁹/L. Platelet count typically remains stable in pregnancy. Isolated mild thrombocytopenia (115-150 × 10⁹/L) occurs in approximately 10% of pregnancies by term. Pregnant women are hypercoagulable due to increased estrogen effects on clotting factors as well as increased venous stasis. There is a marked increase in venous thromboembolic risk continuing through 6 to 8 weeks postpartum. Levels of the following may double by the third trimester: fibrinogen, factors V, VII, VIII, X, von Willebrand factor, and thrombin activation. D-dimer increases by the second trimester and remains elevated to the postpartum period. Protein S level and activity decline during pregnancy, as does sensitivity to activated protein C (APC). Protein C level and activity and antithrombin remain stable in normal pregnancy, but decreased antithrombin may be seen in association with pre-eclampsia and/or proteinuria.

ENDOCRINE

Pancreas

Early normal pregnancy is characterized by accelerated starvation, with mildly decreased fasting plasma glucose and increased ketogenesis, which leads to risk of starvation ketosis after prolonged fasting. By mid to late pregnancy, insulin resistance increases, heralded by large volumes of dilute urine and generally tolerated unless fluid is restricted via human placental lactogen (hPL), human placental growth hormone (hPGH), and likely tumor necrosis factor-alpha (TNF-α). This adaptation supplies the fetoplacental unit with 50 to 100 g of glucose daily by the third trimester. Insulin sensitivity returns to baseline within 48 hours of delivery. Thus, the insulin needs of type 1 and type 2 diabetics may decrease early in pregnancy (particularly if there is significant “morning sickness” causing nausea and vomiting), causing an increased risk of nocturnal hypoglycemia. Insulin doses generally need to be increased later in pregnancy in response to increasing insulin resistance. This physiology is also responsible for the development of gestational diabetes in some women. There is a higher incidence of fetal loss with diabetes, both due to an increase in congenital anomalies related to the teratogenic effect of glucose in patients with elevated hemoglobin A1C and to the renal and vascular complications of the disease itself. Management with a multidisciplinary team that includes specialists with expertise in diabetes in pregnancy is important.

Thyroid

Maternal thyroid hormone production increases by 50%. Hepatic production of thyroid hormone-binding globulin increases by two- to threefold, driven by elevated estrogen levels. Free levels of T4 and T3 remain stable but total levels rise. Maternal iodine requirements increase in order to fulfill T4 production, with increased renal iodine clearance. The fetal thyroid begins to function by 12 weeks and is fully functional by 18 weeks, so it is essential that maternal levels are sufficient for early development. Multidisciplinary collaboration enhances maternal and neonatal outcomes.

In the first trimester, b-hCG levels peak at 8 to 12 weeks and stimulate thyrocytes, which causes transient T4 production and thyroid-stimulating hormone (TSH) suppression. This may be exaggerated in molar pregnancy or hyperemesis gravidarum. If the mother is iodine replete, by the third trimester, there is a mild decrease in T4 and mild increase in TSH.

Parathyroid

Maternal mineral hemostasis is challenged by fetal skeletal formation then further challenged during lactation. Total serum calcium declines slightly due to decline in serum albumin; ionized calcium remains unchanged. Urinary calcium levels rise by 12-week gestation. Parathyroid hormone (PTH) is key to calcium homeostasis in the nonpregnant state, acting directly via renal and bone effects and indirectly via intestinal absorption. Levels of PTH decline during pregnancy, and it would be expected that 1,25 (OH)₂ vitamin D levels would drop as well, but 1,25 (OH)₂ vitamin D levels rise. It is likely that the placenta may contribute 1,25 (OH)₂ vitamin D. Prenatal vitamins provide adequate vitamin D supplementation.

Pituitary

The size of the pituitary increases by up to 70% by the third trimester largely due to hyperplasia of lactotrophic cells in the anterior lobe. Prolactin levels increase due to estrogen and progesterone stimulation of lactotrophic cells, and the placenta also produces prolactin by late pregnancy. Adrenocorticotropic hormone (ACTH) levels rise due to placental corticotropin-releasing hormone (CRH), which is not suppressed by dexamethasone. ACTH levels rise further during labor. Oxytocin levels rise throughout pregnancy, eventually facilitating parturition. Vasopressin levels decline due to placental production of vasopressinase, which may be a cause of transient diabetes insipidus (DI) during pregnancy.

LABOR AND DELIVERY-PERTINENT PHYSIOLOGY

A complex biochemical cascade, beyond the scope of this discussion, culminates in parturition. During labor, cardiac output further increases by one-third from the already augmented output of pregnancy, and systemic vascular resistance increases up to 25% with contractions. With each contraction, 300 to 500 mL of blood is “autotransfused” from the uteroplacental to the maternal circulation. Valsalva maneuvers while pushing increase myocardial oxygen consumption and may increase maternal blood pressure. These changes may be important in patients with underlying cardiac disease who are unable to tolerate increased volume and increased cardiac work.

Regional anesthesia for pain control during delivery, either spinal, epidural, or combined spinal-epidural, may lead to acute vasodilatation and resulting hypotension. Spinal anesthesia has been associated with greater hypotension than epidural anesthesia, however, it can be administered more rapidly if needed urgently. An epidural catheter offers the opportunity to provide continued pain relief after delivery with neuraxial opioids. Hypotension from neuraxial anesthesia may be reduced by preloading with crystalloid, or occasionally colloid, decreased dose, and slower administration.

CONCLUSION

This chapter reviews the physiologic changes that begin at conception and continue throughout pregnancy and the postpartum period, how such changes impact the manifestation and course of a disease process, and maternal vulnerabilities. An understanding of normal and abnormal pregnancy physiology is central to providing optimal care for this population of patients.

SUGGESTED READINGS

INTRODUCTION

Until the middle of the last century there was a widespread belief among both clinicians and patients that the human fetus grew in a protected environment that minimized any potential effects of substances ingested by the mother. This misperception ended dramatically when the effects of thalidomide became widely known in the late 1960s. Ever since this tragedy, a primary driver for both patients and providers of the approach the use of medications in pregnancy is fear of causing adverse fetal effects. Despite this, use of medications during pregnancy remains widespread throughout the world. Therefore, it seems that a dichotomy exists: a widely perceived fear regarding the ingestion of medication during pregnancy juxtaposed against the practical reality that medications are necessary and continue to be used during the course of gestation.

This chapter aims to provide a helpful evidence-based approach to guide hospitalists who may be asked to consult on or care for pregnant women. Table 219-1 lists some references that discuss the safety of particular agents in pregnancy. Table 219-2 makes some clinically based recommendations about which medications are preferred for specific indications during pregnancy. The remainder of this chapter will provide a general approach to prescribing in pregnancy that should guide the reader in the informed use of the information contained in both the listed references and the provided summary table.

KEY CONCEPTS FOR APPROPRIATE USE OF MEDICATIONS IN PREGNANCY

MOST MEDICATIONS “CROSS THE PLACENTA”

With few exceptions, no placental barrier exists for medications that can be administered orally. Drug levels in the fetus may be the same, lower, or higher than in the mother. In general, lipophilic drugs, drugs that are nonionized at physiologic pH, and drugs of low molecular weight cross the placenta more efficiently than other drugs, but the fetus will have exposure to almost any medication that can be administered orally to the mother.

MEDICATION USE DURING PREGNANCY CAN CAUSE A WIDE RANGE OF ADVERSE EFFECTS

Teratogenesis is more than just “missing parts.” Although the thalidomide tragedy drew attention to medication-associated malformations such as limb reduction defects, drugs may have other, perhaps more subtle, effects during pregnancy such as intrauterine growth restriction (eg, atenolol), intrauterine fetal demise (eg, possibly cyclophosphamide), long-term cognitive or behavioral toxicities (eg, valproic acid and mental retardation), and neonatal toxicities (eg, neonatal abstinence syndrome such as may be seen with narcotics and benzodiazepines).

THE LIST OF KNOWN HUMAN TERATOGENS IS SHORT

Despite all the potential effects of medication use during pregnancy, there are really only about 30 known human teratogens that could be prescribed by physicians. Many of these known teratogens are not commonly used in medical practice. The most commonly prescribed human teratogens are listed in the Practice Point on page 1833.

MEDICATION EFFECTS MAY VARY DEPENDING ON THE GESTATIONAL AGE AT WHICH THEY ARE ADMINISTERED

Human gestation can be divided into specific periods, and each of these periods may be associated with distinctive medication-use risks.

The first 14 days after conception (the 2-week period between conception and the first missed menstrual period) are often called the “all or nothing period.” During this time frame, drug effects are likely to be nil or result in miscarriage. At this point, the conceptus has not interfaced significantly with maternal circulation and drug exposures are likely to be only at a very low level. At this same time, all cells in the conceptus are nonspecialized (pluripotential) and are generally believed either to experience lethal effects of drugs (resulting in pregnancy loss) or no effect at all.

Between days 14 and 60 after conception (the embryonic period—a 7-week time frame following the first missed menstrual period) organogenesis is occurring, and drug exposure during these weeks can lead to major or minor malformations. This high-risk period accounts for only 5% of the 280-day human gestation. In fact, most human teratogens probably have even shorter specific periods when the developing embryo is specifically susceptible to their toxicities. For example, thalidomide effects were seen only if the drug was taken between days 21 and 36. Valproic acid, which can cause neural tube defects, will not do so if taken after day 27 because the neural tube has completely closed by this date.

An important consequence of unique vulnerabilities of the embryonic period is that some significant toxicities may have already occurred before a woman or her provider is aware of her pregnancy. Therefore, the onus is on all providers prescribing medication to women of reproductive age to speak to these patients about the potential effects of their medications during pregnancy and the potential for harm even before the pregnancy is clinically apparent.

During the period between days 60 and 280 of gestation, progressive fetal growth and neurologic development is occurring. Toxicities during this period may cause impaired growth (eg, atenolol), neurologic or behavioral abnormalities (eg, valproic acid and mental retardation), or specific organ toxicities (eg, angiotensin converting enzyme [ACE] inhibitors and renal dysfunction). There is, therefore, no period in a pregnancy during which a medication can be considered completely safe. Rather, each distinct period in gestation represents unique potential vulnerabilities.

MEDICATION PREGNANCY SAFETY DATA: SOURCES AND THEIR LIMITATIONS

Much of the data that exist about the effects and safety of drug use in pregnancy are on the basis of animal studies. Before drugs are released on the market in the United States and Canada, animal testing looking for drug-related malformations needs to have occurred. Human data, however, are not required. This is because new drug testing on pregnant women is felt to be unethical and (aside from the important exception of thalidomide) most human teratogens have been found to be teratogenic in laboratory animals as well. However, two major problems with the use of animal data exist. First, animal data cannot always be confidently extrapolated to humans. There is considerable variability between species and even between strains of a species regarding the effects of the medication on a developing fetus. Second, behavioral and intellectual effects of medications are very difficult to recognize in animals. Much of human gestation is a time of progressive neurologic development. Medications that do not cause gross malformations may still have effects on developmental milestones, intelligence, and behavioral health that will not be readily discernable in animal models.

In general, the best use of animal data is when it is paired with human data and the findings suggest a common and biologically plausible association. However, most of the human data we presently have have their own challenges. One of the most significant problems with human data is that there is a large background risk of congenital abnormalities making it difficult to differentiate abnormalities that are caused by medications from those due to other causes. Between 2% and 4% of infants are born with some defect, and of these 20% are due to chromosomal abnormalities. Five percent are due to gene mutations and 65% of these defects remain unexplained. Likely, no more than 10% of identified human malformations are due to teratogenic agents. Because most human teratogens have their effect in only 0.1% to 30% of exposed fetuses, large numbers of exposures need to be studied to clearly identify an increase against the background risk of anomalies. The best evidence for teratogenic effects would be from prospective studies in humans, but these are done infrequently because they are difficult, lengthy, and expensive. Most studies determining effects of drugs in pregnancy are either case-control or cohort studies. In case-control studies, infants with anomalies are paired with infants without a particular anomaly. The number of infants exposed to the studied agent in each group is then compared. In cohort studies, the incidence of a particular anomaly among infants exposed to a particular agent is compared with the incidence of that anomaly among infants not exposed to that agent. In a case-control study, 220 cases and 220 controls must be studied to find a relative risk of 2.5 with a power of 80%.

The problems with such retrospective data are many. Most importantly, associations attributed to medication effects may simply reflect the reason the mother was on the medication rather than the medication itself. One must be cautious about ascribing anomalies to medication effects when in fact the anomaly may be caused by the underlying maternal condition that is being treated, or consider that an untreated maternal condition may also result in an anomaly.

Human case reports and registries are another flawed source of human data. There is substantial recall bias among women with a difficult pregnancy outcome. Women who bear children with an anomaly are much more likely to recall medication use in pregnancy and so are their providers. An illustration of this is the fact that the incidence of teratogenesis of isotretinoin was felt to be 80% with voluntary reporting to a registry at the pharmaceutical company but has been subsequently found to be only 36% in prospective studies.

Another difficulty with human data is that there is a difference in the response of individual human fetuses to different medications much in the same way as there is in adults. A classic example of such a phenomenon is seen with phenytoin. Many teratologists believe that phenytoin can cause something known as fetal hydantoin syndrome in 10% of infants exposed in utero. Fetal hydantoin syndrome (FHS) is a combination of features of intrauterine growth restriction, mild mental deficiency, a large anterior fontanel, a metopic ridge, ocular hypertelorism, depressed nasal bridge, short antevertal rise, bowed upper lip, cleft lip and palate, and nail and distal phalangeal hypoplasia. The risk of this syndrome increases dramatically in subsequent pregnancies if the mother has previously borne a child with FHS. One theory for this phenomenon is that the teratogenic risk of phenytoin varies with the activity of the enzyme epoxide hydrolase in mother and fetus. Decreased activity of this enzyme in patients taking phenytoin may lead to increased levels or toxic arene oxide intermediates, which some investigators suspect may be the direct teratogen in some cases of FHS.

Another problem with human data is that most cautionary information about medication use in pregnancy is related to anatomic defects identified in newborns on the initial exam at birth. Rarely are there studies that examine behavioral, functional, developmental, and/or delayed effects. The logistics and expense of carrying out such studies are daunting. This is especially true if one considers the potential for medications to affect the offspring of offspring through toxicities of a medication on the gametes in utero. Such effects are very unlikely to ever be uncovered.

An illustration of the complexity of drug pregnancy safety data is found in the history of the ACE inhibitors. Captopril was the first ACE inhibitor marketed in the United States and was initially released to market as an FDA category C drug on the basis of animal studies suggesting it is unlikely to be a teratogen. (See the discussion of the FDA pregnancy drug classification later in this chapter.) Postmarketing surveillance of this drug revealed an association with ogliohydramnios, fetal calvarial hypoplasia, fetal pulmonary hypoplasia, intrauterine growth restriction, intrauterine fetal death, and neonatal anuria. Most teratologists believed that the effect of ACE inhibitors was not a direct effect on organogenesis but rather a fetal toxicity. They hypothesized that high levels of angiotensin are probably physiologically necessary to maintain glomerular filtration at the low perfusion pressure seen inside the fetus. Therefore, use of ACE inhibitors in pregnancy is associated with poor perfusion of the kidneys, followed by renal failure and atrophy of the kidneys. Poor urine output contributes to the oligohydramnios, fetal calvarial hypoplasia, and fetal pulmonary hypoplasia seen in infants exposed to the drug. Since this association was made, ACE inhibitors were classified as class C drugs for the first trimester but as class D drugs for second and third trimesters. Subsequent population-based studies of ACE inhibitors, however, have suggested that there may also be a first trimester effect on organogenesis in addition to the later effects on fetal renal function and have led to recommendations to avoid the use of these agents completely during pregnancy, although the FDA has not yet changed the pregnancy safety classification for these agents.

Another example of the complexity of drug safety data in pregnancy is metronidazole. Metronidazole was long considered a human teratogen because it was found to be mutagenic in bacteria, carcinogenic in mice, and associated with congenital anomalies in several case reports in the medical literature. Therefore, this important agent for the treatment of bacterial vaginosis was often not used or used only with hesitation by obstetricians. However, this changed when a series of publications demonstrated no increased human risk associated with the use of metronidazole during pregnancy. Therefore, a drug that was withheld from pregnant women is now widely used during gestation with no evidence of untoward effects.

How then should the clinician sensibly approach this flawed and limited data? Neither the clinician nor the patient should believe that any drug can be called completely safe in pregnancy any more than we would believe that any drug can be called completely safe outside of pregnancy. At the same time, the provider and the patient should not feel that any drug is absolutely contraindicated in pregnancy. A more evidence-based approach is to consider whether benefits of a particular agent warrant any known or theoretical risks. Likewise, it is worth discarding the concept that there are any “safe” periods for medication use in pregnancy; again, a more evidence-based approach is to talk of “more vulnerable” and “less vulnerable” times during the pregnancy.

How then should the clinician approach the problem of deciding what drugs should or can be used during pregnancy? A useful approach is to address this question in four separate parts, listed in the Practice Point and discussed in the proceeding section.

QUESTION 1: IS THE SYMPTOM TO BE TREATED SELF LIMITED AND/OR AMENABLE TO NONPHARMACOLOGIC MANAGEMENT?

It is important when approaching medication use in pregnancy to have the patient (and the provider) understand that pregnancy is a time when unnecessary or unhelpful medications that do not significantly affect the course of an illness should be avoided. As well, the option of nonpharmacologic management should always be considered in pregnancy. Treatment such as biofeedback or relaxation techniques for tension headaches might be preferable to analgesics in some cases.

QUESTION 2: IF THE MEDICATION IS NOT ADMINISTERED, WHAT ARE THE POSSIBLE OUTCOMES FOR THE MOTHER AND THE FETUS?

Many providers incorrectly entertain the idea of there being a central conflict regarding medication use in pregnancy in which the fetal and maternal needs are at odds. This is rarely the case. Fetal well-being is dependent on maternal well-being, and, therefore, treatment of maternal disease to maintain maternal health is generally very much in the interest of the fetus. For this reason, when deciding whether use of a particular medication is justifiable in pregnancy, it is important to consider the possible outcomes for the mother and fetus of not instituting (or continuing) pharmacologic treatment. It is often the case that withholding treatment will place the fetus and mother at greater risk than any potential effects of the medication, such as with antiepileptic drugs.

QUESTION 3: WHAT DATA IS AVAILABLE ON THE SAFETY OF THIS MEDICATION IN PREGNANCY, AND IS THERE A SIMILAR DRUG WITH BETTER SAFETY DATA AVAILABLE THAT MIGHT BE USED INSTEAD?

This is the question that many clinicians find the most challenging. Table 219-1 lists several of the most helpful references available to assist in the answering of this question. Table 219-2 also offers a symptom- and disease-based list summarizing which agents are generally justifiable, sometimes justifiable, and almost never justifiable for a particular indication during pregnancy.

Perhaps somewhat unfortunately, the most commonly used resource in the United States with which question 3 is answered is the US Food and Drug Administration’s (FDA’s) pregnancy categories. These classification categories are found in most prescription medication package inserts and in the Physician’s Desk Reference (PDR). The categories are summarized in the Practice Point and listed as subscripts following each agent in Table 219-2. The intent of the FDA classification was to help the clinician briefly summarize available data about the potential toxicities of an agent in pregnancy. Clinicians tend to use the letter categories as an order of safety, although a drug may be in category B when there are no human data available. Problems result from the fact that the complexity of the data is not fully considered and that the classification of agents rarely changes even after decades of accumulated data.

Even within medications from both the same drug class and pregnancy safety category, it is worth being cautious about the use of the newest agents during pregnancy unless there have been significant human pregnancy data. Many fetal toxicities such as the first trimester effects of ACE inhibitors have been identified in the years following release onto the market. Therefore, even an older drug with a less favorable pregnancy safety category may at times be preferable to a newer agent with an apparently more favorable pregnancy classification. An example of this would be the use of amitripytline (an FDA pregnancy category D drug) to initially treat depression rather than newer agents such as venlafaxine (an FDA category C drug) given the lack of published human data about the use of venlafaxine in pregnancy.

QUESTION 4: HOW DOES THE PATIENT’S AND THE PROVIDER’S UNDERSTANDING AND BELIEF SYSTEM AFFECT DECISIONS ABOUT THE USE OF MEDICATION IN PREGNANCY?

Studies suggest that women believe that medications ingested in pregnancy end in significant malformations in a significant number of cases. Misinformation can come from media, friends, family, and even nurses, pharmacists, and physicians. Therefore, it is important for the provider to know what the patient’s understanding of the potential toxicities are and work with her to clarify and address her concerns. The physician should determine how the patient understands her illness, what the patient’s specific fears are, and what the patient can tolerate in terms of outcome. Often irrational fears can be allayed by exploring these questions. A woman at 20 weeks may want to avoid taking medication for fear that her baby will be born with a missing arm or leg, an outcome that the provider can reassure her could hardly be attributed to any drug taken that late in gestation. These same questions should also be asked of the providers. The provider’s understanding of the patient’s illness, his or her own sense of the patient’s capability of tolerating the symptoms, and what outcomes he or she fears may significantly effect willingness to prescribe medication in pregnancy. Providers need to be cognizant of these issues to avoid being too paternalistic or having their own fears or prejudices guide decision making that should be based on evidence and the patient’s preference rather than the physician’s anxieties. In the end, providers should work with our patients to make a judgment based on the available data, the indication of a particular agent and an awareness of the patient’s belief system to determine whether the available information justifies or warrants the risk inherent in the use of all medication in pregnancy.

Once the best medication choice has been made in conjunction with the patient, the provider should consider pregnancy-related changes in pharmacokinetics that can affect drug dosing and response during pregnancy. A 30% to 50% increase in gastric emptying time during pregnancy may delay absorption of oral agents. An increase in gastric pH related to a 40% decrease in gastric acid secretion that occurs in pregnancy may also affect medication absorption. Renal clearance of medication is increased in pregnancy because glomerular filtration rates increase to 150% of nonpregnant values. Therefore, medications that are cleared renally, such as penicillin, digoxin, and lithium, may require shortened dosing intervals or significant dosage changes in pregnancy. Hepatic clearance of pharmacologic agents may be altered in pregnancy. Progesterone increases hepatic metabolism of some drugs such as phenytoin (Dilantin) but may also decrease metabolism of agents such as theophylline and caffeine through competitive inhibition of microsomal oxidases. The cholestatic effect of estrogen during pregnancy may affect clearance of drugs such as rifampin that are excreted in the biliary system.

The commonly used agent labetalol has an elimination half-life (t1/2) of 102 minutes in patients with pregnancy-induced hypertension as opposed to its t1/2 of 160 to 480 minutes in nonpregnant controls. The nifedipine elimination half-life is 1.35 hours in pregnancy versus 3.4 hours in controls.

Substantial changes in the volume of distribution also occur in pregnancy. Plasma volume increases to 150% of prepregnancy values by 24 to 28 weeks’ gestation so that the volume of distribution for medication is increased and drugs may require dosage increases. At the same time the physiologic dilutional hypoalbuminemia that occurs in pregnancy combined with the displacement of bound drugs by the hormones of pregnancy may lead to an increase in free drug level for a particular serum level.

The main practical applications of the above physiologic and pharmacokinetic changes are as follows:

1. Serious consideration should be made to monitoring of medication levels and adjustment of medication dose during pregnancy.

2. Free drug levels in general are better guides than total serum levels in pregnancy because of altered protein binding.

3. Dosing intervals may need to be shortened in pregnancy.

4. Inadequate dosing frequency always needs to be considered as a possible cause for failure of medications during pregnancy.

The last and perhaps most important issue to be aware of when prescribing in pregnancy is that medication compliance is a significant challenge. Drug labeling warnings, pharmacists, and an unrealistically high perception of teratogenic risks all contribute to this phenomenon. One small study from Wales found that 15% of women with epilepsy who claimed to be taking antiepileptic drugs in pregnancy showed no evidence of having done so on testing of their hair. One of the patients with an absent drug level died suddenly at 30 weeks’ gestation. Providers need to work with their patients to increase understanding about the important interdependence of maternal and fetal health and the justifiable and “healthful” use of indicated medications during pregnancy.

CONCLUSION

All providers prescribing medication to women of reproductive age should speak to these patients about the potential effects of their medications during pregnancy and the potential for harm even before the pregnancy is clinically apparent. The acute hospitalization presents an opportunity to evaluate all medications, adjust dosages, and educate patients and families about their indication and safety profile.

SUGGESTED READINGS

INTRODUCTION

The majority of critical care admissions for pregnant and peripartum women are for obstetric disorders, primarily hypertensive complications (particularly hemorrhagic stroke) or hemorrhage. Medical indications, such as sepsis, respiratory failure, cardiomyopathy, or ischemic stroke are less common. Maternal mortality in developed nations remains rare (650 in the United States annually); however, the proportion attributable to medical disorders has been increasing as women with underlying medical conditions and older women conceive, perhaps with assisted reproductive technology. Standard scoring systems, such as APACHE scores, overestimate mortality in pregnant and peripartum women, particularly if they have an obstetric indication for critical care. Delivery or surgery may contribute to rapid improvement. A small proportion of obstetric patients, approximately 12 per 1000, require critical care. ­Hospitalists and intensivists may have limited experience managing these patients.

PHYSIOLOGIC ADAPTATIONS

Virtually every organ system adapts to accommodate pregnancy and delivery. Hemodynamic alterations prepare for blood loss of one-half to 1 L at delivery. Blood volume increases by 50% (Table 220-1).

Cardiac output increases by 30% to 50% and total peripheral resistance decreases by 20%, leading to blood pressure declining by 10 to 15 mm Hg in the first half of pregnancy, then returning to baseline in the second half. Diastolic blood pressure decreases more than systolic; pulse pressure is widened. Central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) remain unchanged. Blood flow distribution is altered such that up to 25% of maternal cardiac output is directed to the uterus, 20% to kidneys, with an increase in breast flow. When supine, women in the second half of pregnancy experience aortocaval compression (termed supine hypotensive syndrome), in which cardiac output may drop by 30%. Left lateral decubitus positioning relieves aortocaval compression and improves venous return and cardiac output.

Maternal respiratory adaptations help optimize fetal oxygenation. Initial changes are progesterone mediated with diaphragmatic elevation contributing to changes later in pregnancy. Minute ventilation increases 30% to 60% by increased tidal volume; respiratory rate remains unchanged. Tachypnea is abnormal and warrants investigation! Diaphragmatic elevation leads to a 20% reduction in functional residual capacity by late pregnancy. Given that diaphragmatic excursion is usually unchanged in pregnancy, this drop in functional residual capacity is counterbalanced by an increase in inspiratory capacity and the resultant effect is no significant change in total lung capacity. On the other hand, oxygen consumption is significantly increased during pregnancy and rises further during labor and delivery. For those reasons, oxygen reserve is reduced in pregnancy. Arterial blood gas testing reveals a compensated respiratory alkalosis due to the above described changes and enhanced renal bicarbonate excretion. PaO₂ is typically 100 to 105 mm Hg during pregnancy and PaCO₂ decreases to 28 to 32 mm Hg. Maternal pulse oximetry greater than 95% is desirable in order to maintain a PaO₂ greater than 70 mm Hg and optimize placental oxygen diffusion.

Hematologic changes also occur in pregnancy with a progressive activation of the hemostatic system to prepare the parturient for the hemostatic challenge of delivery. The anticoagulant activity of protein S is reduced and activated protein C resistance rises. Procoagulant activity is increased, with higher concentrations of fibrinogen and factors V, VIII, IX, and X, leading to enhanced thrombin production. On the other hand, fibrinolysis is decreased as a result of increased activity of plasminogen activator inhibitor type 1 and type 2 and decreased activity of tissue plasminogen. Shortcomings of these changes are an increase in the risk of venous thromboembolism (VTE) antepartum until 6 weeks, postpartum.

INDICATIONS FOR CRITICAL CARE DURING PREGNANCY/PERIPARTUM

Obstetric indications include preeclampsia and related complications: eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets), hypertensive crisis, pulmonary edema, oliguric renal failure, and cerebral hemorrhage. All of these complications would meet criteria for severe preeclampsia and would warrant urgent delivery. Specific indications for when a patient needs to be transferred to an intensive care unit have been described in a practice bulletin published by the American College of Obstetricians and Gynecologists. Close collaboration with obstetrics is essential for optimal maternal (and fetal/neonatal) outcome. Although often maternal manifestations of preeclampsia are quickly reversible with delivery and judicious fluid and blood pressure management, they may persist or even worsen in the postpartum period, requiring ongoing vigilance. While still pregnant, blood pressure goals must minimize maternal hypertensive complications, which are more likely above 160 mm Hg systolic and 110 mm Hg diastolic, while maintaining sufficient uteroplacental flow. Blood pressure reduction should be attempted promptly with caution in pregnant women given the potential for impaired uteroplacental flow and fetal compromise. Options include intravenous labetalol or hydralazine, noting that hydralazine has been associated with greater hypotension in this setting. Short-acting oral nifedipine may be useful if intravenous access is delayed but may also precipitously lower the blood pressure. Magnesium sulfate infusion is superior to phenytoin and benzodiazepines for preventing seizures in preeclampsia and reducing recurrence of eclamptic seizures. Given that most seizures are self-limited, there are limited studies comparing different drugs; however, benzodiazepines may be helpful for acute seizure treatment, noting risk of neonatal respiratory depression.

Additional obstetric conditions warranting critical care include acute fatty liver of pregnancy, peripartum cardiomyopathy, amniotic fluid embolism, and placental abruption and hemorrhage. Acute fatty liver of pregnancy (AFLP) is rare, estimated to occur in 1 in 13,000 deliveries, but carries a high mortality. Manifestations may include fulminant hepatic failure with hypoglycemia, coagulopathy, and renal failure; about half of cases are associated with preeclampsia. It may initially be difficult to differentiate AFLP from HELLP syndrome (defined as transaminases greater than twice the upper limit of normal and platelet count <100,000 per mm³), but AFLP should be suspected in patients with otherwise unexplained hypoglycemia and severe hepatic dysfunction. Liver transplantation may be necessary. Recurrence rates are significant in subsequent pregnancies.

Peripartum cardiomyopathy is defined as dilated cardiomyopathy with no other known cause, with onset in the last month of pregnancy or within 5 months postpartum. Rates vary markedly across the world, with highest rates reported in Africa. The etiology has not fully been defined. Risk factors include advanced maternal age, multiple gestations, preeclampsia, and African descent. Treatment includes standard congestive heart failure management, including vasodilators, diuretics, and sodium restriction. Prior to delivery, hydralazine and nitrates should be used rather than angiotensin converting enzyme inhibitors, which have adverse fetal renal effects at all stages of gestation. After delivery, enalapril and captopril are considered compatible with breastfeeding. Anticoagulation should be initiated if ejection fraction is less than 35%, mural thrombus is present on imaging, or atrial fibrillation is observed, as thrombosis is a major cause of mortality in these patients. Up to half of women recover ventricular function to baseline levels within 6 months, with variable persistent dysfunction ranging from mild to fatal in the other half. Recurrence rates are high, and women warrant careful counseling and surveillance regarding future pregnancies.

Amniotic fluid embolism (AFE) remains exceptionally rare, described as occurring in between 1 to 8000 and 1 to 80,000 deliveries, with high maternal morbidity and mortality. Reported risk factors include prolonged labor, multiparity, increased maternal age, and oxytocin administration. The pathophysiology remains in question. Some propose terming AFE “the anaphylactoid syndrome of pregnancy,” with maternal response to miniscule amounts of amniotic fluid’s vasoactive and procoagulant factors. This theory remains debatable as amniotic fluid has been found in the maternal circulation in patients without signs or symptoms of AFE. Sudden decline in maternal and/or fetal status intrapartum or maternal status postpartum is the most common presentation, with hypotension, respiratory symptoms, coagulopathy, and cardiac arrest occurring in the majority. Early recognition of the syndrome and initiation of supportive measures, including aggressive blood products, are essential. If onset is antepartum, rapid delivery improves perinatal and maternal outcome. Novel interventions such as the use of recombinant factor VII administration, cardiopulmonary bypass, ventricular assist devices, and ECMO have been reported.

Medical conditions requiring critical care for pregnant and peripartum women include sepsis, pneumonia, acute respiratory distress syndrome (ARDS), venous thromboembolism, status asthmaticus/asthma exacerbations, sepsis, pneumonia, and myocardial infarction. Pyelonephritis is of particular concern during pregnancy, with maternal complications including ARDS and sepsis due to reduced buffering capacity and decreased oncotic pressure. ­Pregnant women with pyelonephritis warrant inpatient management given potential maternal complications plus risk of preterm labor and premature delivery. Careful fluid administration and ongoing monitoring are essential for these women to ensure they are adequately fluid resuscitated but do not progress to fluid overload. Extensive discussion of medical conditions is outside the scope of this chapter and is reviewed in more detail in the chapter on medical disorders in pregnancy.

Trauma also leads to critical care admissions for pregnant and peripartum women, with the majority of cases due to motor vehicle accidents (MVAs). Falls, particularly in the third trimester, and domestic violence are the next leading causes in this population. Improper seat belt positioning contributes to maternal and fetal injury in MVAs; the lap belt should be placed below the gravid uterus and shoulder belt between the breasts. Obstetric complications of traumatic injuries include placental abruption, uterine rupture, and preterm delivery. The gravid uterus upwardly displaces abdominal organs so that bowel may be involved in upper abdominal trauma. Fetal instability often precedes maternal instability. Uteroplacental flow will be compromised to maintain maternal blood pressure. Multidisciplinary care for pregnant trauma patients that includes fetal monitoring will lead to optimal outcome for both mother and fetus.

AIRWAY

In addition to the usual causes of respiratory failure in the nonpregnant population, there are a number of pregnancy-specific conditions that might lead to acute respiratory failure. These causes include preeclampsia, amniotic fluid embolism, peripartum cardiomyopathy, and hemodynamic instability related to massive obstetric hemorrhage. Ovarian hyperstimulation related to hormonal manipulation surrounding assisted reproduction may also be associated with ARDS. Although indications are quite similar, the threshold for intubation might be different in the pregnant population since PaCO₂ is normally decreased and PaO₂ increased in pregnancy and a PaCO₂ of 38 and a PaO₂ of 70 are indications of acute respiratory failure. Arterial oxygen saturation ≥95% is desirable for fetal and maternal well being.

Noninvasive ventilation (NIV)

Case series are accumulating regarding use of NIV for acute respiratory failure in the obstetric population. Successful use of NIV has been described in pregnancy in chronic, stable settings such as in obstructive sleep apnea or chronic respiratory failure from neuromuscular disease. The use of NIV may be suboptimal in acute settings given airway edema and the increased risk of aspiration in pregnancy. However, in patients with a preserved mental status and no other contraindications who may not require assisted ventilation for prolonged periods of time, short trials of NIV may be attempted prior to endotracheal intubation.

Endotracheal intubation

Anesthesia-related mortality ranks seventh in maternal mortality in the United States. This is in part due to the fact that failure rate for endotracheal intubations in pregnant patients is 1 in 250 compared to 1 in 2330 in the general surgical population. Failure to intubate may be associated with a higher risk for cardiac arrest and aspiration.

A number of factors complicate endotracheal intubation in pregnancy. Reduced airway patency is one of the factors. Higher blood volume and estrogen levels in pregnancy cause capillary engorgement and mucosal edema leading to difficult visualization of the landmarks of the upper airway. Mallampati scores, a measure of upper airway patency, increase progressively in pregnancy and upper airway size as measured by acoustic reflectance method is reduced in the supine position. Airway edema may be further exaggerated in patients with a prolonged second stage of labor, excessive intravenous fluids, and preeclampsia. Preeclampsia is associated with lower oncotic pressures with possible coagulopathy worsening airway edema. Weight gain and the increase in breast size can lead to difficulty in manipulating the upper airway and reduced chest compliance. Obesity is also one of the major risk factors for maternal mortality in a review of anesthesia-related maternal mortality.

Pregnant women are also at a higher risk for aspiration related to a progesterone mediated relaxation of the lower esophageal sphincter, an increase in intra-abdominal pressure (due to the enlarging uterus), and delayed gastric emptying. The use of aspiration precautions is advisable.

An important consideration during sedation and paralysis of a pregnant woman is the reduced oxygen reserve given the 20% reduction in functional residual capacity (which is likely more pronounced in the supine position) and the increase in oxygen consumption. Sedation and paralysis eliminate the rise in minute ventilation that usually occurs to compensate for these changes/demands and rapid desaturation and hypoventilation occur.

Therefore, preoxygenation with 100% oxygen should be done before and between intubation attempts during pregnancy and lower doses of sedatives may be needed. This should be done with caution as prolonged manual ventilation may distend the stomach increasing the risk of aspiration even further. Manual left uterine displacement also helps improve venous return in patients with a tenuous hemodynamic status, since cardiac output may be reduced by 25% to 30% in the supine position in the late stages of pregnancy.

An additional complicating factor is the urgent nature of airway intubation in the obstetric population.

Because of the increased risk of morbidity and mortality associated with airway intubation in pregnancy, airway intubation should be performed by providers with the most extensive experience. Airway assessment according to the American Society of Anesthesiology practice guidelines is critical in pregnancy, even in cases of urgent intubation. The management of the difficult airway should follow the American Society of Anesthesiology practice guidelines. In this algorithm, the laryngeal mask airway (LMA) is recognized as the tool of choice for “cannot ventilate, cannot intubate” (CVCI) patients. Video laryngoscopy has been successful in failed direct laryngoscopy in obstetric patients.

A chest radiograph to ensure proper placement of the endotracheal tube carries only a negligible risk of fetal radiation exposure and should be done as in the nonpregnant patient.

HEMODYNAMIC MONITORING

Profound hemodynamic changes occur in pregnancy to prepare for the needs of the growing feto-maternal unit and to compensate for the expected losses during pregnancy. These changes are summarized in Table 220-1. Indications for hemodynamic monitoring specific for obstetric patients include severe preeclampsia with either refractory hypertension, oliguric renal failure, or unclear intravascular volume status. Hemodynamic monitoring may also be needed in obstetric patients with severe structural heart disease in the peripartum period, or cardiovascular collapse such as in the setting of an acute amniotic fluid embolism.

Monitoring may be done either invasively or noninvasively. ­Echocardiography has been shown to correlate with invasive monitoring in the measurement of cardiac output, ventricular filling pressures, stroke volume, and pulmonary artery pressures.

Echocardiography interpretation should be performed with caution in pregnancy given that physiologic chamber dilatation and the increase in flow may overestimate pulmonary artery pressures. Patients with refractory hypertension and oliguria were successfully managed in a small series with echocardiography suggesting that this test may be an effective alternative to pulmonary artery catheterization during pregnancy in specific circumstances.

Invasive monitoring may be needed in cases of severe stenotic valvular disease, severe cardiomyopathy, sudden cardiovascular collapse, ARDS/indeterminate fluid status, refractory oliguria, and unclear volume status despite fluid resuscitation and refractory septic shock. Invasive monitoring may occasionally be indicated for labor and delivery in high-risk patients. Invasive monitoring has somewhat fallen out of favor with recent trials not showing any clear benefit compared to central venous catheters. There are no randomized controlled trials evaluating the clinical usefulness of pulmonary artery catheters in pregnancy in general. Available data suggest that although there is a modest correlation between central venous pressures (measured with a central venous catheter) and a pulmonary capillary wedge pressure in the management of patients with untreated preeclampsia, this correlation may lessen after initial interventions.

VASOPRESSORS

Acute hypotension requiring vasopressor support in the pregnant woman most commonly results from vasodilatation in the setting of neuraxial anesthesia. Additional vasodilatation on top of the physiologic vasodilatation of pregnancy is poorly tolerated. ­Hemodynamic compromise may also be precipitated by hypovolemia, sepsis, anaphylaxis, and cardiogenic shock. A pregnant woman has an additional end organ, the fetus, with uteroplacental flow receiving 20% to 30% of maternal cardiac output. Maternal hypotension risks fetal and neonatal acidosis. It is critical to restore intravascular volume first, as uteroplacental flow is compromised further by vasoconstriction in addition to hypovolemia.

Limited data are available comparing vasopressors during pregnancy, so physician familiarity and drug availability have roles in vasopressor choice. All vasopressors have potential to impair uteroplacental flow. There is minimal information regarding developmental toxicity. Currently, phenylephrine and ephedrine are the most commonly used vasopressors in this population. Phenylephrine is a short-acting alpha agonist with potent vasoconstricting effect that may be easily titrated. It does not act on beta receptors thus does not lead to maternal tachycardia; however, reflex bradycardia due to increased venous return may occur, requiring atropine administration. Ephedrine has been used extensively by obstetric anesthesiologists. It is a direct alpha and beta agonist and also indirectly releases norepinephrine. Maternal cardiac output increases by increased heart rate and contractility. Alpha effect causes peripheral vasoconstriction and increased blood pressure. Titration is difficult due to its slow onset and tachyphylaxis develops after repeated doses.

Reports comparing ephedrine to phenylephrine infusion at cesarean delivery show that ephedrine is associated with more maternal nausea and vomiting, higher heart rate, and a higher incidence of fetal acidosis but comparable effects on blood pressure. A meta-analysis comparing the two drugs reported similar findings including a higher fetal pH associated with phenylephrine. In summary, if hypotension persists after an adequate intravascular volume has been restored, phenylephrine is the drug of choice in pregnant patients with circulatory collapse, unless a clear benefit in restoring hemodynamics is expected from another drug.

CARDIAC ARREST AND RESUSCITATION

The incidence of cardiac arrest in pregnancy has been estimated at 1 in 30,000, causing about 10% of maternal deaths. It remains a rare and potentially catastrophic event for mother and fetus. Outcomes for both depend on the underlying cause of arrest and rapidity of resuscitation. The mnemonic BEAU-CHOPS allows rapid assessment of potential causes for arrest in the parturient: Bleeding/disseminated intravascular coagulation (DIC), embolism: coronary/ pulmonary/­amniotic fluid, anesthetic complications, uterine atony, cardiac disease (myocardial infarction (MI)/ischemia, aortic dissection, cardiomyopathy), hypertension (preeclampsia/eclampsia), other (differential diagnosis per standard ACLS guidelines), placenta: abruptio/ previa, sepsis.

Prompt initiation of cardiopulmonary resuscitation protocols is essential, with attention to a few additional details. Maternal and neonatal resuscitation teams must be activated urgently. Pregnant women are at increased risk of aspiration during resuscitation and desaturate rapidly, therefore immediate intubation with 100% oxygen administration and cricoid pressure is advised in this population. Manual left uterine displacement relieves aortocaval pressure. Hand position for compressions is advised a few centimeters higher on the sternum due to breast engorgement and diaphragmatic elevation but no studies are available to demonstrate that higher compressions result in better cardiac output. Defibrillation energy and locations are unchanged. Any fetal monitoring devices must be removed prior to defibrillation to avoid the possibility of arcing.

Drug administration generally proceeds as usual, with note of potential issues with amiodarone and vasopressin. Alternatives to amiodarone, such as lidocaine and procainamide, would be preferable given concern for its fetal thyroid impact; however, if resuscitation team members are most familiar with amiodarone and it is most quickly available, antiarrhythmic administration should not be delayed as the risk of untreated ventricular arrythmias by far outweighs the risk of fetal thyroid dysfunction. The placenta produces vasopressinase, which could degrade vasopressin, thus epinephrine is preferable.

If the fetus is viable (24 weeks or greater), it is strongly recommended to perform cesarean delivery by 5 minutes into resuscitation to improve maternal and fetal outcomes. In 1986, Katz, et al, recommended perimortem cesarean delivery and in 2005 published data revealing intact neurologic outcome in neonates delivered within 5 minutes of arrest. Maternal chest compressions should continue throughout delivery efforts. Immediately after uterine evacuation, maternal cardiac output increases due to autotransfusion from uterine circulation and relief of aortocaval compression; chest compressions are more effective after delivery as well. Data are lacking regarding therapeutic hypothermia for maternal benefit. Regular maternal cardiac arrest drills are recommended to ensure all pertinent disciplines are prepared for this uncommon event.

CONCLUSION

As women with underlying medical conditions and older women conceive, the proportion of critically ill, pregnant women with medical disorders may increase. This chapter briefly reviews common obstetric disorders that may require critical care and aspects of resuscitation that are unique to pregnancy.

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INTRODUCTION

Although women of childbearing age represent a younger and generally healthy population, currently 40% of women entering pregnancy have chronic medical conditions such as obesity and type 2 diabetes mellitus. Modern medical technology has facilitatedpregnancy in older and sicker women. Diseases and their treatment may impact pregnancy and pregnancy may affect certain diseases.

CARDIAC DISEASES

During pregnancy, blood volume and cardiac output rise, and systemic vascular resistance decreases. Later in pregnancy the gravid uterus may compress the inferior vena cava (IVC), thereby significantly decreasing preload in the supine position. Cardiac output increases 40% by mid-pregnancy until labor and delivery when it increases further. Increased blood volume and left atrial dimensions may contribute to the increase in palpitations and supraventricular tachycardia. If the heart is damaged either by congenital heart disease or by cardiomyopathy, the increase in cardiac work cannot occur as effectively. In addition, just after delivery, with a uterine contraction a liter of blood can be shunted from the uterus into the general circulation. Cardiac lesions associated with a fixed cardiac output will not tolerate this sudden increase in volume. Hence, the most common complications in late pregnancy or immediately after delivery include pulmonary edema and, less commonly, right heart failure. In addition, the risk of a fetus developing congenital heart disease is increased if the mother has the same problem (eg, 1:4 in tetralogy of Fallot and 1:15 in atrial septal defects). Patients with severe pulmonary hypertension and/or Eisenmenger syndrome characterized by a reversed right-to-left shunt have increased mortality rates, especially during the first 48 to 72 hours postpartum.

Systemic vascular resistance decreases about 25%, which may improve any cardiac condition that benefits from after-load reduction such as aortic insufficiency. When compression of the inferior vena cava decreases venous return to the heart, patients with preload-dependent cardiac conditions such as aortic stenosis or poor left ventricular function may experience hypotension, especially when supine. Because the increased cardiac demands peak at 24 to 28 weeks of gestation, cardiac decompensation may become evident at the end of the second trimester.

Labor and delivery may be associated with cardiac decompensation when one to two units of blood leave the uteroplacental circulation during contraction. When the contraction ceases, the blood returns to the uteroplacental circulation.

Patients with peripartum cardiomyopathy that occurs in the third trimester and up to 6 months following delivery have symptoms and signs consistent with congestive heart failure. Approximately, one-third of these patients will completely recover, one-third will have chronic congestive heart failure, and one-third may have a progressive cardiomyopathy that may require cardiac transplantation in severe cases.

Postpartum fluid shifts occur during involution of the uterus and the low-resistance circulation of the placenta, postpartum blood loss, and increase in preload when the uterus no longer compresses the inferior vena cava.

Acute myocardial infarction is a rare complication during pregnancy. Coronary dissection with normal coronary arteries on angiography is more common in the peripartum or postpartum period. Patients with longstanding diabetes may develop myocardial ischemia during pregnancy. Antiphospholipid antibody-associated arterial thrombosis and arterial vasospasm and cocaine ingestion may also result in myocardial infarction.

Women with artificial heart valves who receive anticoagulant treatment will need to continue to do so during pregnancy. ­Decision about type of anticoagulation requires a risk-benefit discussion, monitoring to achieve consistently therapeutic levels of anticoagulation, and should not include warfarin during the first trimester or toward term. Ideally these patients should receive care and obstetric at a tertiary medical center that can provide combined cardiac and obstetric antenatal care.

INFECTIOUS DISEASES

THE FEBRILE PREGNANT FEMALE

Pregnancy may alter the course of some infections while certain infections are more likely to occur in a pregnant woman. Clinicians need to consider maternal-fetal transmission and the impact of antimicrobial therapy upon the fetus.

A primary systemic infection with toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and parvovirus (TORCH infections) can be associated with congenital malformations and disease. Primary infection with coccidiomycoses, which is especially common in the southwestern United States, can be complicated by fungal meningitis in a pregnant woman, which would otherwise be a rare complication in a normal host.

Fever, uterine tenderness, and contractions may suggest chorioamnionitis or infection of the amniotic sac and fluid. The diagnosis is made by consultation with an obstetrician and consideration of amniocentesis (positive Gram stain, amniotic fluid glucose usually <15 mg/dL). Treatment may require delivery.

Infection of the endometrium, an ascending polymicrobial infection, occurs in the postpartum period. Risk factors include prolonged rupture of membranes, delivery requiring instrumentation, and cesarean section, especially unplanned or emergent. ­Obstetricians can advise on the best antibiotic regimen depending on early postpartum endometritis (within the first 48 hours) and later endometritis (more than 1-week postpartum). Septic pelvic thrombophlebitis may be considered when a patient has persistent fevers despite an appropriately treated postpartum endometritis. Consider alternative diagnoses such as abscess, hematomas, and necrotizing fasciitis in a postpartum febrile patient, if computed tomography (CT) or magnetic resonance venography (MRV) of the pelvis rules out pelvic thrombosis.

PYELONEPHRITIS

Acute pyelonephritis complicates 1% to 2% of all pregnancies and can be associated with significant maternal and fetal morbidity, including the development of acute respiratory distress syndrome (ARDS) in up to 10% of patients. It is more common in patients with pyelonephritis and preterm labor who are being treated with beta-agonist tocolysis. Acute pyelonephritis during pregnancy is also associated with preterm delivery, with reported incidence between 6% and 50%, depending upon gestational age at presentation. Asymptomatic bacteriuria in a pregnant patient should always be treated because it is associated with a 25% incidence of pyelonephritis.

Pyelonephritis is most common during the second half of the pregnancy as a result of increased ureteral obstruction and urinary stasis, which result from both mechanical and hormonal factors. Usually unilateral, it affects the right kidney more frequently, because of uterine dextrorotation. Prior history of pyelonephritis, urinary tract malformations, and calculi put patients at a higher risk for development of an acute episode of pyelonephritis.

DIAGNOSIS

Pyelonephritis most commonly presents with systemic signs and symptoms including flank pain, fever, costovertebral angle tenderness, shaking chills, nausea, vomiting, and less often with features of cystitis, such as dysuria and frequency. Laboratory findings generally include a positive urine culture and pyuria on urinalysis. Additional laboratory studies should include a complete blood cell count and serum chemistry evaluation. Transient renal insufficiency with as much as 50% decrease in creatinine clearance is observed in about a quarter of all patients. Although blood cultures are often obtained in these patients, their utility is limited. Pathogens isolated from blood cultures rarely differ from those found in the corresponding urine culture. Blood cultures are recommended in cases that are complicated by sepsis, temperature of at least 39°C, or respiratory distress syndrome. Ovarian vein thrombosis may present as fever and flank pain and should be considered in patients suspected of having pyelonephritis who have normal urinalysis.

MANAGEMENT

Early aggressive treatment of pyelonephritis is important in preventing complications. The current standard of care includes hospitalization and parenteral antibiotics. Several equally efficacious antibiotic regimens are summarized in Table 221-1. Most patients respond within 72 hours. Therapy with the best oral agent, according to culture and sensitivity testing, should be continued to complete a 2-week course. Most experts recommend that suppressive therapy should be continued until delivery for all pregnant patients with a single episode of pyelonephritis. Prophylactic regimens include nitrofurantoin 100 mg once daily or cephalexin 250 mg once daily taken by mouth.

LISTERIOSIS

The incidence of listeriosis in pregnancy is 12 per 100,000, compared with a rate of 0.7 per 100,000 in the general population. In contrast to maternal illness, fetal and neonatal infection is severe and frequently fatal, with a case fatality rate of 20% to 30%. ­Neonatal listerial infection can cause pneumonia, sepsis, or meningitis. A characteristic severe in utero infection, granulomatosisi infantiseptica, may result from transplacental transmission, characterized by widespread abscesses and/or granulomas in multiple internal organs. Most infants with this condition are either stillborn or die soon after birth.

Diagnosis

Although severe maternal illness from listeriosis has been reported, it is rare. In most cases, maternal illness is mild and sometimes even asymptomatic. Fever, chills, back pain, and flu-like symptoms are most commonly reported. Illness can resolve spontaneously and the diagnosis be missed if cultures are not obtained. Patients with comorbidities, such as a history of splenectomy, human immunodeficiency virus (HIV) infection, steroid use, diabetes, or use of immunosuppressive medications, are at increased risk for severe maternal illness, which includes meningitis and meningoenchepalitis.

Diagnosis of listerial infection can only be made by culturing the organism from a sterile site such as blood, amniotic fluid, or spinal fluid. Vaginal or stool cultures are not helpful in diagnosis because some women are carriers but do not have clinical disease. Gram stain is useful in only about 33% of cases, both because Listeria is an intracellular organism and can be entirely missed, and because the organism can resemble pneumococci (diplococci), diphtheroids (Corynebacteria), or Haemophilus species.

Management

Pregnant women with isolated listerial bacteremia can be treated with ampicillin alone (2 g IV every 4 hours). Patients who are allergic to penicillin can be skin tested and desensitized, if necessary, or treated with trimethoprim-sulfamethoxazole (5 mg/kg of the trimethoprim component IV every 6 hours). Vancomycin has also been used in case reports of listerial infection.

ACUTE BRONCHITIS

Acute bronchitis usually refers to a self-limited respiratory illness characterized by the predominance of a productive cough in a patient with no history of chronic obstructive pulmonary disease and no evidence of pneumonia.

No studies have particularly looked at the course of acute bronchitis in pregnancy. A retrospective cohort study found an association between placental abruption and acute respiratory illnesses including acute bronchitis among white women.

MANAGEMENT

Most pregnant patients with acute cough syndromes require no more than reassurance and symptomatic treatment with inhaled beta-agonists. Most cases of acute bronchitis have a viral etiology; however, atypical bacteria including Bordetellapertussis, Chlamydia pneumoniae, and Mycoplasma pneumonia may cause acute bronchitis. The etiologic pathogen is isolated from the sputum in only a minority of patients. A chest x-ray should be performed if clinically indicated. Antimicrobial therapy may be considered in patients when a treatable pathogen is identified or in epidemic settings to limit transmission. Table 221-2 includes suggested antimicrobial regimens for pregnant patients.

There are no compelling data suggesting improved outcomes of acute bronchitis as a result of treatment with antibiotics.

PNEUMONIA

Pregnancy is associated with reduction in cell-mediated immunity, which places pregnant women at an increased risk of severe pneumonia and disseminated disease from some atypical pathogens such as herpes virus, influenza, varicella, and coccidioidomycosis. Mothers who develop pneumonia are more likely to have coexisting medical problems including asthma, drug abuse, anemia, and HIV infection. The use of corticosteroids for enhancement of fetal lung maturity and tocolytic agents has also been associated with antepartum pneumonia.

The incidence of pneumonia requiring hospitalization in pregnancy is between 2.6 to 15.1 per 10,000 deliveries, a rate comparable to that seen in nonpregnant women of a similar age. Pregnancy increases the risk of maternal complications from pneumonia, including the need for mechanical ventilation. Respiratory failure due to pneumonia is the third leading indication for intubation in pregnancy. Other maternal complications include pulmonary edema, bacteremia, empyema, pneumothorax, and atrial fibrillation. Pregnancies complicated by acute respiratory illnesses, including viral and bacterial pneumonia have been shown to be associated with placental abruption. Increased rates of preterm labor and delivery before 34 weeks of gestation have also been described.

The neonatal mortality rate due to antepartum pneumonia ranges from 1.9% to 12%, with most mortality attributable to complications of preterm birth. Although most cases of pneumonia in pregnancy are caused by organisms that do not affect the fetus except through their effects on maternal status, some organisms, such as varicella and CMV may present specific risks to the fetus. The fetus may also be at risk from maternal conditions that predispose to pneumonia.

The etiology of pneumonia in pregnancy is similar to the nonpregnant population, with streptococcus pneumoniae being the most commonly isolated organism (see Chapter 186 [Community Acquired Pneumonia]).

Diagnosis

Pregnant women with pneumonia present no differently than nonpregnant women and pneumonia should be considered in any woman presenting with fever, cough, sputum production, chills, rigors, dyspnea, and pleuritic chest pain. Occasionally, nonrespiratory symptoms such as vomiting, abdominal pain, and fever may predominate. Pulmonary embolism (PE), aspiration, chemical pneumonitis, amniotic fluid embolism, and pulmonary edema related to sepsis, tocolysis, or preeclampsiacan present similarly to an acute pneumonia with dyspnea, cough, chest pain, fever, and chest x-ray infiltrates.

A chest radiograph should be performed in all patients suspected to have pneumonia. Laboratory data should include a complete blood count, serum chemistries for hepatic, renal, glucose evaluation, assessment of oxygenation, and two sets of blood cultures; however, blood cultures may be positive only 7% to 15% of the time. The American Thoracic Society (ATS) does not recommend routine performance of sputum culture and Gram stain. However, if a drug-resistant pathogen oran organism not covered by usual empiric therapy is suspected, sputum culture should be obtained. HIV status should be reviewed for all pregnant women with pneumonia and testing should be offered if it has not previously been done. Testing for pneumocystis carinii infection should occur in all HIV-positive women.

Management

While no specific guidelines exist to help assess severity and the need for hospitalization in pregnant women, it is best to ensure adequate maternal oxygenation (oxygen saturation ≥ 95% or pO₂≥ 70 mm Hg) and fetal well-being before considering outpatient treatment.

Several recommendations exist for treatment of pneumonia in pregnancy. Table 221-3 summarizes some suggested recommendations based upon ATS guidelines. Although levofloxacin and doxycycline are often recommended in the treatment of pneumonia in the nonpregnant population, these drugs should be avoided in pregnancy. Clarithromycin has shown to have adverse effects in animal trials at doses equivalent to 2 to 17 times the maximum recommended human dose. It is therefore best avoided in pregnancy, with use limited to those cases in which no alternative therapy is appropriate.

With appropriate therapy, an improvement can be expected in 72 hours, after which the regimen can be changed to an oral medication to complete 10 to 14 days therapy.

VIRAL HEPATITIS

In general, pregnancy does not affect the diagnosis or clinical course of viral hepatitis. It has been reported, however, that acute hepatitis may be more severe with hepatitis E. The differential diagnosis includes other common causes of liver dysfunction such as biliary obstruction, drug-induced liver disease, as well as liver diseases uniquely associated with pregnancy such as acute fatty liver, preeclampsia or HELLP (hemolysis, elevated liver enzymes, and low platelets), and cholestasis of pregnancy.

Herpes simplex virus (HSV) hepatitis

As a form of disseminated primary herpes infection, usually Herpes simplex type 2, HSV has been reported in the second and third trimester. Pregnant patients may have characteristic mucocutaneous lesions and anicteric liver failure due to severe hepatocyte injury with extreme elevations of serum transaminases, an increased prothrombin time, and only mildly elevated serum bilirubin. If prescribed early in the course of illness, acyclovir may be effective in ameliorating the course of illness.

PULMONARY DISEASE

SHORTNESS OF BREATH

Normal pregnancy is characterized by an increase in minute ventilation, due to an increase in tidal volume but not respiratory rate.

Dyspnea of pregnancy usually begins in the middle of gestation as the patient’s increased perception of dyspnea. These patients should have a completely normal physical examination, oxygenation, chest x-rays, and pulmonary function testing.

If shortness of breath occurs at 24 to 48 weeks when blood volume reaches its maximum, underlying heart disease should be considered. Pregnant women have an increased risk for pulmonary edema due to an increase in blood volume that is predominantly achieved through an increase in plasma-free water and a lower oncotic pressure during pregnancy. Pyelonephritis, medications that are used to stop preterm laborand preeclampsia may precipitate pulmonary edema. Pregnancy-associated pulmonary edema often responds to withdrawal of the precipitating cause and a low diuretic dose. Other causes of dyspnea include venous thromboembolism (VTE) and respiratory illness (see Chapter 85 [Dyspnea]).

A rare cause of dyspnea unique to pregnancy is amniotic fluid embolism occurring during the third trimester but usually during delivery. Rapid and progressive respiratory failure may be associated with hemodynamic instability and disseminated intravascular coagulopathy. This is a diagnosis of exclusion and treatment is supportive care.

Management

The average PaO₂ in pregnancy 100 mm Hg at sea level and PCO₂ in the range of 28 and 32 mm Hg. An arterial blood gas (ABG) with a PaO₂ of 79 mm Hg and a PCO₂ of 40 mm Hg, considered within normal limits for a nonpregnant patient, is very abnormal in a pregnant female. Because fetal hemoglobin has a different oxygen dissociation curve from adult hemoglobin, in order to adequately oxygenate fetal tissue, maternal oxygen saturation needs to remain greater than 95% or PaO₂ > 70 mm Hg.

ASTHMA

Asthma affects 3.7% to 8.4% of all pregnancies and is one of the most common serious medical complications encountered in pregnancy in the United States. Asthma may develop during gestation triggered by an upper respiratory infection with persistent bronchospasm or be triggered due to reflux or sinusitis, both increased during pregnancy.

The course of asthma is usually unpredictable in pregnancy and numerous studies have suggested that a third of the patients improve, a third remain the same, and another third worsen. Factors contributing to improvement may be the pregnancy-associated rise in serum cortisol or the increase in progesterone that acts as a potent smooth muscle relaxant. Several factors may be responsible for worsening. Gestational rhinitis, bacterial sinusitis, and gastroesophageal reflux disease, all of which occur at an increased incidence in pregnancy, may worsen asthma control in the gravid state.

Most studies have shown that well-controlled pregnant patients with asthma do not have a significantly higher rate of adverse outcomes than those without asthma. However, patients with poorly controlled asthma are more likely to have miscarriages or therapeutic abortions, infants with low birth weight, and intrauterine growth restriction, and are more likely to undergo cesarean section. Preterm delivery and maternal hypertension have also been noted in poorly controlled women with asthma, but these risks have not been shown consistently and may partly be related to use of systemic steroids in these patients. Preeclampsia has also been associated with severe asthma in some studies.

Management

Management of asthma in pregnancy does not significantly differ from the nonpregnant patient. Table 221-4 discusses the use and safety of commonly used asthma medications in pregnancy. While dealing with an acute asthma exacerbation in a pregnant woman, it is of vital importance to recognize that normal CO₂ in pregnancy is 28 to 32 mm Hg, which is lower than the nongravid state. Therefore, a tachypneic pregnant patient with a PaCO₂ above this range might be in impending respiratory failure. Figure 221-1 shows the recommendations for assessment and management of acute asthma exacerbation in the hospital setting. These are based on the NAEP guidelines for asthma management in pregnancy.

While asthma exacerbations are rare in labor and delivery, it is important to ensure that asthma medications are not discontinued through labor and delivery. Most drugs used for asthma treatment can be safely used in breastfeeding women. Whether breastfeeding decreases the likelihood of the development of asthma in offspring is as yet controversial, but it does appear to decrease atopy.

PLEURAL EFFUSION IN PREGNANCY

Pleural effusions can be caused by a variety of conditions, both specific and unrelated to pregnancy. Physiologic changes of pregnancy, including an increased blood volume and decreased colloid osmotic pressure, promote transudation of fluid into the pleural space. Benign postpartum pleural effusions have been noted on chest radiographs and ultrasound studies after normal vaginal delivery with an incidence of about 25%. Pregnancy-specific conditions that predispose to pulmonary edema such as preeclampsia, amniotic fluid embolism, chorioamnionitis, or endometritis, may also result in pleural effusion.

Diagnosis

Diagnostic approach is largely guided by findings on history and physical examination and conditions being considered in the differential. A diagnostic thoracocentesis should always be considered in the presence of fever, hemoptysis, weight loss, or when hemothorax or emphysema is suspected.

Management

Management usually involves treatment of the underlying condition. Rarely, a therapeutic thoracentesis may be necessary, particularly in case of a large (eg, TB) or rapidly accumulating effusion (eg, malignancy). Presence of blood, pus, or chylous effusion warrants placement of a thoracostomy tube. While performing these procedures in pregnancy, it is important to remember that the diaphragm is about 4 to 5 cm elevated and a higher approach with ultrasound guidance is advisable.

PNEUMOTHORAX IN PREGNANCY

Primary spontaneous pneumothorax (PSP) usually resolves satisfactorily with simple observation, aspiration, or tube drainage. Recurrence occurs more frequently in pregnant patients. Majority of these recurrences occur during the same pregnancy or in the postpartum period.

Management

Observation may suffice for a small pneumothorax (<2 cm) in patients without shortness of breath. Further intervention should be considered in patients with difficulty breathing or if the pneumothorax is larger than 2 cm. Chest tube drainage would be indicated in patients with persistent air leak. Surgical correction may be considered in the postpartum period to prevent recurrence in subsequent pregnancies.

Risk of recurrence may be increased in labor and delivery due to the repeated Valsalva maneuvers during vaginal birth, with resulting increase in intrathoracic pressures. Therefore in a pregnant woman with a past history of PSP, vaginal delivery should be assisted with forceps or vacuum to limit Valsalva breathing. Should a cesarean section be necessary, it is best performed under regional anesthesia to avoid intrathoracic pressure increases associated with intubation and general anesthesia.

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)

Acute respiratory distress syndrome is an acute, diffuse, inflammatory lung injury that leads to increased pulmonary vascular permeability, increased lung weight, and a loss of aerated tissue. Although no studies clearly elucidate the frequency of ARDS in the obstetric population, the incidence is felt to be similar to the general population (see Chapter 142 [ARDS]).

Pregnancy does not change total lung capacity, nor does it increase the A-a gradient. Noncardiogenic pulmonary edema is known to occur more frequently in pregnant women with an estimated incidence of 80 to 500 cases per 100,000 and is responsible for 25% of transfers of obstetric patients to intensive care units. Both the normal decrease in serum oncotic pressure that occurs in pregnancy due to a physiologic dilutional hypoalbuminemia and changes in maternal endothelium may explain this pregnancy-related propensity to pulmonary edema.

The effect of maternal ARDS on neonatal outcomes is not well studied, but high rates of fetal death, spontaneous preterm labor, and fetal heart rate abnormalities are reported.

Diagnosis

Eighty-five percent of all ARDS cases result from four causes, with sepsis being the most common:

• Sepsis from pulmonary or nonpulmonary sources

• Major trauma

• Multiple transfusions

• Aspiration of gastric contents

In the obstetric patient, several causes unique to pregnancy have to be considered. These are listed in Table 221-5.

Cardiac causes of pulmonary edema such as peripartum cardiomyopathy, ischemic heart disease, or occult valvular heart disease and fluid overload should be considered in the differential diagnosis of ARDS. Other conditions such as interstitial pneumonia, acute eosinophilic pneumonia, acute bronchiolitis obliterans pneumonia, acute hypersensitivity pneumonitis, and diffuse alveolar hemorrhage may have a clinical and radiological picture similar to ARDS.

Management

Pulmonary edema in pregnancy is a medical emergency. The first and immediate goal is to maintain adequate maternal oxygenation (PaO₂ ≥ 70 mm Hg equivalent to oxygen saturation 95%) through the use of oxygen supplementation to avoid hypoxia in the fetus. Mechanical ventilation may be needed in severe cases to ensure adequate oxygenation.

Tables 221-6 and 221-7 list the salient features of investigation and management of ARDS in the pregnant patient.

When pulmonary edema is suspected to be related to preeclampsia, initial management consists of oxygen supplementation, fluid restriction, and blood pressure (BP) control while plans are made for delivery. Intravenous magnesium is used as a first-line agent for seizure prophylaxis and treatment in preeclampsia/eclampsia, based on two randomized controlled trials that confirm superiority over dilantin. However, its use in the setting of ARDS may not be justified given the possible causative association with noncardiogenic pulmonary edema. Dilantin may be preferable for seizure prophylaxis in this setting.

Many preeclamptic patients are relatively intravascularly volume contracted, despite having massive amounts of peripheral edema and pulmonary edema. Over-diuresis of a preeclamptic patient can impair maternal renal perfusion, cardiac output, and uteroplacental perfusion, leading to fetal distress. Most patients with pulmonary edema in pregnancy will respond dramatically to doses of furosemide as low as 10 mg IV especially if renal function is normal. Despite the need for careful fluid restriction and gentle diuresis, there is little evidence that central hemodynamic monitoring in these patients improves outcomes.

Whether delivery has a positive impact on maternal condition in patients with ARDS is unclear. There are case reports describing improvement in maternal oxygenation after delivery in patients with ARDS, but the mechanism for this is not well understood and may be partly related to resultant decreased cardiac work.

For the most part, patients with ARDS secondary to chorioamnionitis, placental abruption, amniotic fluid embolism and preeclampsia need immediate delivery, while those with pyelonephritis or varicella pneumonia can often recover without delivery.

RENAL DISEASE

NEPHROLITHIASIS

Renal stones are commonly encountered in pregnancy, complicating about 1 in 200 pregnancies. While some data suggests an increased risk of preterm labor in patients with stones, most available reports do not suggest a significant increase in obstetric complications.

Pregnancy is associated with physiologic dilatation of the ureters, resulting from smooth muscle relaxation induced by progesterone. This may occur as early as the first trimester. Furthermore, there is decreased peristalsis and anatomic dilatation resulting from mechanical obstruction of the collecting system from the gravid uterus. With the resultant urinary stasis, there is increased propensity for infection and crystal aggregation. In addition, increases in glomerular filtration rate (GFR) lead to higher concentration of urinary calcium that further predisposes to stone formation.

Diagnosis

Pregnant patients with urolithiasis present no differently from nonpregnant patients, usually with renal colic or severe pain associated with complete or partial obstruction of the ureters. The diagnosis of urolithiasis may be challenging in pregnancy due to the physisologic changes in the renal system in the gravid state.

Ultrasonography (USG) is the preferred initial test, as opposed to abdominal CT scan, to avoid fetal radiation exposure. Bilateral hydronephrosis may be seen on ultrasound (US) due to physiologic changes. It is therefore important to identify the presence of ureteral jets in the bladder, which would rule out a ureteral obstruction by stone.

The sensitivity of ultrasound in confirming urolithisis ranges from 34% to 86%. If a stone is clinically suspected despite ultrasound findings, a single shot IVP may be performed. If diagnosis still remains in question, magnetic resonance urography may be helpful. Whenever possible, the stone should be collected for analysis.

Management

The initial management plan for urinary stones in pregnancy is conservative (hydration, analgesics, and antibiotics if infection is present). Opioid analgesics can safely be used in pregnancy. ­Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided due to oligohydramnios and premature narrowing or closure of the patent ductusarteriosis. Most patients will spontaneously pass the stone with conservative management. Urology consult may be appropriate in patients with prolonged or recurrent symptoms in which ureteral stents may be needed. Indications for a diversion procedure, stenting, or percutaneous nephrostomy, include persistent pain, infection or high-grade hydronephrosis beyond normal pregnancy-related dilatation.

ACUTE RENAL FAILURE

By definition, acute renal failure (ARF) is a syndrome of rapid decrease in glomerular filtration rate, increasing serum creatinine, and urea levels and oliguria or anuria (see Chapter 239 [Acute Kidney Injury]).

Acute renal injury is rare in pregnancy, but transient mild to moderate renal dysfunction is more common. Adverse fetal outcomes associated with acute renal insufficiency are typically due to altered uteroplacental hemodynamics. It is therefore crucial to maintain volume and maternal acid-base balance and prevent further renal deterioration. If delivery is imminent in these patients, the neonate may be subject to rapid dehydration as a result of increased solute load in fetal circulation leading to osmotic diuresis.

Diagnosis

The physiologic increase in GFR leads to lower serum creatinine and BUN during pregnancy. Renal dysfunction in pregnancy is therefore defined as creatinine above 0.8 mg/dL (Table 221-8).

Acute renal injury can result from prerenal, intrarenal, or postrenal causes (see Table 221-9).

Management

Initial management of ARF commences with identification and treatment of underlying causes. Judicious fluid management and avoidance of nephrotoxins are important. Care should be taken to adjust dosing of medications that are renally cleared. Low-dose dopamine has not been found to be effective and is not recommended. Loop diuretics may be helpful in treatment of volume overload; however, there is no data to support the use of diuretics in patients with oliguric renal failure from preeclampsia, a disease of hemoconcentration and vasospasm. Renal replacement therapy should be considered in the case of volume overload, hyperkalemia refractory to medical management, metabolic acidosis, or symptomatic uremia (mental status changes, pericarditis, neuropathy).

Dialysis

Although uncommon, pregnancy does occur in women on chronic dialysis. Conversely, dialysis may become necessary in a pregnant woman with ARF from worsening underlying renal disease or de novo causes. There is no difference in outcomes with peritoneal or hemodialysis. In general, an increased dose of dialysis is recommended for pregnant patients to achieve a target predialysis blood urea nitrogen of less than 50 mg/dL.

HYPERTENSIVE DISORDERS

Hypertensive disorders represent one of the most common medical problems in pregnancy and encompass the diagnoses of chronic hypertension, gestational hypertension, and preeclampsia.

CHRONIC HYPERTENSION

Chronic hypertension in pregnancy is defined as a blood pressure of 140/90 or greater on two separate occasions before 20 weeks’ gestation or persisting beyond 12 weeks’ postpartum. It is associated with a 20% risk of developing preeclampsia. While essential hypertension is the most common cause, consideration of secondary causes is necessary in this young population.

Physiologic changes in the cardiovascular system during pregnancy allow for a decrease in blood pressure in the first two trimesters, with a return toward baseline in the third trimester. In the second half of pregnancy, inferior vena cava compression from a gravid uterus in the supine position may falsely lower blood pressure readings, so it is important to measure blood pressure in a pregnant woman in the seated position.

Treatment of mild to moderate hypertension in pregnancy neither benefits the fetus nor prevents preeclampsia. In addition, excessive lowering of blood pressure may result in adverse fetal outcomes from decreased placental perfusion. Oral agents that are commonly used to treat hypertension in pregnancy include labetalol, nifedipine, and methyldopa. Clonidine has also been used in pregnancy without increased risk of congenital malformations; however, an effect on offspring behavior has been suspected based on human and animal studies. Other oral agents that are reasonably safe for pregnancy but with limited efficacy include hydralazine and hydrochlorthiazide. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are contraindicated at any gestational age in pregnancy. Table 221-10 outlines the pharmacologic management of hypertensive urgency in a pregnant woman.

GESTATIONAL HYPERTENSION

Gestational hypertension is defined as elevation in blood pressure developing after 20 weeks’ gestation without proteinuria. Women with gestational hypertension progress to preeclampsia in 15% to 45% of cases and often require early delivery. Surveillance for development of preeclampsia and close fetal monitoring is recommended.

PREECLAMPSIA

Preeclampsia is a pregnancy-specific complication that occurs in 5% to 10% of all pregnancies. It is defined as a BP ≥ 140/90 accompanied by proteinuria of > 300 mg per 24 hours after the 20th week of gestation in a previously normotensive patient. When it is diagnosed in a patient with pre-existing chronic hypertension, it is referred to as chronic hypertension with superimposed preeclampsia. Most cases of preeclampsia occur close to term.

Risk factors for development of preeclampsia include first pregnancy or pregnancy with a new partner, age less than 18 years or older than 35, past history of preeclampsia, chronic hypertension, renal disease, diabetes mellitus (type I, II, or gestational), obesity, systemic lupus erythematosus (SLE), thrombophilia, multiple gestation, and molar pregnancy.

Etiology of preeclampsia is unclear. On a pathophysiologic level, preeclampsia is characterized by systemic endothelia dysfunction brought about by an imbalance between proangiogenic (VEGF, PlGF) and antiangiogenic factors (sFlt-1) resulting in various inflammatory responses leading to hypertension, hemoconcentration, and vasospasm.

Diagnosis

The main symptoms of preeclampsia include headache, visual disturbance, epigastric or right upper quadrant abdominal discomfort, edema, and rapid weight gain. Signs include hypertension, retinal vasospasm, right upper quadrant tenderness, and clonus. Lab studies supporting the diagnosis of preeclampsia are outlined in Table 221-11.

Severe preeclampsia is defined as the presence of one of the following symptoms or signs in the presence of preeclampsia (1) systolic BP of ≥ 160 mm Hg or diastolicBP of ≥ 110 mm Hg on two occasions at least 6 hours apart; (2) proteinuria of more than 5 g in 24-hour period; (3) pulmonary edema; (4) oliguria (< 400 mL in 24 h); (5) persistent headaches and/or seizures (eclampsia); (6) epigastric pain and/or impaired liver function; (7) thrombocytopenia; and (8) intrauterine growth restriction. HELLP syndrome characterized by hemolysis, elevated liver enzymes and low platelet count is a variant of severe preeclampsia occurring in about 20% of cases of severe preeclampsia.

Treatment

The only known treatment of preeclampsia once it occurs is delivery as soon as obstetrically feasible. Despite this, it is important to note that preeclampsia can present postpartum, and both preeclampsia and eclampsia have been reported for up to 21 days following delivery. Management of preeclampsia includes treatment of hypertension, seizure prophylaxis, and limitation of fluids due to the risk of pulmonary edema. Table 221-12 outlines the management of a pregnant woman hospitalized with severe preeclampsia.

ENDOCRINE DISORDERS

DIABETES

Insulin requirements often decrease by 10% to 20% in the first trimester of pregnancy due to increased insulin sensitivity. The risk of overall and nocturnal hypoglycemia during this time is further compounded if the patient has hyperemesis or pre-existing gastroparesis.

Rising human placental lactogen and human placental growth hormone levels from the beginning of the second trimester then cause an increase in insulin resistance, and insulin requirements rise gradually until approximately 36 weeks of gestation. Women with pre-existing type 2 diabetes controlled with diet and exercise will usually require pharmacologic treatment by mid–second trimester. A sudden decrease in insulin requirements in the third trimester needs to be taken very seriously, as it may be a signal of placental failure, and close fetal surveillance is required.

All metabolic processes are accelerated during pregnancy and the threshold of starvation ketoacidosis occurring after a prolonged fast is much lower. This coupled with hyperemesis in early pregnancy and subsequent increased insulin resistance in later pregnancy increases the risk of diabetic ketoacidosis (DKA) in pregnant women.

It is recommended that a baseline eye check occur as part of preconception counseling as pre-existing diabetic retinopathy has been shown to progress more quickly during pregnancy due to the increased production of growth factors as well as the hypercoagulable state of pregnancy. Laser therapy during pregnancy is as effective as outside pregnancy and can be safely used if required.

In women with pre-existing diabetic nephropathy, pregnancy may worsen the degree of proteinuria, cause progression of renal sufficiency, and aggravate hypertension. Discontinuation of ACE inhibitors or angiotensin II receptor blockers before conception together with an increase in GFR are the main reasons for a physiologic increase in proteinuria during pregnancy. Although pregnancy may accelerate the progression of nephropathy, postpartum renal function usually returns to prepregnancy levels in most cases. In women with moderate renal insufficiency, pregnancy has been estimated to shorten the time to end-stage renal failure by 36 months.

Hypertension occurs in 30% of women with diabetic nephropathy in the first trimester and in 75% by the third trimester. Deteriorating renal function and superimposed preeclampsia are responsible for the high rates of preterm delivery, low birth weight, and operative delivery. Differentiating preeclampsia from worsening nephropathy can be very difficult as proteinuria and worsening hypertension occur in both situations.

Women with pre-existing types 1 and 2 diabetes are at increased risk of preeclampsia, operative delivery, and antenatal infections (such as urinary tract and respiratory). These risks are further increased if the mother has premorbid obesity as well.

The rate of early pregnancy loss or congenital anomalies is increased for women with poor preconception glycemic control. Glucose is a potent teratogen and there is a linear increase in rates of congenital anomalies with rising HgbA1C levels. Late pregnancy losses are also increased in women with poor glycemic control during pregnancy. It is thought that oxidative stress resulting from oxygen depletion caused by hyperglycemia is the underlying mechanism for these findings. It has been shown that the overall rate of adverse pregnancy outcome is much lower in women who receive preconception counseling and are euglycemic at conception and during organogenesis.

The incidence of macrosomia is increased in diabetic pregnancies. Excess fetal growth is due to fetal hyperinsulinemia in response to maternal hyperglycemia. Macrosomic babies (> 4000 g) are at increased risk for traumatic or surgical delivery, shoulder dystocia, and brachial plexus injury. Neonatal hypoglycemia due to fetal hyperinsulinemia and neonatal hyperbilirubinemia are metabolic complications that are more common in babies born to diabetic mothers.

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variable severity that is first detected during pregnancy. It is the leading endocrine condition in pregnancy and continues to rise in the face of the obesity epidemic. Pregnancy is effectively a stress-test in which the insulin-resistant hormones of pregnancy trigger overt hyperglycemia in women who have a background of previously undiagnosed insulin resistance and/or decreased pancreatic beta-cell reserve.

It is usually diagnosed at the end of the second trimester via a diagnostic glucose tolerance test. Treatment needs to begin immediately as there is only a short window of opportunity to achieve euglycemia in order to minimize its impact on the fetus. If the following targets are not met with diet and exercise therapy alone (fasting blood glucose level or BGL < 5.3 mmol/L or 95 mg/dL and/or 1-hour postprandial BGL < 7.8 mmol/L or 140 mg/dL and/or 2-hour postprandial BGL < 6.7 mmol/L or 120 mg/dL), insulin therapy is commenced though glyburide, or metformin therapy may be recommended if the patient refuses insulin therapy and/or the degree of hyperglycemia is only mild. Glyburide has traditionally been the preferred agent as it does not cross the placenta, but more recent studies have emerged regarding the safety and efficacy of metformin use beyond the first trimester.

Glucose tolerance returns to normal immediately after delivery of the placenta and so treatment can be ceased. Women with GDM are at much greater risk of developing type 2 diabetes in the future and so they should be tested for such on a regular basis by their primary care physicians.

The use of oral hypoglycemic agents, subcutaneous insulin regimes, and insulin pumps

Insulin is considered the gold standard of treatment for both pre-existing and gestational diabetes. However, there has been a trend toward increasing use of glyburide and metformin in recent times. There is currently no data to suggest that the use of either in the first trimester is associated with an increase in congenital anomalies. Glyburide does not cross the placenta and can be used throughout the second and third trimesters as well.

Metformin is frequently used as an ovulation induction agent in women with polycystic ovarian syndrome and for these women, continuing its use during the first trimester has been shown to reduce miscarriage rates. Its use during the second and third trimesters had been questionable in the past given that significant placental transfer does take place (cord blood levels similar to maternal levels) but recent data suggests that there is no long-term deleterious effects on the fetus and it may in fact reduce the risk of the offspring developing type 2 diabetes in the future.

None of the other oral hypoglycemic agents currently on the market are recommended or approved for use during pregnancy.

All the insulin types available on the market are safe for use in pregnancy. These include the newer insulin analogs, which are more rapid in onset (Humalog, Novolog) and longer in action (Lantus, Levemir) compared with the traditional recombinant human insulins (Humulin-R, Humulin-NPH).

An increasing number of women of childbearing age with type 1 diabetes are using insulin pumps that provide a continuous subcutaneous infusion of insulin for glycemic control. The main caveat here is that they need to recognize potential problems such as a blockage or kink in the infusion set that can precipitate an episode of diabetic ketoacidosis more quickly in pregnant patients.

Management of diabetic ketoacidosis

The presentation of DKA is similar in the nonpregnant and pregnant patient, but the acidosis tends to be more pronounced at a lower serum glucose level in the pregnant patient. This is due to the combination of the accelerated starvation state of pregnancy, lower buffering capacity due to the physiologic respiratory alkalosis of pregnancy that leads to lower serum bicarbonate levels and the increased GFR in pregnancy that leads to increased renal excretion of glucose.

Treatment requires prompt recognition and maternal stabilization with rehydration, intravenous insulin therapy, and electrolyte replacement. Infections such as those of the urinary tract should be excluded. As starvation ketosis is often the main component of ketoacidosis, the mother needs to receive adequate dextrose (with the insulin infusion) in order to meet fetal-placental glucose needs until she is eating normally. Ketone bodies and glucose cross the placenta readily and so there is high fetal morbidity and mortality associated with DKA. Fetal compromise will improve once the metabolic acidosis reverses. An urgent C-section while the mother is still acidotic is not generally recommended because of high maternal risk.

Management at time of labor and delivery

It is recommended that an insulin plan for the time of labor and delivery be provided to all patients well before the expected due date so that there is no confusion between the patient and various medical and nursing caregivers. It is important to avoid maternal blood glucose levels more than 9.0 mmol/L (162 mg/dL) in the intrapartum period as this has been associated with an increased risk of neonatal hypoglycemia (which may require NICU admission), but it is also important to avoid hypoglycemia for maternal safety and well-being during this strenuous process.

In early labor, subcutaneous insulin use should be continued while the woman is still eating but these doses will need to be reduced if oral intake is decreased. When the woman is in active labor and no longer eating, an intravenous insulin and dextrose infusion should be commenced to keep the blood glucose levels in the desired range of 4.0 to 8.0 mmol/L (72-144 mg/dL).

For patients with active proliferative retinopathy, using the ­Valsalva maneuver repeatedly in the second stage of labor is a concern as there is an increased risk of retinal hemorrhage.

Management in the immediate postpartum period

With delivery of the placenta, insulin requirements rapidly decrease back to prepregnancy levels. The target range of blood glucose levels postpartum in the pre-existing diabetic is much more relaxed compared with during pregnancy, with levels between 6.0 and 10.0 mmol/L (108-180 mg/dL) all being acceptable. Breastfeeding will lower blood glucose levels and having extremely tight glycemic control may increase the risk of hypoglycemia in a lactating woman. The usual postpartum insulin requirement is approximately two-thirds of the prepregnancy insulin dosage.

Women with type 2 diabetes may be able to discontinue insulin therapy and use diet and exercise and/or oral hypoglycemic agents in the postpartum period. The two oral hypoglycemic agents that have been documented to be safe in breastfeeding are glyburide and metformin. The former does not enter breast milk at all and infant exposure to the latter has been estimated to be only approximately 0.5% of the maternal dose.

ACE-inhibitors or angiotensin II receptor blockers can also be recommenced in lactating women, though it is recommended that a preterm infant not be exposed to it until he has reached an age equivalent to full term.

OBESITY IN PREGNANCY

The prevalence of obesity worldwide has increased dramatically over the past 25 years. It affects 26% of the population in the USA. Of concern is the fact that the majority of the obese population tend to be women of reproductive age, according to the WHO.

Overweight and obese women are at increased risk of maternal, fetal and peripartum complications. Maternal complications include gestational diabetes mellitus, gestational hypertension, preeclampsia, cesarean delivery, and postpartum weight retention. It is also well recognized that obesity is an independent risk factor for spontaneous abortion among women who conceive naturally or undergo infertility treatment, and hence it is recommended that obese women be provided with counseling for weight reduction prior to conception. Nutrition and exercise counseling should be provided at this time as well as continuing throughout the pregnancy, in the postpartum period and subsequently before attempting another pregnancy. Institute of Medicine guidelines published in 2009 recommend that overweight women (BMI 25.0-29.9) should put on no more than 15 to 25 lbs and obese women (BMI >30.0) no more than 11 to 20 lbs during the entire pregnancy.

Associated fetal risks include an increased rate of congenital anomalies (eg, neural tube defects), lower detection rate of fetal anomalies during prenatal ultrasonography, macrosomia, prematurity, stillbirth, as well as subsequent childhood and adolescent obesity.

At the time of delivery, the use of regional anesthesia is preferred as the rate of failed or difficult intubation is as high as one in three for obese pregnant women. It is recommended that anesthesiology consultation occurs early on during the laboring process in order to better identify strategies to reduce the failure rate of administering epidural or spinal anesthesia. The presence of obstructive sleep apnea may further complicate airway and postoperative management. Obese women who require cesarean deliveries have increased rates of excessive blood loss, operative time greater than 2 hours, wound infection and endometritis. Postoperative wound disruption is thought to be less prevalent with the use of suture closure of the subcutaneous layer. Consideration should be given to using a higher dose of preoperative antibiotics for surgical prophylaxis. Obesity is also an additional risk factor for thromboembolic events and hence the routine use of pneumatic compression devices following cesarean deliveries is recommended. Prophylactic anticoagulation for 2 weeks is also recommended in obese individuals with additional risk-factors. Obese women are less likely to initiate and sustain breastfeeding.

The number of obese reproductive-aged women undergoing bariatric surgery is increasing. The two most common procedures currently performed are gastric bypass and sleeve gastrectomy (about 50% each). It is generally recommended that pregnancy be delayed for 12 to 18 months postoperatively. With gastric bypass patients, there is an increased risk of failure in absorption of medications (eg, oral contraceptive pill, extended release formulations such as metformin). Care should be taken to monitor and supplement these patients with micronutrients such as iron, folate, vitamin B12, calcium and vitamin D. Oral glucose tolerance tests may not be well tolerated due to the dumping syndrome and so routine blood glucose monitoring is often recommended in these patients.

THYROID

Hypothyroidism

Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Avoiding maternal (and fetal) hypothyroidism is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery. However, universal screening of pregnant women for thyroid disease is not yet supported by adequate studies, but case finding targeted to specific groups of patients who are at increased risk is currently strongly supported.

Both overt and subclinical hypothyroidism can have an adverse impact on the course of pregnancy or fetal development. Overt hypothyroidism should be corrected before initiation of pregnancy and preconception thyroxine (T4) dosage should bring the thyroid-stimulating hormone (TSH) level < 2.6 mU/L. Women with subclinical hypothyroidism (serum TSH above the upper reference limit but free T4 [fT4] within the reference limits) should also be treated with T4 replacement. This recommendation is based on observational evidence demonstrating that women suffering from overt or subclinical hypothyroidism deliver babies with an average intelligence quotient (IQ) score seven points below the mean IQ score of children born to healthy women and women on T4 replacement. The importance of maternal thyroid hormone replacement is emphasized by the fact that the fetal thyroid does not develop until the second trimester of pregnancy and fetal thyroid hormone production does not become optimal until mid-gestation.

Maintaining a serum TSH < 3.0 mU/L is acceptable in the second and third trimesters of pregnancy. After delivery, the dose of T4 therapy can usually be reduced back to the preconception dosage after checking a repeat set of thyroid function tests at the 6-week postpartum visit.

Hyperthyroidism

If a suppressed TSH is detected during pregnancy, hyperthyroidism must be distinguished from normal physiology (gestational thyrotoxicosis) and hyperemesis gravidarum because of the potential adverse effects on the mother and fetus.

Hyperthyroidism in pregnancy is not rare; estimated prevalence is 0.1% to 0.4% with Graves disease accounting for 85% of cases and toxic solitary or multiple nodules plus thyroiditis accounting for most of the rest. Hydatidiform molar disease is a very uncommon cause these days due to the advent of dating ultrasounds.

Gestational thyrotoxicosis presents in the mid- to late first trimester, often with hyperemesis. Classical hyperthyroid symptoms are absent or minimal apart from weight loss, which is often the result of malnutrition secondary to vomiting. The suppression in TSH is mediated by rising human chorionic gonadotropin (hCG) levels and therefore it will usually self-resolve by mid-gestation at the latest. Approximately 50% of women suffering from hyperemesis have a subnormal TSH and elevated fT4 level. In this setting, the assessment of free triiodothyronine (fT3) level and thyroid-stimulating immunoglobulin (TSI) level are helpful as 90% of hyperemesis cases have normal fT3 and most cases of Graves disease will be TSI positive.

If Graves disease or hyperfunctioning nodules are diagnosed, propylthiouracil is preferred to methimazole because of the association with congenital abnormalities with the latter medication. Therapy should be adjusted to maintain maternal fT4 in the upper nonpregnant reference interval. Though rare, the possibility of neonatal Graves disease needs to be entertained if the maternal TSI levels are high in the third trimester. Women with well-controlled Graves disease during pregnancy should be warned about the possibility of postpartum flare-up, which usually occurs between 6-weeks and 6-months postpartum. It is not recommended that radioactive iodine therapy be used during pregnancy and lactation.

Postpartum thyroiditis

Postpartum thyroiditis may occur in up to 10% of all pregnancies, usually between 6 weeks and 6 months after delivery, but it can occur up to 1 year later (see Chapter 222 [Postpartum Consultation for Common Complaints]). A hypothyroid phase often follows the hyperthyroid phase and is occasionally permanent. Monitoring is necessary, as women may be hypothyroid at the time of any subsequent pregnancy.

PARATHYROID

Hypercalcemia

Primary hyperparathyroidism is usually diagnosed during pregnancy through routine blood testing following prolonged or extremely severe hyperemesis gravidarum or else the serendipitous finding of nephrocalcinosis, renal calculi, or excessive calcification of the placenta during fetal ultrasonography. It may frequently be part of the multiple endocrine neoplasia (MEN-1 or MEN-2a) syndrome. Urinary calcium excretion is typically not used as part of the diagnostic evaluation as it is increased in normal pregnancy.

Symptomatic hyperparathyroidism is best treated by minimally invasive surgical removal of the parathyroid adenoma during the second trimester, after embryogenesis is complete and before such time that premature labor may be stimulated. In skilled hands, the procedure takes no more than 30 minutes.

Surgery can also be offered in late pregnancy (after 35 weeks’ gestation) if the patient becomes profoundly symptomatic, as the neonatal outcome is much improved with surgery. This is due to the reduced risk of stillbirth, intrauterine growth restriction (IUGR), premature labor, and especially neonatal hypocalcemictetany, which can frequently cause prolonged neonatal intensive care unit admissions especially if fetal parathyroid suppression takes a long time to recover.

Hypocalcemia

Hypoparathyroidism is very rare in pregnancy and is usually part of the autoimmune polyglandular syndrome, which would frequently be associated with mucocutaneous candidiasis and adrenal insufficiency. Maintenance of normocalcemia involves substantial oral supplementation with calcium and activated vitamin D (calcitriol). The doses of supplementation usually have to be increased, particularly in the third trimester, as there is high fetal uptake of calcium into the skeleton.

PITUITARY

Pituitary insufficiency

The differential diagnosis of pituitary insufficiency in the pregnant patient is diverse and is listed in Table 221-13.

The management of the pregnant woman with pre-existing pituitary insufficiency centers on adequate hormonal replacement. In general, thyroid hormone and cortisol requirements increase throughout pregnancy due to increased hepatic production of thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG). It is vital that fT4 rather than TSH level is monitored as the latter will always be low in patients with hypopituitarism. Hydrocortisone is generally the preferred glucocorticoid replacement therapy of choice as there is minimal transplacental passage to the fetus.

Mineralocorticoid replacement is not required in pituitary insufficiency as the renin-angiotensin-aldosterone axis is intact. Regular obstetrical follow-up with serial ultrasounds to detect IUGR is recommended.

Stress doses of glucocorticoids must be given at the time of labor and delivery; please refer to the section on Primary Adrenal Insufficiency for recommended doses.

See Chapter 222: Postpartum Consultation for Common Complaints on lymphocytic hypophysitis and Sheehan syndrome.

PROLACTINOMAS

It is uncommon for pregnancy to occur in women with untreated prolactinomas because hyperprolactinemia is associated with infertility. However, the ability of dopamine agonists to reduce prolactin levels to the normal range restores ovulation in about 90% of patients, many of whom are then able to achieve pregnancy.

Rising estrogen levels during pregnancy have a stimulatory effect on prolactin secretion that can cause the growth of the lesion. The risk is much higher for macroadenomas compared with microadenomas. For this reason, dopamine agonists are always discontinued once pregnancy is confirmed in someone with a microadenoma.

With macroadenomas, dopamine agonists are frequently continued throughout pregnancy in order to prevent tumor growth. Numerous studies have shown that there are no adverse effects on the fetus with the use of bromocriptine. There is much less data on cabergoline, but it is thought to be safe as well, though it is not favored in any case due to its longer half-life.

It is recommended that prepregnancy baseline visual field testing and MRI imaging of the pituitary be done for women with macroadenoma and that they be reviewed on a regular basis (every 4-6 weeks) throughout gestation for evidence of tumor expansion. There is no role for measuring prolactin levels throughout pregnancy as the levels increase in any case.

In the postpartum period, lactation has not been shown to increase the size of adenomas and is strongly encouraged.

Diabetes insipidus

The development of new-onset diabetes insipidus in the third trimester is usually due to increased vasopressinase activity either due to increased placental production or decreased hepatic vasopressinase metabolism due to liver damage from various causes including preeclampsia, acute fatty liver of pregnancy, or HELLP, syndrome. This phenomenon is called transient vasopressin-resistant diabetes insipidus (DI) of pregnancy.

Pre-existing central diabetes insipidus often worsens during pregnancy due to the increased clearance of endogenous vasopressin by increasing levels of vasopressinase. Subclinical central DI can also be unmasked for the first time during pregnancy due to this mechanism.

DDAVP is the treatment of choice for both central DI and transient vasopressin-resistant DI of pregnancy as it is not degraded by vasopressinase. Thiazide diuretics, which are used for the treatment of nephrogenic diabetes insipidus, are safe to be continued during pregnancy. Transient vasopressin-resistant DI of pregnancy tends to resolve a few days to weeks after delivery.

ADRENAL

Adrenal insufficiency

The most common cause is immune-mediated destruction of the adrenal cortex (Addison disease). This diagnosis should always be entertained in patients who have irretractable lethargy, nausea, and vomiting that is out of keeping with normal symptoms of pregnancy. A normal pregnancy outcome should be expected as long as the patient takes the appropriate dosages of glucocorticoids and mineralocorticoids; these doses often need to be increased slightly throughout pregnancy as rising progesterone levels act as antagonists to the glucocorticoid and mineralocorticoid receptors.

Hydrocortisone and prednisone are the preferred glucocorticoid replacement agents as their placental passage to the fetus is much lower compared with dexamethasone or betamethasone. Stress doses must always be administered in times of severe hyperemesis or physical stress as well as at the time of labor and delivery; please refer to Table 221-14 for a suggested protocol of the latter.

Pheochromocytoma

This condition can have profound effects on both mother and fetus and so it is important that it be considered as part of the differential diagnosis for hypertension in the pregnant woman, particularly in the first half of pregnancy.

Fasting plasma metanephrine levels are the most sensitive and specific diagnostic test, though it should be noted that the levels are slightly increased in pregnancy. Falsely elevated levels can be caused by pharmacologic agents such as tricyclic antidepressants, labetalol, and methyldopa.

Anatomic localization is required for definitive treatment once a biochemical diagnosis has been made. In pregnancy, the modality of choice to achieve this is MRI. Nuclear scanning with metaiodobenzylguanidine (MIBG) is contraindicated in pregnancy.

Medical therapy in the form of alpha-blockade should be initiated once a biochemical diagnosis is made; and the patient should be counseled that the benefits of alpha-blockade in pregnancy far outweigh any potential unknown effects. Beta-blockade is then instituted after alpha-blockade is achieved to avoid tachyarrhythmias; the dose should be titrated to achieve a maternal heart rate of 80 to 100 beats/min.

Surgery, in the form of laparoscopic adrenalectomy, can be considered once adequate medical therapy and localization of the lesion have been achieved. If the lesion is diagnosed during the first two trimesters, the best time to operate is during the second trimester, and if the lesion is diagnosed during the third trimester, surgery should be delayed until delivery though the timing of this will need to be brought forward if the mother remains symptomatic despite the medical blockade. An elective C-section is the delivery method of choice as the process of labor exacerbates the catecholamine surges.

Primary hyperaldosteronism

This condition is frequently unmasked in the postpartum period as the high progesterone levels during pregnancy antagonize the action of mineralocorticoids on their own receptors. Hypertension with hypokalemia is the classic presentation, though often the potassium level may be normal.

Both renin and aldosterone levels are increased during pregnancy. Therefore a suppressed renin level may be useful in diagnosing this condition during pregnancy. Medications that suppress renin levels such as β-blockers and calcium channel blockers need to be discontinued for at least 2 weeks before formal testing of renin and aldosterone levels.

It is recommended that spironolactone not be used in pregnancy due to its antiandrogenic effects; there is a theoretical risk that feminization of a male fetus may occur. Calcium channel blockers are regarded to be the most effective antihypertensive agent, as they have some effect in reducing aldosterone synthesis and release. If the hypertension and/or hypokalemia cannot be controlled medically, laparoscopic removal of the affected adrenal gland during the second trimester may be warranted.

DEPRESSION

Depressive disorders affect at least 12% of women at some time in their lives. In the United States, depression is the leading cause of nonobstetric hospitalization among women age 18 to 44 years. The peak period for onset of depression occurs during the childbearing years and its impact extends to the offspring and the families involved. Unfortunately, perinatal depression remains underdiagnosed and undertreated in ob-gyn and primary care settings. Furthermore, the diagnosis of depression in pregnant women can be challenging because there is great overlap between the diagnostic symptoms of depression and the symptoms of normal pregnancy.

A systematic review found prevalence rates of depression that vary from trimester to trimester: 7.4% in the first, 12.8% in the second, and 12% in the third trimester. Risk factors for depression in pregnancy include a previous depressive episode, recent negative life events, adolescence, unmarried status, financial disadvantage, African American or Hispanic ethnicity, and poor social support. Untreated depression can lead to harmful prenatal health behaviors such as poor nutrition, poor prenatal medical care, smoking, alcohol, and other substance use. The fetus of untreated depressed women may demonstrate abnormal neurobehavioral responses such as altered heart rate reactivity.

Obstetric complications associated with depression include preeclampsia, preterm delivery, low birth weight, miscarriage, ­small-for-gestational age babies, low Apgar scores, neonatal complications, and high neonatal cortisol levels at birth. Exposure to higher cortisol levels is thought to be the mechanism of the effect on later childhood development that may include language and cognitive impairment, sleep problems, impulsivity, attention deficit disorders, behavioral dyscontrol, and psychopathology.

ANTIDEPRESSANT USE AND PREGNANCY

How can depressive symptoms be treated during pregnancy? Depression in nonpregnant patients is mostly treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRI). Up to 9% of women have taken an antidepressant at some point during gestation, given that at least one-half of pregnancies are unplanned. Most of these exposures will be to one of the newer antidepressant medications. The odds ratio of 1.7 for spontaneous miscarriage with SSRI exposure, and reports of a 1.45 relative risk are within the range of the normal population.

Most meta-analyses report that newer antidepressants do not increase the risk of malformation rates above the 1% to 3% population baseline risk. The teratogenicity data from Denmark reports a 1.34 increased relative risk, but it does not control for underlying maternal psychiatric disorders. Small increased risk in omphalocele, craniosynostosis, and anencephaly with all SSRIs, and right ventricular outflow tract obstruction with paroxetine have been found in some other studies, but these findings were not replicated in other studies. Nevertheless, the Food and Drug Administration issued a public health advisory in 2005 regarding paroxetine and the FDA pregnancy category was changed from C to D.

Neonatal adaptation symptoms with maternal SSRI exposure have been reported. The syndrome described includes transient and usually mild jitteriness, poor muscle tone, weak or absent cry, respiratory distress, hypoglycemia, low Apgar scores, and possible seizures. The drugs with the highest association with the neonatal adaptations syndrome include paroxetine, fluoxetine, and venlafaxine, with one study reporting on citalopram as well. Long-term sequelae have not been systematically studied and an accurate blinded infant assessment as well as a neonatal behavioral symptom scale should be helpful in examining this syndrome more accurately.

A case control study published in 2006 showed an increased risk of persistent pulmonary hypertension of the newborn (PPHN) from a baseline of 1 to 2 per 1000, to 6 to 12 per 1000 for infants exposed to SSRI after 20 weeks of gestation. The authors of the study suggest that SSRIs may promote pulmonary artery constriction after birth by inhibiting nitric oxide or by a direct effect on pulmonary smooth muscle cells. These theories have been challenged, and furthermore, SSRI use before week 20 seemed to be a somewhat protective factor against PPHN, so it is difficult to advise patients about the absolute risk.

Other psychotropic medications and pregnancy

Benzodiazepines are used during pregnancy for management of anxiety or insomnia. Meta-analyses have identified a small increased risk of oral cleft with in utero exposure, though a case-control study failed to confirm this teratogenic risk. Pyloric stenosis and alimentary tract atresias have also been reported, as well as low birth weight and floppy infant syndrome.

If benzodiazepines need to be used, consider delaying treatment until after oral cleft closure and choose medications with shorter half-lives at the lowest possible dose.

Mood stabilizers are the most widely used medications for management of mood instability (mania, depression, and psychosis in bipolar patients) and include lithium and the antiepileptic medications. The main concern with first trimester exposure to lithium is an increased risk (0.1%) in Ebstein anomaly, which has a risk of 0.05% in the unexposed population. Lithium remains one of the preferred treatments for bipolar disorder and this increased risk needs to be weighed against the risk of a mood decompensation. Stable serum levels may require increase in dosages as the pregnancy progresses due to the normal changes in blood volume in pregnancy. Careful monitoring of dosage and lithium level at delivery is recommended to avoid toxicity.

Valproate has an increased risk of neural tube defects of 5% to 9% with first trimester exposure and a fetal valproate syndrome that includes cardiovascular abnormalities and developmental delays, and craniofacial abnormalities have been described. There is newer information that exposure to valproate later in gestation may be associated with neurobehavioral changes as well. Toxicity at birth with valproate may include decreased fibrinogen levels, liver toxicity, hypoglycemia, deceleration in heart rate, abnormal muscle tone, and lower IQ. Women of reproductive age who are planning to have children should be switched from valproate to another agent prior to pregnancy so that the disease can be controlled by an alternative agent before gestation.

Exposure to carbamazepine in the first trimester carries an increased risk of craniofacial abnormalities, fingernail hypoplasia, growth restriction, and a risk of neural tube defect of 0.5% to 1%.

Lamotrigene is associated with an increased risk of congenital malformations similar to the general population (2%-3%). Some studies have suggested an increased risk of cleft palate deformity and it is worth noting that infants with antigen characteristics that differ from the mother may be at increased risk for skin rash and liver toxicity.

Haloperidol is the most commonly used antipsychotic in pregnancy because several studies have not found increased risks of congenital malformations. Chlorpromazine has a poor side-effect profile in pregnancy due to orthostasis and sedation and has an increased risk of malformations of 2.4% and so should generally be avoided.

Newer antipsychotics are better tolerated than the above mentioned medications, but the data regarding safety with these is limited. Some studies have shown no increased risk of major malformations with olanzapine, risperidone, quetiapine, and clozapin but have found lower birth weight. Side effects of these medications can also be problematic in pregnancy, particularly weight gain and glucose intolerance.

Postpartum blues, depression, and psychosis

Between 15% and 85% of normal postpartum women may experience the blues (postpartum blues), which present within the first 10 days after giving birth with a peak incidence at the fifth day. It can be difficult to distinguish from a true depressive disorder given that symptoms include mood swings, mild elation, irritability, tearfulness, fatigue, and confusion. Women who experienced postpartum blues may have a history of premenstrual dysphoria and depression. No treatment is required other than improved sleep and support, but it can be a risk factor for postpartum depression.

The DSM IV classifies postpartum depression as a major depressive disorder with a specifier of postpartum onset within 1 month after childbirth. Screening with a specific tool such as the Edinburgh Postnatal Depression Scale (EPDS) is important since it emphasizes clinical domains of depression and may help differentiate from normal postpartum findings. Risk factors for postpartum depression include depression during or prior to the pregnancy, previous premenstrual dysphoria, stressful life events during the pregnancy, poor social support, marital conflict, low income, immigrant status, and young maternal age. It is thought that the etiology may be related to hormonal fluctuations, either as a direct influence in mood or due to their affect on sleep patterns in the postpartum period.

Postpartum psychosis is a true psychiatric emergency that occurs in 1 to 2 per 1000 births. The onset usually occurs within the first 4 weeks after delivery, although manifestations of the clinical picture can be present in the first 3 days postpartum. The cognitive disorganization that occurs with postpartum psychosis may result in a mother’s neglect of her infant’s needs and unsafe practices. It is highly associated with bipolar disorder and most of the time requires inpatient psychiatric hospitalization for rapid stabilization and decreased risk of suicide or infanticide. Patients present with acute confusion, delusions, and grossly disorganized behavior.

The use of antidepressants during lactation for treatment of PPD or other psychiatric disorders such as obsessive-compulsive disorder and panic disorder is an important clinical issue. The evidence on the effects of antidepressants during breastfeeding consists of small sample studies and case reports. It is important to take into account the amount of medication present in the breast milk, the reported adverse events, and the infant serum level of the drug to discuss recommendations with patients. Pooled analyses indicate that sertraline and paroxetine tend to have undetectable infant serum drug levels. Fluoxetine and citalopram were more likely to result in elevated breast milk levels. Of the tricyclic antidepressants, nortriptyline and imipramine have the largest serum level data showing levels that are not detectable. Doxepin, on the other hand, has been associated with sedation and respiratory depression and is considered contraindicated in breastfeeding women.

Antipsychotics and breastfeeding

Studies of the safety of both first- and second-generation antipsychotics are quantitatively insufficient to make specific recommendations regarding breastfeeding. Risperidone and chlorpromazine have the lowest degree of excretion in breast milk and there is only one case report of drowsiness with chlorpromazine. One antipsychotic, clozapine, is considered contraindicated with breastfeeding due to high infant-relative dosage and reported adverse effects.

The available data suggests that the amount of medications (anxiolytics) to which newborns are exposed is not very high; it is important to note that neonates metabolize these medications more slowly than adults and accumulation may occur, causing infant sedation, nausea, and poor feeding. Therefore, long-acting medications are not recommended, and the lowest possible dose of a short-acting benzodiazepine should be used if these medications are needed while breastfeeding.

NEUROLOGY

HEADACHES

In general, pregnancy does not have a consistent impact on the frequency or severity of migraine headaches and the onset of migraines may begin during pregnancy. Migraine that presents for the first time after 20 weeks’ gestation should prompt an investigation for preeclampsia. Pseudotumorcerebri is an unusual cause of headache that is more frequently seen in pregnant women. The fundoscopic examination will reveal papilledema but otherwise the neurologic examination will be normal. Increased intracranial pressure on the optic nerve may cause progressive visual loss. The postpartum period (defined as 6 weeks after delivery) but not pregnancy is associated with an increased risk of stroke and intracerebral hemorrhage, which may be related to thrombosis and/or preeclampsia.

EPILEPSY

Seizure disorders complicate approximately 1% of all pregnancies, and up to 10% of epileptic women will present for the first time during pregnancy. Not all seizures result from epilepsy. Both patients with and without known seizure disorders may have seizures as a consequence of preeclampsia or eclampsia, so investigation for preeclampsia is necessary for all third-trimester seizures.

Although most antiepileptic drugs have teratogenicity of various degrees, epileptic women have an increased risk of fetal malformations even without their administration. The maternal and fetal risk of uncontrolled seizures resulting in hypoxemia and acidosis must be part of any risk-benefit assessment of withdrawing effective treatment. If a patient has been seizure free for greater than a year, holding treatment first trimester in consultation with a neurologist could be considered.

The dosage of antiepileptic medications may be influenced by the increased volume of distribution and by increases in hepatic and renal clearance.

Valproate and carbamazepine are preferred in breastfeeding women, given the low degree of excretion in breast milk and limited reported adverse effects in infants. Lamotrigene has its own particular set of concerns. Even though only 60% of the drug is transferred to the breast milk, infants present with higher-than-expected drug levels when breastfed.

GASTROINTESTINAL DISEASE

ABDOMINAL PAIN

Gastroesophageal reflux disease occurs due to delayed gastric emptying and decreased gastroesophageal sphincter tone from progesterone effects on smooth muscle. Constipation is also common and related to the effects of progesterone upon the smooth muscle of the bowel. The differential of abdominal pain is broad and includes contractions, pain from adhesions interfering with expansion of the uterus into the abdomen, urinary retention, degenerating fibroid, ectopic pregnancy, ovarian torsion, stress on the round ligaments as the uterus expands, rupture of an ovarian cyst, and bleeding into a corpus luteal cyst. Late in pregnancy, uterine contractions, abruption placentae, pelvic arthropathy, and rarely rectus hematoma may occur.

Vomiting, pyelonephritis, appendicitis, cholecystitis, and rarely volvulus of the large bowel may also be seen during pregnancy.

CHOLELITHIASIS

Pregnancy is a risk factor for the development of cholesterol gallstones and biliary sludge. Higher estrogen levels increase biliary cholesterol secretion and higher progesterone levels decrease gallbladder smooth muscle motility. Preexisting gallstones are more likely to cause symptoms.

BUDD-CHIARI SYNDROME

Pregnancy-associated hypercoagulability is also a risk factor for hepatic vein thrombosis or the Budd-Chiari syndrome. Typically, patients suddenly develop abdominal pain and ascites after delivery.

JAUNDICE

Common causes of jaundice during pregnancy include cholestasis from raised estrogen levels, acute fatty liver of pregnancy, disseminated intravascular coagulopathy, severe preeclampsia, hyperemesis, and severe septicemia in late pregnancy. Drug effects (chlorpromazine, tetracycline, steroids), chronic liver disease, gall stones, and chronic hemolysis should also be considered.

LIVER DISEASE

Pregnancy-associated changes

Some of the physiologic changes of pregnancy can simulate laboratory abnormalities seen with liver disease. For example, serum albumin concentrations typically decrease from a mean of 4.2 g/dL in nonpregnant women without liver disease to 3.1 g/dL at the end of gestation due to an increase in plasma volume. Due to leakage of placental alkaline phosphatase into the maternal blood during the fifth month, typically serum alkaline phosphatase levels rise. Hepatosplenomegaly should not be found in the normal pregnancy and bilirubin, AST, ALT, and 5’nucleotidas, and γ-glutamyl levels should be normal. Telangiectasis of the chest, back, and face and palmar erythema may occur in up to 60% of normal pregnant women but should disappear after delivery. Acute fatty liver of pregnancy (AFLP) can lead to jaundice, liver failure, and death.

Diagnosis

The week of gestation may provide an important clue to the diagnosis. Liver diseases specifically associated with pregnancy occur at certain times. In the first trimester, nausea and vomiting with jaundice is consistent with hyperemesis gravidarum and AFLP has not been reported to occur during this time. Cholestasis of pregnancy typically presents at 30 weeks, usually with generalized pruritis, malaise, and fatigue due to symptoms being worse at night. Jaundice may develop in one-third to one-half of patients after the onset of pruritis. In 5% to 10% of pregnancies, liver diseases may develop with preeclampsia and eclampsia in the third trimester. In approximately 1 in 13,000 pregnancies, AFLP occurs in the third trimester.

The pattern of serum liver enzyme abnormalities may be helpful in establishing the diagnosis. The jaundice of cholestasis of pregnancy is usually not severe, less than 6 mg/dL along with elevated alkaline phosphatase levels three to four times the upper limit of normal in pregnancy and elevated serum bile acids. With preeclampsia and eclampsia, the liver injury is due to hepatocellular injury or ischemia so aminotransferase levels are more elevated than alkaline phosphatase or bilirubin. When patients develop abdominal pain, hypotension, fever, leukocytosis, nausea, and vomiting with abnormal liver tests in the third trimester, hepatic infarction, subcapsular hematoma, and hepatic rupture are rare complications of preeclampsia and eclampsia. AFLP is a disease of acute hepatocyte failure so laboratory tests may be initially unimpressively abnormal. If the serum transaminases rise to more than 10 times the upper limit of normal, alternative diagnoses should be considered. The prothrombin time and rising bilirubin are the most reliable indicators of hepatic failure.

Treatment

For patients with AFLP, supportive care and early delivery are critical due to the high fetal and maternal mortality. If hepatic failure is present, patients should be referred to a transplant unit early in the course. Likewise, the preferred treatment of patients with severe preeclampsia-related liver diseases is delivery.

Effect of chronic liver disease on pregnancy

Pregnancy does not alter the progression of chronic liver disease, but the outcome of the pregnancy may be influenced by the patient’s overall health, resulting in a higher incidence of miscarriage and prematurity.

HEMATOLOGIC CONDITIONS

SICKLE CELL DISEASE

Rates of severe preeclampsia, chest and urinary infections, and biliary disease are higher in pregnant patients with sickle cell disease. Even in high-risk perinatal clinics, the perinatal mortality rate and maternal mortality rate is increased.

VENOUS THROMBOEMBOLISM IN PREGNANCY

INCIDENCE

There is a five-fold increase in the incidence of venous thromboembolism in pregnancy that occurs at an incidence of 0.5 to 3 per 1000 pregnancies. VTE continues to be the leading nonobstetric cause of maternal death in the developed world. Thromboembolic events are evenly distributed throughout the three trimesters and the postpartum period, although more recent studies suggest a slightly higher incidence in the first trimester. In addition, because the postpartum period is by definition shorter (6 weeks, as compared to 12 weeks in a trimester), the day-to-day risk of VTE in the postpartum period is higher. The incidence of fatal pulmonary embolism is also higher in the postpartum period.

Pregnancy is a hypercoagulable state, characterized by an increase in levels of clotting factors, decrease in anticoagulant activity (lower levels of protein S and increased activated protein C resistance), and decreased fibrinolytic activity. In addition, stasis induced by venous compression by the gravid uterus and hormonal influence on vasculature further adds to the coagulant risk.

Risk factors that may contribute to the development of VTE in pregnancy include prolonged bed rest, cesarean section, obesity, parity >3, underlying thrombophilia, prior VTE, or preeclampsia.

The genetic predisposition to VTE may be identified by a positive family history in those patients for whom pregnancy is an additional risk factor.

Diagnosis

Clinical features of deep vein thrombosis (DVT) include pain and swelling in the affected leg, but it is important to remember that lower-extremity edema in pregnancy is common and is often asymmetric. Anatomy of the pelvic vasculature is such that the right iliac artery crosses over the left iliac vein. With the cardiovascular changes of pregnancy, there is compression of the left iliac vein by the right iliac artery, resulting in asymmetric lower-extremity edema (left greater than right) and the finding that the vast majority of DVTs occur in the left leg.

Symptoms of pulmonary embolism include dyspnea, chest pain that may be pleuritic, syncope, hemoptysis, and apprehension. Shortness of breath is a very common complaint in pregnancy, but tachypnea is always an abnormal finding. The diagnosis of PE should be considered in a dyspneic pregnant woman who is tachycardic and tachypneic.

Clinical diagnosis of DVT and PE in pregnancy is unreliable. Compression of pelvic veins by the gravid uterus can make interpretation of results difficult. In addition, isolated iliac vein thrombosis may not be picked up by routine methods of detection. D-dimers are known to be elevated in pregnancy. Clinical prediction rules for PE have not been validated in pregnancy. Pregnant patients with PE are younger and less likely to have comorbid conditions compared with nonpregnant patients, and generally appear “well” and in more than 60% of cases have normal arterial blood gases.

Doppler ultrasound is the noninvasive test of choice in the pregnant woman with suspected DVT. In symptomatic patients with a high pretest probability but a negative test, serial Dopplers should be done and an MRV of the pelvis should be considered to look for an isolated iliac clot. A recent study found that 60% of DVT in pregnancy is found in the proximal veins without evidence of calf thrombosis, suggesting that propagation from calf vein clots may not be the mechanism of proximal thrombosis in pregnancy. Chest x-ray and ECG are helpful in a patient with suspected PE to rule out other causes. Both ventilation-perfusion lung scan (V/Q scan) and CT angiogram can be safely used in pregnancy for diagnosis of PE. Fetal radiation exposure with either of these tests is minimal (Table 221-15). In the majority of cases of fatal PE in the UK. Confidential Enquiry into Maternal Mortality, the diagnosis was not made antemortem because of the mistaken belief that diagnostic testing would be harmful to the fetus. Pulmonary angiogram is usually reserved for severe cases in which localization of embolus is necessary prior to embolectomy.

Management

Treatment of VTE in pregnancy involves anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). Dosing is weight based, and may require increases with increasing gestation. Warfarin is a known human teratogen and its use in pregnancy is contraindicated for this indication. Table 221-16 lists medications for treatment of acute DVT and PE in pregnancy.

Most centers maintain patients on full therapeutic anticoagulation for the rest of their pregnancy until 6 weeks postpartum or at least 6 months, whichever is longer. Trials investigating lowering the intensity of anticoagulation after 4 to 12 weeks are currently underway, but this practice has not yet been validated in pregnancy. LMWH is the preferred agent in pregnancy, and has been associated with less thrombocytopenia and osteoporosis. Weight gain, increased blood volume, and increased clearance with pregnancy progression may require change in dosing, but this is usually guided by checking peak anti-Xa levels, which are done monthly.

Peripartum management of anticoagulation can be challenging. Epidural analgesia for pain control during labor or spinal anesthesia may be necessary for an operative delivery. Guidelines from the American society of Regional Anesthesia and Pain management (ASRA) recommend that in patients on therapeutic doses of LMWH, regional anesthesia be delayed at least 24 hours after last dose of LMWH injection to decrease the risk of spinal hematoma. This may be possible in a patient undergoing an elective induction of labor, but in most cases, the onset of labor cannot be predicted. We therefore switch the patient over to subcutaneous unfractionated heparin in the last month of pregnancy, two or three times a day, at a dose sufficient to keep the mid-interval aPTT approximately twice normal. The patient is instructed to stop heparin injections at the first sign of labor and aPTT is monitored closely once the patient is admitted to the hospital. Provided the aPTT is normal, regional anesthesia can be used with no contraindication. Following delivery, LMWH can be resumed 24 hours after removal of epidural or spinal catheter. In the postpartum period, warfarin can be safely used, even in breastfeeding mothers. Anecdotal evidence suggests that there is increased incidence of bleeding from surgical sites during the overlap of warfarin and LMWH. In patients who have had an operative delivery, we usually start warfarin 2 weeks after delivery, to avoid the risk of surgical bleeding.

Women with prior VTE are believed to have a higher risk of recurrent VTE in a subsequent pregnancy. There is evidence to suggest that this is especially true in patients whose first event was related to pregnancy, puerperium, or oral contraceptive use. An underlying thrombophilia and a family history of VTE are considered additional risk factors. Thromboprophylaxis is therefore recommended in these patients in subsequent pregnancies. Table 221-17 lists some anticoagulant prophylaxis regimens in pregnancy and the postpartum period. Prophylaxis needs to be continued for 6 weeks postpartum.

CONCLUSION

Any hospitalized patient of childbearing age contemplating children should have optimal medical management and counseling prior to becoming pregnant. Clinicians should take steps to identify coexisting diseases in the pregnant patient and complications of pregnancy before they become more severe. Optimally, management of medical problems requires prevention strategies to reduce progression of illness that would otherwise necessitate multiple medications, emergency treatment, and readmissions to the hospital. Team management of these patients with obstetric internists, high-risk obstetricians, and appropriate subspecialty consultation is recommended to achieve optimal medical status and function. Care of this unique population also requires optimal communication among team members so that it is clear who will be responsible for monitoring treatment and patient and family education.

SUGGESTED READINGS

INTRODUCTION

The postpartum period, lasting 6 months, is a unique time during which there is a physiological return to the prepregnancy state. Night sweats, mood disturbance, urinary frequency, perineal and vaginal discomfort, and breast engorgement are all common complaints from postpartum women. Clinicians treating postpartum patients in the hospital setting must be able to differentiate these normal changes from disease states.

POSTPARTUM FEVER

EPIDEMIOLOGY AND RISK STRATIFICATION

Low-grade fever frequently occurs in the first 24 hours after delivery. Postpartum fever is defined as a temperature of ≥ 38.0°C (100.4°F) on any two of the first 10 days postpartum exclusive of the first 24 hours. Infection is the leading cause of postpartum fever in the United States; the overall postpartum infection rate is around 6%, with the incidence in planned cesarean deliveries up to 10%, and higher in unplanned deliveries. Endometritis is the most common infection in the postpartum period, followed by urinary tract infection, lower genital tract infection, wound infection, pulmonary infection, thrombophlebitis, cholecystitis, and breast infections. Mastitis and abscess are rare in women who do not breastfeed but occur in 2% to 3% of breastfeeding women. A recent pregnancy also increases the risk for pneumonia, appendicitis, and cholecystitis.

EVALUATION AND INPATIENT MANAGEMENT

POSTPARTUM ENDOMETRITIS

Postpartum endometritis is typically a polymicrobial infection with lower genital tract flora infecting the upper genital tract. The prevalence of endometritis has been greatly reduced with the standard use of antibiotic prophylaxis with cesarean deliveries. The risk of endometritis is increased by various factors listed in Table 222-1.

The criteria for diagnosis of endometritis include fever and uterine tenderness. Other signs and symptoms include foul lochia and chills. The postpartum uterus should be firm, nontender, and below the umbilicus; with endometritis a soft, subinvoluted uterus may lead to excessive vaginal bleeding.

When endometritis is suspected, laboratory or imaging data are rarely needed before initiating treatment. If despite treatment, a patient has persistent fever or unusually severe or localized pain, further studies may be helpful. A white blood cell with differential, blood cultures (which are positive in 10%-20% of patients), and endometrial cultures may be diagnostic and can help direct antimicrobial therapy. Endometrial cultures should be acquired with a double or triple lumen technique to prevent vaginal and cervical contamination. Pelvic ultrasonography can identify retained products of conception, which need to be removed by dilatation and curettage because they are an ongoing nidus of infection. Computed tomography (CT) or magnetic resonance imaging (MRI) is used to diagnose alternative causes of persistent pain and fever including ovarian vein thrombosis, abscess, or hematoma. Please refer to a full discussion of ovarian vein thrombosis in Chapter 221 (Common Medical Problems in Pregnancy).

The most common infectious agents when endometritis is suspected in the first 24 to 48 hours postpartum are ­Gram-positive cocci (predominantly group B streptococci, ­Staphylococcus epidermidis, and Enterococcus spp.) or Gram-negative bacteria (predominantly Gardnerella vaginalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis). After 48 hours, involvement of anaerobic bacteria (predominantly peptostreptococci, ­Bacteroides spp., and Prevotella spp.) is likely, and by 7 days, Chlamydia trachomatis is often found. The treatment regimen for postpartum endometritis includes broad-spectrum parenteral antibiotics. In the first 48 hours after delivery, the recommended regimen is clindamycin (900 mg every 8 hours) plus gentamicin (1.75 mg/kg every 8 hours or 5 mg/kg every 24 hours). If there is persistent fever or enterococcus is suspected, ampicillin or vancomycin in penicillin allergy should be added. Alternative regimens include cefotetan, cefoxitin, piperacillin/tazobactam, and ampicillin/sulbactam. Treatment continues until a patient has been afebrile for 48 hours and uterine tenderness has resolved. Oral therapy after parenteral therapy is not recommended as there is no evidence for improved outcome or decreased risk of recurrence. However, patients with bacteremia confirmed by positive blood cultures should complete a 7- to 10-day course of antibiotics. Late postpartum endometritis (48 hours-6 weeks postpartum) may be treated with oral metronidazole and doxycycline (100 mg IV or orally every 12 hours) for 14 days.

BREAST INFECTION

The majority of postpartum patients experience breast discomfort with swollen, firm, and tender breasts. Simple engorgement causes low-grade fevers without any other clinical signs of infection and typically resolves within 48 hours. The patient with a breast infection may describe chills, flu-like symptoms, and have high fevers (102^°F-104^°F). Mastitis causes localized erythema and swelling with a cellulitic appearance. A breast abscess is characterized by fluctuance and diffuse erythema, with a localized area of tenderness.

The most frequent pathogen in postpartum breast infection is Staphylococcus aureus and toxic shock has been reported with mastitis in the postpartum period. Other less common pathogens include β-hemolytic streptococci, Haemophilus influenzae, ­Haemophilus parainfluenzae, E. coli, and K. pneumoniae.

Clinical evaluation includes culture of expressed breast milk and aspirated fluid if there is a fluctuant mass. Prompt antibiotic treatment is required and should continue for 7 days or until resolution of infection. Recommended antibiotic coverage includes clindamycin 300 mg orally three times a day, dicloxacillin 500 mg orally every 6 hours, or cephalexin 500 mg orally every 6 hours. Alternative regimens include amoxicillin/clavulanate 875 mg orally every 12 hours or azithromycin 500 mg orally initially, then 250 mg orally daily. If methicillin-resistant S. aureus (MRSA) is suspected then TMP-SMX-DS orally every 12 hours or vancomycin 1 g IV every 12 hours are recommended.

For mastitis, the patient should be encouraged to avoid milk stasis by continuing to nurse or pump expressed milk. Hot compresses also aid in comfort and expression of milk. Patients should be closely followed as an abscess can develop even after antibiotics have begun. If a patient has a breast abscess, then incision and drainage or needle aspiration may be warranted. Patients with breast abscesses should be advised to discontinue breastfeeding until after drainage is performed, if indicated, and signs of infection are resolved. In communities with a high rate of MRSA, it is found in up to 50% of women with postpartum breast abscesses.

POSTACUTE CARE AND DISCHARGE CHECKLIST

Once diagnosis is confirmed and treatment established the febrile postpartum patient should have postdischarge follow-up with an outpatient provider. The patient should be aware of the medication instructions and expected course of the infection. A patient should also be warned of the symptoms such as recurrent fever, pain or intolerance to medications that prompt immediate medical attention.

POSTPARTUM HEADACHE

RISK STRATIFICATION

Hormonal fluctuations, sleep deprivation, and anxiety all contribute to the increased frequency of headaches in the postpartum period. The differential diagnosis of headache varies from minor to ­life-threatening causes and therefore warrants a prompt and thorough clinical evaluation. Alarm symptoms that warrant emergent evaluation with neurologic imaging include headache of acute onset, abnormal or focal neurologic findings, seizure, and/or decreased level of consciousness. If a postpartum patient has a new Horner’s syndrome, the anterior and posterior circulation should be imaged at the same time to rule out dissection. The hypercoagulable state present during pregnancy and postpartum is a significant risk factor for thrombosis, including cerebral venous thrombosis. Additional risk factors include thrombophilia, cesarean section, anemia, dehydration, and infection.

EPIDEMIOLOGY

Migraines have an increased predominance in the postpuberty years of females over males, suggesting a role of ovarian sex hormones in their pathogenesis. It is thought that migraines may be trigged by the decline of estrogen levels after a period of elevated estrogen, which occurs during the menstrual and postpartum periods. The majority of women who suffer from migraines have an improvement during pregnancy, and 30% to 50% of women experience a recurrence postpartum. Tension-type headaches (TTHSs) are the most common type of headaches in adulthood. Similar to migraines, there is a female predominance in TTHS prevalence, suggesting a female sex hormone contribution to their pathophysiology. There are fewer studies on TTHS in pregnancy compared with migraines, but remission in pregnancy and recurrence in postpartum has been suggested. The accidental dural puncture (ADP) rate with epidural insertion is rare amongst practiced obstetric anesthesiologist (<2%). However when ADP occurs the headache incidence is 60% to 80%. The incidence of cerebral vein thrombosis (CVT), subarachnoid hemorrhage, and posterior reversible encephalopathy syndrome (PRES), especially in association with preeclampsia, increases in the postpartum period. In adulthood, CVT is more common in women than men, with 75% of cases found in women.

EVALUATION AND INPATIENT MANAGEMENT

Table 222-2 summarizes the differential diagnosis of postpartum headache along with common features, and modes of evaluation or treatment.

POSTACUTE CARE AND DISCHARGE CHECKLIST

Depending on the nature of the headache in postpartum, a patient may warrant follow-up with a headache specialist for long-term management and prevention. A patient should be warned of the risk for medication overuse headaches if treatments such as acetaminophen or NSAIDs are used on a daily basis.

POSTPARTUM NEUROPATHIES

EPIDEMIOLOGY AND RISK STRATIFICATION

Neuropathies are common in the postpartum period. An inpatient postpartum woman with new neurologic complaints warrants a thorough history and physical exam to rule more ominous causes of neurologic changes such as a stroke.

EVALUATION AND INPATIENT MANAGEMENT

Bell’s palsy

Bell’s palsy, facial nerve palsy, is caused by compression or ischemia to the nerve. Bell’s palsy is most commonly seen in the third trimester, but can be seen in the postpartum period. After careful examination, treatment includes reassurance, as the majority of patients gradually improve within 3 months. Corticosteroids and antivirals should be considered for treatment to shorten the course and limit long-term sequelae. Both have been used safely in pregnancy. Bell’s palsy may be a presenting feature of preeclampsia, probably related to edema. All patients with Bell’s palsy are at risk for eye dryness and corneal injury, therefore artificial tears during the day and a lubricant at night is recommended.

Carpal tunnel syndrome (CTS)

The edema from fluid retention in pregnancy can predispose women to median nerve entrapment causing CTS. The symptoms can first present in the postpartum period and may last until after weaning in breastfeeding women. Due to the transient nature of CTS in the postpartum period, conservative management is recommended. This includes wrist splints, modifications of daily activities that exacerbate symptoms, and NSAIDs. As in nonpregnant patients, hypothyroidism should be excluded.

de Quervain tenosynovitis

Stenosing tenosynovitis of the first dorsal compartment of the wrist, known as de Quervain tenosynovitis, may occur during the postpartum period due to repetitive activities in newborn care. Ice and NSAIDs and physical and/or occupational therapy may be used for symptomatic relief.

Lumbosacral spine and lower-extremity nerve injuries

While rare, stretch and compression nerve injuries may occur during vaginal and cesarean section deliveries. Risk of these injuries is increased by prolonged labor and fetal macrosomia or malposition. Lateral femoral cutaneous nerve injury (also known as meralgiaparesthetica) is a sensory-only deficit of the anterolateral thigh that is a common postpartum complaint. Femoral nerve injury can cause decreased sensation in the anterolateral thigh and medial calf along with impaired knee extension. Common peroneal nerve injury causes decreased sensation at the anterloateral calf and dorsum of the foot and foot drop. Obturator nerve injury causes decreased sensation to the medial thigh and decreased adduction of the leg. Prognosis from these injuries is typically good, and physical therapy may play a role in recovery.

POSTACUTE CARE AND DISCHARGE CHECKLIST

The postpartum patient should be advised of the expected duration for their neuropathy symptoms and told when to seek medical attention if symptoms worsen or fail to resolve. If medication is needed for symptom relief, clinicians should consider medication metabolism as the patient returns to the prepregnancy state, and how these and any new medications may impact the breastfed infant.

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