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.
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.
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.
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.
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.
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.
TABLE 221-1Suggested Antimicrobial Regimens for the Treatment of Pyelonephritis in Pregnancy ||Download (.pdf) TABLE 221-1 Suggested Antimicrobial Regimens for the Treatment of Pyelonephritis in Pregnancy
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.
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.
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 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.
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.
TABLE 221-2Recognized Causes of Acute Bronchitis and Treatment Options ||Download (.pdf) TABLE 221-2 Recognized Causes of Acute Bronchitis and Treatment Options
|Pathogen ||Comments ||Treatment Options in Pregnancy |
|Influenza virus ||Precipitous onset with fever, chills, headache, cough and myalgias ||Antiviral agents recommended for treatment of influenza have either very little or concerning pregnancy safety data. With the H1N1 pandemic, pregnant women have been found to be at increased risk of complications and treatment with oseltamivir 75 mg orally twice daily is recommended |
|Parainfluenza virus ||Epidemic may occur in fall. Croup in a child at home suggests the presence of this organism ||No treatment available |
|Respiratory syncytial virus ||Outbreaks occur in winter or spring. Approximately 45% of adults exposed to an infant with bronchiolitis become infected ||No treatment available |
|Coronavirus ||Severe respiratory symptoms may occur ||No treatment available |
|Adenovirus ||Infection is clinically similar to influenza, with abrupt onset of fever ||No treatment available |
|Rhinovirus ||Fever is uncommon, infection is generally mild. ||No treatment available |
|Bordetella pertussis ||Incubation period is 1-3 wk. Post-tussive vomiting may be present. Fever is uncommon || Azithromycin for 5 d (500 mg on day 1, 250 mg days 2-5) or Erythromycin for 14 d (500 mg 4 times daily) or Trimethoprim/Sulfamethoxazole for 14 d (160/800 mg twice daily) |
|Mycoplasma pnemoniae ||Gradual onset over 2-3 d of headache, fever malaise, and cough. Wheezing may occur. Dyspnea is uncommon ||Azithromycin for 5 d (500 mg on day 1, 250 mg days 2-5) or no therapy |
|Chlamydia pneumoniae ||Gradual onset of cough with preceding hoarseness ||Azithromycin for 5 d (500 mg on day 1, 250 mg days 2-5) or no therapy |
There are no compelling data suggesting improved outcomes of acute bronchitis as a result of treatment with antibiotics.
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]).
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.
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.
TABLE 221-3Recommendations for Treating Pneumonia in Pregnancy ||Download (.pdf) TABLE 221-3 Recommendations for Treating Pneumonia in Pregnancy
|Type of Pneumonia ||Recommended Antibiotics Acceptable for Use in Pregnancy ||Comments |
Ceftriaxone (2 g IV daily) or cefotaxime or ampicillin/sulbactam (3 g IV every 6 h)
Macrolide (azithromycin, erythromycin)
If concern for MRSA, add vancomycin (15 mg/kg every 12 h)
Avoid tetracycline and doxycycline in pregnant or breastfeeding mothers
Antipneumococcal fluoroquinolone may be used in nonpregnant patient but generally avoided in pregnancy or breastfeeding mothers
Hospital-acquired pneumonia/health care-associated pneumonia/ventilator-associated pneumonia
Aerobic Gram-negatives (P. aeruginosa, Escherichia coli, Klebsiella pneumoniae, Acinetobacter spp.)
Gram-positive cocci Staphylococcus aureus, especially methicillin resistant (MRSA)
Oropharyngeal commensals (viridans group strep, coagulase negative staph, Neisseria spp., Corynebacterium spp.)
Ceftriaxone(2 g IV daily) or ampicillin/sulbactam (3 g IV every 6 h)
If concern for MDR:
Ceftazidime (2 g IV every 8 h) or cefepime (2 g IV every 8 h) or imipenem (500 mg every 6 h) or piperacillin/tazobactam (4.5 every 6 h) or aztreonam (2 g every 6-8 h)
Gentamycin or tobramycin
Vancomycin (15 mg/kg every 12 h)
|Efficacy of once daily dosing for gentamycin in pregnancy not well established |
Oropharyngeal commensals (viridans group strep, coagulase negative staph, Neisseria spp., Corynebacterium spp.)
|Clindamycin or Penicillin || |
|Varicella pneumonia ||Acyclovir IV 10 mg/kg every 8 h || |
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.
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.
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.
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 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 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.
Management of asthma exacerbations during pregnancy and lactation: Emergency department and hospital-based care. FEV1, forced expiratory volume in 1 second; MDI, metered-dose inhaler; PCO2, carbon dioxide partial pressure; PEF, peak expiratory flow. (From the Asthma and Pregnancy Report. NAEPP Report of the working group on Asthma and Pregnancy. NIH publication No. 93-3279. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute 1993. Available from URL: http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.txt.)
TABLE 221-4Safety of Asthma Medications in Pregnancy ||Download (.pdf) TABLE 221-4 Safety of Asthma Medications in Pregnancy
|Medication Type ||Data Suggests Use Justifiable When Indicated ||Data Suggests Use Justifiable in Rare Circumstances ||Data suggests Use Almost Never Justifiable ||Useful Review Articles and Comments |
|Short-acting inhaled beta-2 adrenergic agonists || |
| || ||Published experience with these drugs in animals and humans suggests that beta-sympathomimetics do not increase the risk of congenital anomalies. Albuterol is the most studied of these agents. Metaproterenol is the second most studied. NAEP guidelines for the management of asthma in pregnancy can be obtained through the NHLBI at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm |
|Long-acting inhaled beta-2 adrenergic agonists || |
| || ||Of the few studies that have examined pregnancy outcomes with prenatal exposure to long-acting beta-2 agonists, no adverse events were found. However, due to small numbers in the studies, and because animal models have shown delayed ossification, use of this agent should be reserved for patients who have failed low potency steroids and/or cromolyn alone |
|Xanthines || |
| || ||These drugs do not appear to be human teratogens. The clearance of aminophylline and theophylline is increased in pregnancy but may be variable. If daily dose exceeds 700 mg, blood levels should be checked for optimal dosing |
|Inhaled corticosteroids || |
Low potency: beclomethasone dipropionateC
Medium potency: trimacinolone acetonideC
High potency: fluticasone propionateC budesonideB flunisolideB
| || || |
Beclomethasone and budenoside are the most widely studied of the inhaled corticosteroids in pregnancy and should be considered the preferred inhaled steroids in pregnancy. Relatively little of these agents are absorbed and human data has not suggested any teratogenic effects of these agents
Triamcinolone is the next most studied inhaled steroid in pregnancy, with this limited experience suggesting no adverse pregnancy effects
Fluticasone has not been studied in pregnancy; however its minimal systemic absorption and the safety of the other steroids in pregnancy make its use in pregnancy generally felt to be justifiable
|Systemic steroids ||prednisoneC methylprednisoloneC dexamethasoneC hydrocortisoneC || || || |
Most data suggest that systemic steroids do not present a teratogenic risk in human pregnancy. In doses equivalent to prednisone 25 mg/d, they do not cross the placenta because of placental metabolism (the same is not true for betame-thasone or dexamethasone). Even in higher doses, the effect of hydrocortisone or prednisone on the fetus in terms of suppression of the hypothalmo-pituitary-adrenal axis is minimal
Several case control studies have found a significant association with first trimester steroid use and oral clefts; however this was not seen in cohort studies. Even if this association is real, the risk is still small. For every 1000 embryos exposed during the susceptible days of first trimester, probably no more than three will develop an oral cleft. The background risk in the general population is 1 per 1000. Therefore, the benefits of controlling a life-threatening disease make steroid use when indicated in the first trimester still generally justifiable
|Mast cell stabilizers ||Cromolyn sodiumB NedocromilB || || ||Human and animal data suggest these agents are not teratogens. These agents are virtually not absorbed through mucosal surfaces and the swallowed portion is largely excreted in the feces |
|Inhaled anticholinergics ||IpratropiumB || || ||Although animal studies are reassuring, no published human data exists. These drugs are poorly absorbed by the bronchial mucosa so fetal exposure is likely minimal |
|Leukotriene inhibitors || ||ZafirlukastB MontelukastB OmalizumabB ||Zileuton B ||Although these agents have reassuring animal data and are widely used in pregnancy because of the FDA category B rating, published safety data in human pregnancy is limited at this point. Their use should be limited in pregnancy to those cases in which a woman has had significant improvement in asthma control with these medications prior to becoming pregnant that was not obtainable through other methods. Zileuton is different than other agents in this class as there is some animal data to suggest association with adverse pregnancy outcomes |
|Antihistamines || |
DiphenhydramineB (but avoid in first trimester)
| ||While the newest generation antihistaminic agents are widely used in pregnancy and have not had any concerning animal data associated with them, we still consider them to be second-line agents in pregnancy because of the lack of published human pregnancy safety data about them |
|Cough || |
| || || |
|Nasal congestion || |
| || || |
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.
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 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.
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.
Eighty-five percent of all ARDS cases result from four causes, with sepsis being the most common:
In the obstetric patient, several causes unique to pregnancy have to be considered. These are listed in Table 221-5.
TABLE 221-5Causes of Acute Respiratory Distress Syndrome Unique to Pregnancy ||Download (.pdf) TABLE 221-5 Causes of Acute Respiratory Distress Syndrome Unique to Pregnancy
Tocolytic induced pulmonary edema
Acute fatty liver of pregnancy
Amniotic fluid embolism
Retained products of conception
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.
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.
TABLE 221-6Diagnostic Tests Indicated in the Obstetric Patient with Acute Lung Injury ||Download (.pdf) TABLE 221-6 Diagnostic Tests Indicated in the Obstetric Patient with Acute Lung Injury
CBC with differential white blood cell count: Rule out anemia as a contributing factor and look for bandemia, suggesting infection
Creatinine and BUN: rule out renal failure
PTT, fibrinogen, and FDP: Look for evidence of amniotic fluid embolism
AST, uric acid, and urine protein creatinine ratio (in addition to CBC and creatinine mentioned above): Look for evidence of preeclampsia
Blood and urine cultures in all patients with fever or bandemia
Urine drug screen: Look for evidence of cocaine or narcotics as a cause
Echocardiogram: Rule out underlying cardiac cause for pulmonary edema or evidence of cardiac compromise in preeclampsia
TABLE 221-7Salient Features in Management of Acute Respiratory Distress Syndrome in Pregnancy ||Download (.pdf) TABLE 221-7 Salient Features in Management of Acute Respiratory Distress Syndrome in Pregnancy
Supplemental oxygen to maintain maternal oxygen saturation above 95%
Consider intubation for PaO2 < 70 mm Hg or PaCO2 > 45 mm Hg on 100% oxygen
Look for precipitating causes listed in Table 221-5 in addition to sepsis, massive transfusion, aspiration of gastric contents, or trauma
Appropriate diagnostic testing as listed in Table 221-6
Immediate discontinuation of tocolytic therapy when applicable
IV furosemide 10-20 mg
IV antibiotics if infection suspected
Echocardiogram to rule out cardiac cause for pulmonary edema
Consider afterload reduction with sodium nitroprusside or hydralazine if patient is pregnant, and angiotensin converting enzyme inhibitors or angiotensin-receptor blockers in the postpartum 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 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.
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.
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.
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.
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).
TABLE 221-8Severity Ranges of Creatinine in Pregnancy ||Download (.pdf) TABLE 221-8 Severity Ranges of Creatinine in Pregnancy
|Severity ||Creatinine Range (mg/dL) |
|Mild ||0.9-1.4 |
|Moderate ||1.4-2.9 |
|Severe ||3.0 or greater |
Acute renal injury can result from prerenal, intrarenal, or postrenal causes (see Table 221-9).
TABLE 221-9Causes of Renal Failure in Pregnancy ||Download (.pdf) TABLE 221-9 Causes of Renal Failure in Pregnancy
Blood loss resulting from abrution, postpartum hemorrhage, placenta previa
Volume contraction: preeclampsia, eclampsia, hyperemesis
Infection: sepsis resulting from pyelonephritis, chorioamnionitis, endometritis, septic abortion
HELLP; acute fatty liver of pregnancy, TTP; HUS; amniotic fluid embolism
Obstruction from pelvic hematoma, damage to ureters during cesarean section, ureteral stones or strictures, compression by gravid uterus or tumor
Related to underlying disease: Lupus nephritis, scleroderma crisis, antiphospholipid antibody syndrome
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).
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 represent one of the most common medical problems in pregnancy and encompass the diagnoses of chronic hypertension, gestational hypertension, and preeclampsia.
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.
TABLE 221-10Pharmacologic Treatment of Hypertensive Urgency in a Pregnant Woman ||Download (.pdf) TABLE 221-10 Pharmacologic Treatment of Hypertensive Urgency in a Pregnant Woman
|Medication ||Onset of Action and Duration of Action ||Acute Dosing for Severe Hypertension ||Maintenance Dose |
|Labetalol || |
Begins to work in 5-10 min
Lasts 3-6 h
Labetalol is given as a series of boluses until BP comes down to the desired level:
10 mg IV push
Then in 10 min, 20 mg IV push
Then in 10 min, 40 mg IV push
Then in 10 min, 80 mg IV push
Then in 10 min, 80 mg IV push up to a total dose of no more than 300 mg total
Then followed with oral labetalol or a labetalol drip
Oral labetalol 100-200 mg 2-3 times a day (100-600 mg 2-3 times a day; maximum 2400 mg/d)
IV labetalol infusion 0.5-2.0 mg/min (Labetalol comes in vials of 100 mg/20 mL)
Put 5 vials (100 mL) of labetalol into 150 mL of IV fluid (D5W/LR/NS) to get a solution of 2 mg/mL
Start at 15 mL/h (0.5 mg/min)
Titrate up to as high as 60 mL/h (2 mg/min)
|Nifedipine || |
Begins to work in < 30 min
Lasts 4-5 h
|10-20 mg orally every 30 min to a maximum of 50 mg ||Maintenance 10-20 mg orally 3 times a day of the short-acting or 30-120 mg once daily of long-acting formulation |
|Hydralazine || |
Begins to work in 10-20 min
Lasts for 3-6 h
|2.5-10 mg IV every 30 min ||Maintenance dose starts at 10 mg orally 4 times a day and can be gradually increased to 50 mg orally 4 times a day |
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 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.
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.
TABLE 221-11Lab Abnormalities in Pre-eclampsia ||Download (.pdf) TABLE 221-11 Lab Abnormalities in Pre-eclampsia
Hemoglobin > 12 g/dL (normally near 10 g/dL in pregnant women near term)
Platelet count < 150,000/mm3
Elevated liver enzymes (AST and ALT)
Creatinine > 0.8 mg/dL (normal for pregnancy 0.5-0.7 mg/dL)
Uric acid > 0.5 mg/dL
24-h urine collection with > 300 mg of protein
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.
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.
TABLE 221-12Labor and Delivery Sample Admission Orders for Severe Pre-eclampsia ||Download (.pdf) TABLE 221-12 Labor and Delivery Sample Admission Orders for Severe Pre-eclampsia
Bed rest with seizure precautions
Vital signs (blood pressure, pulse, respiration); deep tendon reflexes; and mental status every 15-60 min until stable, then every 60 min while on magnesium sulfate
Accurate intake and output; Foley catheter if needed
Administer lactated Ringer solution at 75 mL/h IV to maintain urine output of 30-40 mL/h; total intake (IV and oral) should not exceed 125 mL/h or 3000 mL/d
Continuous fetal heart rate monitoring
Dipstick urine collection for protein level on admission
24-h urine collection for total protein level
CBC with platelets, peripheral blood smear
BUN, creatinine, uric acid
AST, ALT, LDH
Fetal evaluation: nonstress test on admission; obstetric ultrasonography for estimated fetal weight, amniotic fluid volume, and umbilical artery Doppler measurements
Loading dose of 4-6 g diluted in 100 mL of normal saline, given IV over 15-20 min, followed by a continuous infusion of 2 g/h
Assess serum magnesium level if urine output is < 30 mL/h or there is a loss of deep tendon reflexes, decreased respiratory rate, or altered mental status
Therapeutic range for serum magnesium is 4-7 mg/dL
Corticosteroids (if between 24 and 34 wk of gestation and not previously administered)
Betamethasone (Celestone), 12 mg IM initially, then repeat in 24 h
Dexamethasone, 6 mg IM initially, then repeat every 12 h for three additional doses
For systolic blood pressure > 160 mm Hg or diastolic > 110 mm Hg, one of the following should be given to achieve a systolic measurement of 140-155 mm Hg and/or a diastolic measurement of 90-105 mm Hg
Hydralazine, 5-10 mg IV every 15-30 min (maximal dose: 30 mg)
Labetalol, 20 mg IV initially; if the initial dose is not effective, double the dose to 40 mg and then 80 mg at 10-min intervals until target blood pressure is reached or a total of 220 mg has been administered; the maximal dose of IV labetalol is 220 mg in a 24-h period
Calcium gluconate, 1 g IV; keep at bedside in case of respiratory depression from magnesium sulfate use
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.
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.
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.
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 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.
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.
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.
The differential diagnosis of pituitary insufficiency in the pregnant patient is diverse and is listed in Table 221-13.
TABLE 221-13Causes of Hypopituitarism in the Pregnant Patient ||Download (.pdf) TABLE 221-13 Causes of Hypopituitarism in the Pregnant Patient
Pre-existing before Pregnancy
Infiltrative disorders (hemochromatosis, sarcoidosis, amyloidosis)
Hypothalamic tumors (craniopharyngiomas, germinoma, meningioma, glioma)
Eosinophilic granuloma (histiocytosis X)
Prior surgical or radiotherapy treatment
During Pregnancy or Postpartum
Sheehan syndrome (peripartum necrosis)
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.
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.
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.
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.
TABLE 221-14Stress Dose Steroids During Surgery or Delivery ||Download (.pdf) TABLE 221-14 Stress Dose Steroids During Surgery or Delivery
Hydrocortisone 100 mg IV on call to operating room or at onset of labor
Hydrocortisone 100 mg IV every 8 h over course of surgery or labor and delivery
Hydrocortisone 50 mg IV every 8 h day 1 postoperative or postpartum
Hydrocortisone 25 mg orally every 8 h day 2 postoperative or postpartum
Usual preadmission doses of hydrocortisone orally from day 3 postoperative or postpartum
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
TABLE 221-15Fetal Radiation Exposure with Maternal Testing ||Download (.pdf) TABLE 221-15 Fetal Radiation Exposure with Maternal Testing
|Study ||Radiation Exposure (RADS) |
|Chest x-ray ||<.001 |
|Lung scan || |
|Pulmonary angiogram || |
<.050 via brachial route
0.2-0.3 via femoral route
|CT angiogram ||0.2-0.3 |
|Ultrasound ||None |
|MRI/MRA/MRV ||None |
|Upper GI series ||0.1 |
|Lumbar spine series ||0.9 |
|Barium enema ||1 |
|Complete IVP ||0.5 |
|Head CT ||<0.01 |
|CT abdomen ||2.0-3.0 |
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.
TABLE 221-16Medications for Treatment of Venous Thromboembolism in Pregnancy ||Download (.pdf) TABLE 221-16 Medications for Treatment of Venous Thromboembolism in Pregnancy
|Drug ||Dose ||Route ||Frequency |
|Unfractionated heparin ||80 units/kg bolus, then 18 units/kg/h ||Intravenous ||Continuous, with dose adjustment using a PTT values |
|Enoxaparin ||1 mg/kg ||Subcutaneous (SQ) ||Every 12 h. Due to increased clearance once daily dosing at 1.5 mg/kg may not be adequate |
|Tinzaparin ||175 units/kg ||SQ ||Every 24 h |
|Dalteparin ||200 units/kg ||SQ ||Every 24 h |
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.
TABLE 221-17Suggested Regimens for Thromboprophylaxis in Pregnancy ||Download (.pdf) TABLE 221-17 Suggested Regimens for Thromboprophylaxis in Pregnancy
Enoxaparin 40 mg SQ once daily until 20 wk gestation, then 40 mg twice daily. At 36-wk gestation, switch to UFH 10,000 units SQ twice daily until delivery
UFH 5000 units SQ twice daily in the first trimester, 7500 units SQ twice daily in the second trimester, and 10,000 units SQ twice daily in the third trimester
Suggested regimens for postpartum prophylaxis
Enoxaparin 40 mg SQ once daily
Warfarin, with target INR of 1.5-2
UFH 5000 units SQ twice daily
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.
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