Sixty-five percent of newborns develop visible jaundice with a total serum bilirubin (TSB) level higher than 6 mg/dL during the first week of life. Bilirubin, a potent antioxidant and peroxyl scavenger, may protect the normal newborn, who is deficient in antioxidants such as vitamin E, catalase, and superoxide dismutase, from oxygen toxicity in the first days of life. Approximately 8%–10% of newborns develop excessive hyperbilirubinemia (TSB > 17 mg/dL), and 1%–2% have TSB above 20 mg/dL. Extremely high and potentially dangerous TSB levels are rare but can cause kernicterus, characterized by injury to the basal ganglia and brainstem.
Kernicterus caused by hyperbilirubinemia was common in neonates with Rh-isoimmunization until the institution of exchange transfusion for affected infants and postpartum high-titer Rho (D) immune globulin treatment to prevent sensitization of Rh-negative mothers. For several decades after the introduction of exchange transfusion and phototherapy aimed at keeping the neonate’s TSB below 20 mg/dL, there were no reported cases of kernicterus in the United States. Since the early 1990s, however, there has been a reappearance of kernicterus, with more than 120 cases reported. Common factors in the recent cases are newborn discharge before 48 hours, breast-feeding, delayed measurement of TSB, unrecognized hemolysis, lack of early post discharge follow-up, and failure to recognize the early symptoms of bilirubin encephalopathy.
Bilirubin is produced by the breakdown of heme (iron protoporphyrin) in the reticuloendothelial system and bone marrow. Heme is cleaved by heme oxygenase to iron, which is conserved; carbon monoxide, which is exhaled; and biliverdin, which is converted to bilirubin by bilirubin reductase. This unconjugated bilirubin is bound to albumin and carried to the liver, where it is taken up by hepatocytes. In the presence of the enzyme uridyl diphosphoglucuronyl transferase (UDPGT; glucuronyl transferase), bilirubin is conjugated to one or two glucuronide molecules. Conjugated bilirubin is then excreted through the bile to the intestine. In the presence of normal gut flora, conjugated bilirubin is metabolized to stercobilins and excreted in the stool. Absence of gut flora and slow GI motility, both characteristics of the newborn, cause stasis of conjugated bilirubin in the intestinal lumen, where mucosal β-glucuronidase removes the glucuronide molecules and leaves unconjugated bilirubin to be reabsorbed (enterohepatic circulation).
Excess accumulation of bilirubin in blood depends on both the rate of bilirubin production and the rate of excretion. It is best determined by reference to an hour-specific TSB level above the 95th percentile for age in hours (Figure 2–1).
Risk designation of full-term and near-term newborns based on their hour-specific bilirubin values. (Reproduced with permission from Bhutani VK, Johnson L, Sivieri EM: Predictive ability of a predischarge hour-specific serum bilirubin test for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999 Jan;103(1):6–14.)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Visible jaundice appearing after 24 h of age.
Total bilirubin rises by < 5 mg/dL (86 mmol/L) per day.
Peak bilirubin occurs at 3–5 days of age, with a total bilirubin of no more than 15 mg/dL (258 mmol/L).
Visible jaundice resolves by 1 wk in the full-term infant and by 2 wk in the preterm infant.
Factors contributing to physiologic jaundice in neonates include low UDPGT activity, relatively high red cell mass, absence of intestinal flora, slow intestinal motility, and increased enterohepatic circulation of bilirubin in the first days of life. Hyperbilirubinemia outside of the ranges noted in Figure 2–1 is not physiologic and requires further evaluation.
2. Pathologic Unconjugated Hyperbilirubinemia
Pathologic unconjugated hyperbilirubinemia can be grouped into two main categories: overproduction of bilirubin or decreased conjugation of bilirubin (Table 2–6). The TSB is a reflection of the balance between these processes. Visible jaundice with a TSB greater than 5 mg/dL before 24 hours of age is most commonly a result of significant hemolysis.
Table 2–6.Causes of pathologic unconjugated hyperbilirubinemia. ||Download (.pdf) Table 2–6.Causes of pathologic unconjugated hyperbilirubinemia.
Overproduction of bilirubin
Hemolytic causes of increased bilirubin production (reticulocyte count elevated)
Immune-mediated: positive direct antibody (DAT, Coombs) test
Nonimmune: negative direct antibody (DAT, Coombs) test
Abnormal red cell shapes: spherocytosis, elliptocytosis, pyknocytosis, stomatocytosis
Red cell enzyme abnormalities: glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, hexokinase deficiency, other metabolic defects
Patients with bacterial or viral sepsis
Nonhemolytic causes of increased bilirubin production (reticulocyte count normal)
Extravascular hemorrhage: cephalohematoma, extensive bruising, intracranial hemorrhage
Exaggerated enterohepatic circulation of bilirubin: bowel obstruction, functional ileus
Breast-feeding–associated jaundice (inadequate intake of breast milk causing exaggerated enterohepatic circulation of bilirubin)
Decreased rate of conjugation
Crigler-Najjar syndrome (rare, severe)
Type I glucuronyl transferase deficiency, autosomal-recessive
Type II glucuronyl transferase deficiency, autosomal-dominant
Gilbert syndrome (common, milder)
A. Increased Bilirubin Production
1. Antibody-mediated hemolysis (Coombs test–positive)
a. ABO blood group incompatibility—This finding can accompany any pregnancy in a type O mother. Hemolysis is usually mild, but the severity is unpredictable because of variability in the amount of naturally occurring maternal anti-A or anti-B IgG antibodies. Although 15% of pregnancies are “setups” for ABO incompatibility (mother O, infant A or B), only 33% of infants in such cases have a positive direct Coombs test and less than 10% of these infants develop jaundice that requires therapy. Since maternal antibodies may persist for several months after birth, the newborn may become progressively more anemic over the first few weeks of life, occasionally to the point of requiring transfusion.
b. Rh-isoimmunization—This hemolytic process is less common, more severe, and more predictable than ABO incompatibility. The severity increases with each immunized pregnancy because of an anamnestic maternal IgG antibody response. Most Rh-disease can be prevented by giving high-titer Rho (D) immune globulin to the Rh-negative woman after invasive procedures during pregnancy or after miscarriage, abortion, or delivery of an Rh-positive infant. Affected neonates are often anemic at birth, and continued hemolysis rapidly causes hyperbilirubinemia and more severe anemia. The most severe form of Rh-isoimmunization, erythroblastosis fetalis, is characterized by life-threatening anemia, generalized edema, and fetal or neonatal heart failure. Without antenatal intervention, fetal or neonatal death often results. The cornerstone of antenatal management is transfusion of the fetus with Rh-negative cells, either directly into the umbilical vein or into the fetal abdominal cavity. Phototherapy is usually started in these infants upon delivery, with exchange transfusion frequently needed. Intravenous immune globulin (IVIG; 0.5–1 g/kg) given to the infant as soon as the diagnosis is made may decrease the need for exchange transfusion. Ongoing hemolysis occurs until all maternal antibodies are gone; therefore, these infants require monitoring for 2–3 months for recurrent anemia severe enough to require transfusion.
2. Nonimmune hemolysis (Coombs test–negative)
a. Hereditary spherocytosis—This condition is the most common of the red cell membrane defects and causes hemolysis by decreasing red cell deformability. Affected infants may have hyperbilirubinemia severe enough to require exchange transfusion. Splenomegaly may be present. Diagnosis is suspected by peripheral blood smear and family history. See Chapter 30 for a more in-depth discussion.
b. G6PD deficiency—This condition is the most common red cell enzyme defect causing hemolysis, especially in infants of African, Mediterranean, or Asian descent. Onset of jaundice is often later than in isoimmune hemolytic disease, toward 1 week of age. The role of G6PD deficiency in neonatal jaundice is probably underestimated as up to 10%–13% of African Americans are G6PD-deficient. Although the disorder is X-linked, female heterozygotes are also at increased risk of hyperbilirubinemia due to X-chromosome inactivation. Their increased bilirubin production is further exaggerated by a decreased rate of bilirubin conjugation. Since G6PD enzyme activity is high in reticulocytes, neonates with a large number of reticulocytes may have falsely normal enzyme tests. A low G6PD level should always raise suspicions. Repeat testing in suspect cases with initially normal results is indicated at 2–3 months of age. Please also see Chapter 30 for more details.
3. Nonhemolytic increased bilirubin production
Enclosed hemorrhage, such as cephalohematoma, intracranial hemorrhage, or extensive bruising in the skin, can lead to jaundice. Polycythemia leads to jaundice by increased red cell mass, with increased numbers of cells reaching senescence daily. Bowel obstruction, functional or mechanical, leads to an increased enterohepatic circulation of bilirubin.
B. Decreased Rate of Conjugation
1. UDPGT deficiency: Crigler-Najjar syndrome type I (complete deficiency, autosomal recessive) and type II (partial deficiency, autosomal dominant)
These rare conditions result from mutations in the exon or encoding region of the UDPGT gene that cause complete or nearly complete absence of enzyme activity. Both can cause severe unconjugated hyperbilirubinemia, bilirubin encephalopathy, and death if untreated. In type II, the enzyme can be induced with phenobarbital, which may lower bilirubin levels by 30%–80%. Liver transplantation is curative.
This is a common mild autosomal dominant disorder characterized by decreased hepatic UDPGT activity caused by genetic polymorphism at the promoter region of the UDPGT gene. Approximately 9% of the population is homozygous, and 42% is heterozygous for this abnormality, with a gene frequency of 0.3. Affected individuals tend to develop hyperbilirubinemia in the presence of conditions that increase bilirubin load, including G6PD deficiency. They are also more likely to have prolonged neonatal jaundice and breast-milk jaundice.
C. Hyperbilirubinemia Caused by Unknown or Multiple Factors
Asians (23%) are more likely than whites (10%–13%) or African Americans (4%) to have a peak neonatal TSB greater than 12 mg/dL (206 mmol/L). It is likely that these differences result from racial variations in prevalence of UDPGT gene polymorphisms or associated G6PD deficiency.
Premature infants often have poor enteral intake, delayed stooling, and increased enterohepatic circulation, as well as a shorter red cell life. Infants at 35–36 weeks’ gestation are 13 times more likely than term infants to be readmitted for hyperbilirubinemia. Even early-term infants (37–38 weeks’ gestation) are four times more likely than term neonates to have TSB greater than 13 mg/dL (224 mmol/L).
3. Breast-feeding and jaundice
a. Breast-milk jaundice—Unconjugated hyperbilirubinemia lasting until 2–3 months of age is common in breast-fed infants. An increased prevalence of the Gilbert syndrome promoter polymorphism is likely involved. Moderate unconjugated hyperbilirubinemia for 6–12 weeks in a thriving breast-fed infant without evidence of hemolysis, hypothyroidism, or other disease strongly suggests this diagnosis.
b. Breast-feeding–associated jaundice—This common condition has also been called “lack-of-breast-milk” jaundice. Breast-fed infants have a higher incidence (9%) of unconjugated serum bilirubin levels greater than 13 mg/dL (224 mmol/L) than do formula-fed infants (2%). The pathogenesis is probably poor enteral intake and increased enterohepatic circulation. There is no apparent increase in bilirubin production as measured by carbon monoxide exhalation. Although rarely severe enough to cause bilirubin encephalopathy, nearly 100% of the infants with kernicterus reported over the past 20 years were exclusively breast-fed, and in 50%, breast-feeding was the only known risk factor. Excessive jaundice should be considered a possible sign of failure to establish an adequate milk supply, and should prompt specific inquiries. The best way to evaluate successful breast-feeding is to monitor the infant’s weight, urine, and stool output (see Table 2–3). If intake is inadequate, the infant should receive supplemental formula and the mother should be instructed to nurse more frequently and to use an electric breast pump every 2 hours to enhance milk production. Consultation with a lactation specialist should be considered. Because hospital discharge of normal newborns occurs before the milk supply is established and before jaundice peaks, a follow-up visit 2 days after discharge is recommended by the AAP to evaluate adequacy of intake and degree of jaundice.
Unconjugated bilirubin anion is the agent of bilirubin neurotoxicity. The anion binds to the phospholipids (gangliosides) of neuronal plasma membranes causing injury, which then allows more anion to enter the neuron. Intracellular bilirubin anion binds to the membrane phospholipids of subcellular organelles, causing impaired energy metabolism and cell death. The blood-brain barrier undoubtedly has a role in protecting the infant from brain damage, but its integrity is impossible to measure clinically. The amount of albumin available to bind the unconjugated bilirubin anion and the presence of other anions that may displace bilirubin from albumin-binding sites are also important. It is unknown whether there is a fixed level of bilirubin above which brain damage always occurs. The term kernicterus describes the pathologic finding of staining of basal ganglia and brainstem nuclei, as well as the clinical syndrome of chronic brain injury due to hyperbilirubinemia. The term acute bilirubin encephalopathy describes the signs and symptoms of evolving brain injury in the newborn.
The risk of bilirubin encephalopathy is small in healthy, term neonates even at bilirubin levels of 25–30 mg/dL (430–516 mmol/L). Risk depends on the duration of hyperbilirubinemia, the concentration of serum albumin, associated illness, acidosis, and the concentrations of competing anions such as sulfisoxazole and ceftriaxone. Premature infants are at greater risk than term infants because of the greater frequency of associated illness affecting the integrity of the blood-brain barrier, reduced albumin levels, and decreased affinity of albumin-binding sites. For these reasons, the “exchange level” (the level at which bilirubin encephalopathy is thought likely to occur) in premature infants may be lower than that of a term infant.
4. Acute Bilirubin Encephalopathy
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Lethargy, poor feeding.
Irritability, high-pitched cry.
Arching of the neck (retrocollis) and trunk (opisthotonos).
Apnea, seizures, coma (late).
Newborn infants with evolving acute bilirubin encephalopathy may be described as “sleepy and not interested in feeding.” Although these symptoms are nonspecific, they are also the earliest signs of acute bilirubin encephalopathy and should trigger, in the jaundiced infant, a detailed evaluation of the birth and postnatal history, feeding and elimination history, an urgent assessment for signs of bilirubin-induced neurologic dysfunction (BIND), and a TSB and albumin measurement. Correlation between TSB level and neurotoxicity is poor. Although 65% of recently reported cases of kernicterus had TSB levels above 35 mg/dL, 15% had levels below 30 mg/dL and 8% had TSB levels below 25 mg/dL. Currently the most sensitive means of assessing neurotoxicity may be the auditory brainstem evoked response, which shows predictable, early effects of bilirubin toxicity.
5. Chronic Bilirubin Encephalopathy (Kernicterus)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Extrapyramidal movement disorder (choreoathetoid cerebral palsy).
Gaze abnormality, especially limitation of upward gaze.
Auditory disturbances (deafness, failed auditory brainstem evoked response with normal evoked otoacoustic emissions, auditory neuropathy, auditory dyssynchrony).
Dysplasia of the enamel of the deciduous teeth.
Kernicterus is an irreversible brain injury characterized by choreoathetoid cerebral palsy and hearing impairment. Intelligence is probably normal but may be difficult to assess because of associated hearing, communication, and coordination problems. The diagnosis is clinical but is strengthened if audiologic testing shows auditory neuropathy and auditory dyssynchrony in which the otoacoustic emission test is normal but the auditory brainstem response is absent. Infants with such findings are usually deaf. Infants with milder kernicterus may have normal audiograms but abnormal auditory processing and subsequent problems with speech comprehension. Magnetic resonance imaging (MRI) scanning of the brain is nearly diagnostic if it shows abnormalities isolated to the globus pallidus, the subthalamic nuclei, or both.
Evaluation of Hyperbilirubinemia
Because most newborns are discharged at 24–48 hours of age, before physiologic jaundice peaks and before maternal milk supply is established, a predischarge TSB or a transcutaneous bilirubin measurement (TcB) is recommended to help predict which infants are at risk for severe hyperbilirubinemia. In all infants, an assessment of risk for severe hyperbilirubinemia should be performed before discharge (Table 2–7). The greater the number of risk factors, the greater the likelihood of developing severe hyperbilirubinemia. As recommended by the AAP, follow-up within 24–48 hours for all infants discharged before 72 hours of age is imperative. Visual estimation of the bilirubin level is inaccurate. TSB should be measured and interpreted based on the age of the infant in hours at the time of sampling. Term infants with a TSB level greater than the 95th percentile for age in hours have a 40% risk of developing significant hyperbilirubinemia (see Figure 2–1). Serial bilirubin levels should be obtained from a single laboratory whenever possible to make interpretation of serial measurements more meaningful. It is important to remember that these nomograms apply only to infants 36 weeks and older.
Table 2–7.Factors affecting the risk of severe hyperbilirubinemia in infants 35 or more weeks’ gestation (in approximate order of importance). ||Download (.pdf) Table 2–7.Factors affecting the risk of severe hyperbilirubinemia in infants 35 or more weeks’ gestation (in approximate order of importance).
Major risk factors
Predischarge TSB or TcB level in the high-risk zone (> 95th percentile; Figure 2–1)
Jaundice observed in the first 24 h
Blood group incompatibility with positive direct Coombs test, other known hemolytic disease (eg, G6PD deficiency), or elevated ETCO
Gestational age 35–36 wk
Previous sibling required phototherapy
Cephalohematoma or significant bruising
Exclusive breast-feeding, particularly if weight loss is excessive
East Asian racea
Minor risk factors
Predischarge TSB or TcB level in the high-intermediate-risk zone (75–95th percentile)
Gestational age 37–38 wk
Jaundice observed before discharge
Previous sibling with jaundice
Macrosomic infant of a diabetic mother
Decreased risk (these factors are associated with decreased risk of significant jaundice, listed in order of decreasing importance)
Infants with visible jaundice on the first day of life or who develop excessive jaundice require further evaluation. The minimal evaluation consists of the following:
Feeding and elimination history
Birth weight and percent weight change since birth
Examination for sources of excessive heme breakdown
Assessment of blood type, Coombs testing, complete blood count (CBC) with smear, serum albumin, and TSB
G6PD test if jaundice is otherwise unexplained, and in African-American infants with severe jaundice
Fractionated bilirubin level in infants who appear ill, those with prolonged jaundice, acholic stool, hepatosplenomegaly, or dark urine to evaluate for cholestasis
Treatment of Indirect Hyperbilirubinemia
Phototherapy is the most common treatment for indirect hyperbilirubinemia. It is relatively noninvasive and safe. Light of wavelength 425–475 nm (blue-green spectrum) is absorbed by unconjugated bilirubin in the skin converting it to a water-soluble stereoisomer that can be excreted in bile without conjugation. Intensive phototherapy should decrease TSB by 30%–40% in the first 24 hours, most significantly in the first 4–6 hours. The infant’s eyes should be shielded to prevent retinal damage. Diarrhea, which sometimes occurs during phototherapy, can be treated if necessary by feeding a nonlactose-containing formula.
Phototherapy is started electively when the TSB is approximately 6 mg/dL (102 mmol/L) lower than the predicted exchange level for that infant (eg, at 16–19 mg/dL [272–323 mmol/L] for a full-term infant for whom exchange transfusion would be considered at a TSB of approximately 22–25 mg/dL [374–425 mmol/L]). AAP guidelines for phototherapy and exchange transfusion in infants of 35 or more weeks’ gestation are shown in Figures 2–2 and 2–3. Hyperbilirubinemic infants should be fed by mouth if possible to decrease enterohepatic bilirubin circulation. Casein hydrolysate formula to supplement breast milk decreases enterohepatic circulation by inhibiting mucosal β-glucuronidase activity. IVIG (0.5–1.0 g/kg) in severe antibody-mediated hemolysis may interrupt the hemolytic process. Although phototherapy has been shown to decrease the need for exchange transfusion, its long-term benefits, if any, in infants with less severe jaundice are unknown.
Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation. These guidelines are based on limited evidence and levels shown are approximations. (Reproduced with permission from the AAP Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004 Jul;114(1):297–316.)
Guidelines for exchange transfusion in infants of 35 or more weeks’ gestation. These guidelines represent approximations for which an exchange transfusion is indicated in infants treated with intensive phototherapy. (Reproduced with permission from the AAP Subcommittee on Hyperbilirubinemia: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004 Jul;114(1):297–316.)
Although most infants with indirect hyperbilirubinemia can be treated with phototherapy, extreme indirect hyperbilirubinemia is a medical emergency. Infants should be admitted at once to a neonatal intensive care unit where exchange transfusion can be performed before irreversible neurologic damage occurs. Intensive phototherapy should be instituted immediately, during transport to the hospital if possible. As TSB nears the potentially toxic range, serum albumin should be determined. Albumin (1 g/kg) will aid in binding and removal of bilirubin during exchange transfusion, as well as afford some neuroprotection while preparing for the procedure.
Double-volume exchange transfusion (~160–200 mL/kg body weight) is most often required in infants with extreme hyperbilirubinemia secondary to Rh isoimmunization, ABO incompatibility, or hereditary spherocytosis. The procedure decreases serum bilirubin acutely by approximately 50% and removes about 80% of sensitized or abnormal red blood cells and offending antibody so that ongoing hemolysis is decreased. Exchange transfusion is also indicated in any infant with TSB above 30 mg/dL, in infants with signs of encephalopathy, or when intensive phototherapy has not lowered TSB by at least 0.5 mg/dL/h after 4 hours. The decision to perform exchange transfusion should be based on TSB, not on the indirect fraction of bilirubin.
Exchange transfusion is invasive, potentially risky, and infrequently performed. It should therefore be performed at a referral center. Mortality is 1%–5% and is greatest in the smallest, most immature, and unstable infants. Sudden death during the procedure can occur in any infant. There is a 5%–10% risk of serious complications such as necrotizing enterocolitis (NEC), infection, electrolyte disturbances, or thrombocytopenia. Isovolemic exchange (withdrawal through an arterial line with infusion through a venous line) may decrease the risk of some complications.
Tin and zinc protoporphyrin or mesoporphyrin (Sn-PP, Zn-PP; Sn-MP, Zn-MP) are inhibitors of heme oxygenase, the enzyme that initiates the catabolism of heme (iron protoporphyrin). Studies are underway involving a single injection of these substances shortly after birth to prevent the formation of bilirubin. Although results are promising, these drugs are not yet approved for use in the United States.
NJ: Hyperbilirubinemia in the newborn. Pediatr Rev 2011;32:341
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Blood glucose < 40 mg/dL at birth to 4 h, or < 45 mg/dL at 4–24 h of age.
LGA, SGA, preterm, and stressed infants at risk.
May be asymptomatic.
Infants can present with lethargy, poor feeding, irritability, or seizures.
Blood glucose concentration in the fetus is approximately 15 mg/dL less than maternal glucose concentration. Glucose concentration decreases in the immediate postnatal period, to as low as 30 mg/dL in many healthy infants at 1–2 hours after birth. Concentrations below 40 mg/dL after the first feeding are considered hypoglycemic. By 3 hours, the glucose concentration in normal full-term infants stabilizes at 45 mg/dL or greater. The two groups of full-term newborn infants at highest risk for hypoglycemia are infants of diabetic mothers and growth-restricted infants.
A. Infants of Diabetic Mothers
The infant of a diabetic mother (IDM) has abundant glucose stores in the form of glycogen and fat but develops hypoglycemia because of hyperinsulinemia induced by maternal and fetal hyperglycemia. Increased energy supply to the fetus from the maternal circulation results in a macrosomic infant. The IDM is at increased risk for multiple neonatal problems including trauma during delivery, cardiomyopathy (asymmetrical septal hypertrophy) which may present with murmur, respiratory distress, or cardiac failure, and microcolon which causes symptoms of low intestinal obstruction similar to Hirschsprung disease. Other neonatal problems include hypercoagulability and polycythemia, a combination that predisposes the infant to large vein thromboses (especially the renal vein). IDMs are often somewhat immature for their gestational age and are at increased risk for surfactant deficiency, hypocalcemia, feeding difficulties, and hyperbilirubinemia.
B. Intrauterine Growth-Restricted Infants
The intrauterine growth-restricted (IUGR) infant has reduced glucose stores in the form of glycogen and body fat, and is prone to hypoglycemia. In addition, marked hyperglycemia and a transient diabetes mellitus–like syndrome occasionally develops, particularly in the very premature IUGR infant. These problems usually respond to adjustment in glucose intake, although insulin is sometimes needed transiently. Some IUGR infants have hyperinsulinemia that persists for 1 week or more.
C. Other Causes of Hypoglycemia
Hypoglycemia occurs in disorders with islet cell hyperplasia, including Beckwith-Wiedemann syndrome, nesidioblastosis, and genetic forms of hyperinsulinism. Hypoglycemia also occurs in certain inborn errors of metabolism such as glycogen storage disease and galactosemia. Endocrine causes of hypoglycemia include adrenal insufficiency and hypopituitarism, which should be suspected in the setting of hypoglycemia and micropenis. Hypoglycemia also occurs in infants with birth asphyxia, hypoxia, and bacterial or viral sepsis. Premature infants are at risk for hypoglycemia due to decreased glycogen stores.
Clinical Findings and Monitoring
The signs of hypoglycemia in the newborn infant may be nonspecific and subtle: lethargy, poor feeding, irritability, tremors, jitteriness, apnea, and seizures. Hypoglycemia due to increased insulin is the most severe and most resistant to treatment. Hypoglycemia in hyperinsulinemic states can develop within the first 30–60 minutes of life.
Blood glucose can be measured by heelstick using a bedside glucometer. All infants at risk should be screened, including IDMs, IUGR infants, premature infants, and any infant with suggestive symptoms. All low or borderline values should be confirmed by laboratory measurement of blood glucose concentration. It is important to continue surveillance of glucose concentration until the baby has been on full enteral feedings without intravenous supplementation for 24 hours, with a target of greater than 45 mg/dL before feeding. Relapse of hypoglycemia thereafter is unlikely.
Infants with hypoglycemia requiring IV glucose infusions for more than 5 days should be evaluated for less common disorders, including inborn errors of metabolism, hyperinsulinemic states, and deficiencies of counterregulatory hormones.
Therapy is based on the provision of enteral or parenteral glucose. Treatment guidelines are shown in Table 2–8. In hyperinsulinemic states, glucose boluses should be avoided and a higher glucose infusion rate used. After initial correction with a bolus of 10% dextrose in water (D10W; 2 mL/kg), glucose infusion should be increased gradually as needed from a starting rate of 6 mg/kg/min, and weaned slowly when normoglycemic. IDMs and IUGR infants with polycythemia are at greatest risk for symptomatic hypoglycemia.
Table 2–8.Hypoglycemia: suggested therapeutic regimens. ||Download (.pdf) Table 2–8.Hypoglycemia: suggested therapeutic regimens.
|Screening Testa ||Presence of Symptoms ||Action |
|30–40 mg/dL ||No symptoms of hypoglycemia ||Draw blood glucoseb; if the infant is alert and vigorous, feed; follow with frequent glucose monitoring. |
| || ||If the infant continues to have blood glucose < 40 mg/dL or is unable to feed, provide intravenous glucose at 6 mg/kg/min (D10W at 3.6 mL/kg/h). |
|< 40 mg/dL ||Symptoms of hypoglycemia present ||Draw blood glucoseb; provide bolus of D10W (2 mL/kg) followed by an infusion of 6 mg/kg/min (3.6 mL/kg/h). |
|< 30 mg/dL ||With or without symptoms of hypoglycemia ||Draw blood glucoseb; provide bolus of D10W followed by an infusion of 6 mg/kg/min. |
| || ||If IV access cannot be obtained immediately, an umbilical vein line should be used. |
The prognosis of hypoglycemia is good if therapy is prompt. CNS sequelae are more common in infants with hypoglycemic seizures and in neonates with persistent hyperinsulinemic hypoglycemia. Hypoglycemia may also potentiate brain injury after perinatal depression, and should be avoided.
DH; Committee on Fetus and Newborn: Clinical report—postnatal glucose homeostasis in late preterm and term infants. Pediatrics 2011;127:575
WW Jr: Care of the infant of the diabetic mother. Curr Diab Rep 2012;12(1):415
WW Jr: Neonatal hypoglycemia. NeoReviews 2010;11:e681.
WW Jr. New approaches to management of neonatal hypoglycemia. Maternal Health Neonatol Perinatol May 2016;10:3
RESPIRATORY DISTRESS IN THE TERM NEWBORN INFANT
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Respiratory distress is one of the most common symptom complexes of the newborn. It may result from cardiopulmonary and noncardiopulmonary causes (Table 2–9). Chest radiography, arterial blood gases, and pulse oximetry are useful in assessing the cause and severity of the distress. It is important to consider the noncardiopulmonary causes, because the natural tendency is to focus on the heart and lungs. Most of the noncardiopulmonary causes can be ruled out by the history, physical examination, and a few simple laboratory tests. The most common pulmonary causes of respiratory distress in the full-term infant are transient tachypnea, aspiration syndromes, congenital pneumonia, and pneumothorax.
Table 2–9.Causes of respiratory distress in the newborn. ||Download (.pdf) Table 2–9.Causes of respiratory distress in the newborn.
Hypothermia or hyperthermia
Drug intoxications or withdrawal
Insult to the central nervous system
Phrenic nerve injury
Left-sided outflow tract obstruction
Transposition of the great vessels
Total anomalous pulmonary venous return
Right-sided outflow obstruction
Upper airway obstruction
Vocal cord paralysis
Clear fluid aspiration
Hyaline membrane disease
A. Transient Tachypnea (Retained Fetal Lung Fluid)
Respiratory distress is typically present at birth, usually associated with a mild-to-moderate oxygen requirement (25%–50% O2). The infant is usually full term or late preterm, nonasphyxiated, and born following a short labor or cesarean section without labor. The pathogenesis of the disorder is related to delayed clearance of fetal lung fluid via the circulation and pulmonary lymphatics. The chest radiograph shows perihilar streaking and fluid in interlobar fissures. Resolution usually occurs within 12–24 hours. Nasal CPAP can be very helpful in the clearance of the fluid.
Typically occurs in full-term or late preterm infants with fetal distress prior to delivery or depression at delivery. Blood or meconium may be present in the amniotic fluid. Aspiration of meconium most commonly occurs in utero as a stressed infant gasps. Delivery room management of these infants is discussed in the resuscitation section. Respiratory distress is present from birth, often accompanied by a barrel chest appearance and coarse breath sounds. Pneumonitis may cause an increasing O2 need and may require intubation and ventilation. The chest radiograph shows coarse asymmetric infiltrates, hyperexpansion, and, in the worst cases, lobar consolidation. In some cases, because of secondary surfactant deficiency, the radiograph shows a diffuse homogeneous infiltrate pattern. Infants who aspirate are at risk of pneumothorax because of uneven aeration with segmental overdistention and are at risk for persistent pulmonary hypertension (see section Cardiac Problems in the Newborn Infant).
The lungs are the most common site of infection in the neonate. Infections usually ascend from the genital tract before or during labor, with the vaginal or rectal flora the most likely agents (group B streptococci and Escherichia coli). Infants of any gestational age, with or without a history of prolonged rupture of membranes, chorioamnionitis, or maternal antibiotic administration, may be affected. Respiratory distress may begin at birth or may be delayed for several hours. The chest radiograph may resemble that of retained lung fluid or hyaline membrane disease. Rarely, there may be a lobar infiltrate or pleural effusion. Congenital pneumonia may be complicated by acquired surfactant deficiency or systemic sepsis.
Shock, poor perfusion, absolute neutropenia (< 2000/mL), and elevated C-reactive protein provide supportive evidence for pneumonia. Gram stain of tracheal aspirate may be helpful. Because no signs or laboratory findings can confirm a diagnosis of pneumonia, all infants with respiratory distress should have a blood culture performed and should receive broad-spectrum antibiotic therapy (ampicillin, 100 mg/kg in two divided doses, and gentamicin, 4 mg/kg q24h or 2.5 mg/kg q12h) until the diagnosis of bacterial infection is eliminated.
D. Spontaneous Pneumothorax
Spontaneous pneumothorax occurs in 1% of all deliveries. Risk is increased by interventions such as positive-pressure ventilation (PPV) in the delivery room. Respiratory distress (primarily tachypnea) is present from birth and typically is not severe. Breath sounds may be decreased on the affected side; heart tones may be shifted toward the opposite side and may be distant. The chest radiograph shows pneumothorax.
Treatment usually consists of supplemental O2 and watchful waiting. Drainage by needle thoracentesis or tube thoracostomy is occasionally required. There is a slightly increased risk of renal abnormalities associated with spontaneous pneumothorax. Thus, careful physical examination of the kidneys and monitoring of urine output are indicated. If pulmonary hypoplasia with pneumothorax is suspected, renal ultrasound is indicated.
E. Other Respiratory Tract Causes
Other respiratory tract causes of respiratory distress are rare. Bilateral choanal atresia should be suspected if there is no air movement when the infant breathes through the nose. These infants have good color and heart rate while crying at delivery but become cyanotic and bradycardiac when they resume normal nasal breathing. Other causes of upper airway obstruction usually produce some degree of stridor or poor air movement despite good respiratory effort. Pleural effusion is likely in hydropic infants. Space-occupying lesions cause a shift of the mediastinum with asymmetrical breath sounds and are apparent on chest radiographs. Many are associated with severe respiratory distress.
Whatever the cause, neonatal respiratory distress is treated with supplemental oxygen sufficient to maintain a Pao2 of 60–70 mm Hg and an oxygen saturation by pulse oximetry (Spo2) of 92%–96%. Oxygen should be warmed, humidified, and delivered through an air blender. Concentration should be measured with a calibrated oxygen analyzer. An umbilical or peripheral arterial line should be considered in infants requiring more than 45% fraction of inspired oxygen (Fio2) by 4–6 hours of life to allow frequent blood gas determinations. Noninvasive monitoring with pulse oximetry should be used.
Other supportive treatment includes IV glucose. Unless infection can be ruled out, blood cultures should be obtained, and broad-spectrum antibiotics started. Volume expansion (normal saline) can be given in infusions of 10 mL/kg over 30 minutes for low blood pressure, poor perfusion, and metabolic acidosis. Other specific testing should be done as indicated by the history and physical examination. In most cases, a chest radiograph, blood gas measurements, CBC, and blood glucose determination allow a diagnosis.
Intubation and ventilation should be undertaken if there is respiratory failure (Pao2< 60 mm Hg in > 60% Fio2, Paco2 > 60 mm Hg, or repeated apnea). Peak pressures should be adequate to produce chest wall expansion and audible breath sounds (usually 18–24 cm H2O). Positive end-expiratory pressure (4–6 cm H2O) should be used. Ventilation rates of 20–40 breaths/min are usually required. The goal is to maintain a Pao2 of 60–70 mm Hg and a Paco2 of 45–55 mm Hg.
Most respiratory conditions of the full-term infant are acute and resolve in the first several days. Meconium aspiration and congenital pneumonia carry a mortality rate of up to 10% and can produce significant long-term pulmonary morbidity. Mortality has been reduced by use of high-frequency oscillatory ventilation and inhaled nitric oxide for treatment of pulmonary hypertension. Only rarely is ECMO needed as rescue therapy.
K: Respiratory distress of the term newborn infant. Paediatr Resp Rev 2013;14(1):2937
Heart murmurs are common in the first days of life and do not usually signify structural heart problems (see also Cardiac Problems in the Newborn Infant). If a murmur is present at birth, it should be considered a valvular problem until proved otherwise because the common benign transitional murmurs (eg, patent ductus arteriosus) are not audible until minutes to hours after birth.
If an infant is pink, well-perfused, and in no respiratory distress, with palpable and symmetrical pulses (right brachial pulse no stronger than the femoral pulse), the murmur is most likely transitional. Transitional murmurs are soft (grade 1–3/6), heard at the left upper to midsternal border, and generally loudest during the first 24 hours. If the murmur persists beyond 24 hours of age, blood pressure in the right arm and a leg should be determined. If there is a difference of more than 15 mm Hg (arm > leg) or if the pulses in the lower extremities are difficult to palpate, a cardiologist should evaluate the infant for coarctation of the aorta. If there is no difference, the infant can be discharged home with follow-up in 2–3 days for auscultation and evaluation for signs of congestive failure. If signs of congestive failure or cyanosis are present, the infant should be referred for evaluation without delay. If the murmur persists without these signs, the infant can be referred for elective evaluation at age 2–4 weeks.
Most birth trauma is associated with difficult delivery (eg, large fetus, abnormal presenting position, or fetal distress requiring rapid extraction). The most common injuries are soft tissue bruising, fractures (clavicle, humerus, or femur), and cervical plexus palsies. Skull fracture, intracranial hemorrhage (primarily subdural and subarachnoid), and cervical spinal cord injury can also occur.
Fractures are often diagnosed by the obstetrician, who may feel or hear a snap during delivery. Clavicular fractures may cause decreased spontaneous movement of the arm, with local tenderness and crepitus. Humeral or femoral fractures usually cause tenderness and swelling over the shaft with a diaphyseal fracture, and always cause limitation of movement. Epiphyseal fractures are harder to diagnose radiographically owing to the cartilaginous nature of the epiphysis. After 8–10 days, callus is visible on radiographs. Treatment in all cases is gentle handling, with immobilization for 8–10 days: the humerus against the chest with elbow flexed; the femur with a posterior splint from below the knee to the buttock.
Brachial plexus injuries may result from traction as the head is pulled away from the shoulder during delivery. Injury to the C5–C6 roots is most common (Erb-Duchenne palsy). The arm is limp, adducted, and internally rotated, extended, and pronated at the elbow, and flexed at the wrist (so-called waiter’s tip posture). Grasp is present. If the lower nerve roots (C8–T1) are injured (Klumpke palsy), the hand is flaccid. If the entire plexus is injured, the arm and hand are flaccid, with associated sensory deficit. Early treatment for brachial plexus injury is conservative, because function usually returns over several weeks. Referral should be made to a physical therapist so that parents can be instructed on range-of-motion exercises, splinting, and further evaluation if needed. Return of function begins in the deltoid and biceps, with recovery by 3 months in most cases.
Spinal cord injury can occur at birth, especially in difficult breech extractions with hyperextension of the neck, or in midforceps rotations when the body fails to turn with the head. Infants are flaccid, quadriplegic, and without respiratory effort at birth. Facial movements are preserved. The long-term outlook for such infants is poor.
Facial nerve palsy is sometimes associated with forceps use but more often results from in utero pressure of the baby’s head against the mother’s sacrum. The infant has asymmetrical mouth movements and eye closure with poor facial movement on the affected side. Most cases resolve spontaneously in a few days to weeks.
Subgaleal hemorrhage into the large potential space under the scalp (Figure 2–4) is associated with difficult vaginal deliveries and repeated attempts at vacuum extraction. It can lead to hypovolemic shock and death from blood loss and coagulopathy triggered by consumption of clotting factors. This is an emergency requiring rapid replacement of blood and clotting factors.
Sites of extracranial bleeding in the newborn. (Reproduced with permission from Pape KE, Wigglesworth JS: Haemorrhage, ischemia, and the perinatal brain. Clinics in Developmental Medicine. Spastics International Medical Publications. William Heinemann Medical Books Limited, London, and JB Lippincott Company, Philadelphia, 1979.)
INFANTS OF MOTHERS WHO ABUSE DRUGS
Current studies estimate that up to 15% of women use alcohol and 5%–15% use illicit drugs during pregnancy, depending on the population studied and the methods of ascertainment. Drugs most commonly used are tobacco, alcohol, marijuana, cocaine, and methamphetamine. Because mothers may abuse many drugs and give an unreliable history of drug usage, it is difficult to pinpoint which drug is causing the morbidity seen in a newborn infant. Early hospital discharge makes recognition of these infants based on physical findings and abnormal behavior difficult. Except for alcohol, a birth defect syndrome has not been defined for any substance of abuse.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Cocaine and methamphetamine are often used in association with other drugs such as tobacco, alcohol, and marijuana. These stimulants can cause maternal hypertension, decreased uterine blood flow, fetal hypoxemia, uterine contractions, and placental abruption. Rates of stillbirth, placental abruption, symmetric IUGR, and preterm delivery are increased in users. In the high-risk setting of no prenatal care, placental abruption, and preterm labor, urine toxicology screens should be performed on the mother and infant; consent from the mother for testing her urine may be required. Meconium or an umbilical cord sample should be sent for drug screening as it enhances diagnosis by indicating cumulative drug exposure from the first trimester forward. Although no specific malformation complex or withdrawal syndrome is described for cocaine and methamphetamine abuse, infants may show irritability, tremors, increased stress response, and poor state regulation.
Children of mothers who use methamphetamines are at particularly high risk for neglect and abuse. Social services evaluation is especially important to assess the home environment for these risks. The risk of SIDS is three to seven times higher in infants of users than in those of nonusers (0.5%–1% of exposed infants). The risk may be lessened by environmental interventions such as avoidance of tobacco smoke and supine infant positioning.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
CNS—irritability, hyperactivity, hypertonicity, incessant high-pitched cry, tremors, seizures.
GI—vomiting, diarrhea, weight loss, poor feeding, incessant hunger, excessive salivation.
Metabolic and respiratory—nasal stuffiness, sneezing, yawning, sweating, hyperthermia.
The withdrawal signs seen in infants born to narcotic-addicted mothers, whether heroin, prescription narcotics, or methadone, are similar. These symptoms include problems with feeding and sleep, fever, increased tone, tremors, and seizures, and are referred to as neonatal abstinence syndrome (NAS). The symptoms in infants born to methadone-maintained mothers may be delayed in onset, more severe, and more prolonged than those seen with heroin addiction. Symptoms usually begin within 1–3 days of life. The clinical picture is typical enough to suggest a diagnosis even if a maternal history of narcotic abuse has not been obtained. Confirmation should be made with maternal and newborn toxicology screening.
If opioid abuse or withdrawal is suspected, the infant is not a candidate for early discharge. A serial scoring system should be used, to objectively diagnose NAS and quantify the severity of symptoms. Supportive treatment includes swaddling the infant and providing a quiet, dimly lit environment, minimizing procedures, and disturbing the infant as little as possible. Specific treatment should be used when the infant has severe symptoms or excessive weight loss. No single drug has been identified as optimally effective. Oral morphine (0.1–0.5 mg/kg/dose q6–12h) or methadone (0.05–0.1 mg/kg/dose q6–12h) are the most commonly used first-line agents for NAS. Phenobarbital (5 mg/kg/dose daily) may be used for increased irritability, particularly in patients who were exposed to multiple drugs. Treatment can be tapered over several days to 2 weeks, as tolerated. It is also important to review maternal tests for HIV, hepatitis B, and hepatitis C, as all are common in intravenous drug users.
These infants often have chronic neurobehavioral handicaps; however, it is difficult to distinguish the effects of in utero drug exposure from those of the environment. Infants of opioid abusers have a four- to fivefold increased risk of SIDS.
Alcohol is the only recreational drug of abuse that is clearly teratogenic, and prenatal exposure to alcohol is the most common preventable cause of mental retardation. Prevalence estimates of fetal alcohol syndrome (FAS) in the United States range from 0.5 to 2 per 1000 live births with up to 1 in 100 having lesser effects (fetal alcohol spectrum disorders). The effects of alcohol on the fetus and newborn are determined by the degree and timing of ethanol exposure and by the maternal, fetal, and placental metabolism of ethanol, which is likely genetically determined. Although there is no clear evidence that minimal amounts of alcohol are harmful, there is no established safe dose. Fetal growth and development are adversely affected if drinking continues throughout the pregnancy, and infants can occasionally experience withdrawal similar to that associated with maternal opioid abuse. Clinical features of FAS that may be observed in the newborn period are listed in Table 2–10. This diagnosis is usually easier to recognize in older infants and children.
Table 2–10.Features observed in fetal alcohol syndrome in the newborn. ||Download (.pdf) Table 2–10.Features observed in fetal alcohol syndrome in the newborn.
Central nervous system
The fetus is exposed to nicotine concentrations that are 15% higher than in maternal blood. Smoking has a negative effect on fetal growth rate. The more the mother smokes, the greater the degree of IUGR. There is a twofold increase in low birth weight even in light smokers (< 10 cigarettes per day). Infants exposed to nicotine prenatally are also at increased risk for preterm labor and SIDS. Smoking during pregnancy has been associated with irritability, hypertonicity, hyperexcitability, and tremors in the newborn.
Marijuana is the most frequently used illegal drug, and now that it is legal in certain states, there is concern for increased use among pregnant women. It does not appear to be teratogenic, and although a mild abstinence-type syndrome has been described, infants exposed to marijuana in utero rarely require treatment. Some long-term neurodevelopmental problems, particularly increased impulsivity and hyperactivity and problems in abstract and visual reasoning, have been noted.
Other drugs with potential effects on the newborn fall in two categories. First are drugs to which the fetus is exposed because of therapy for maternal conditions. The human placenta is relatively permeable, particularly to lipophilic solutes. If possible, maternal drug therapy should be postponed until after the first trimester to avoid teratogenic effects. Drugs with potential fetal toxicity include antineoplastics, antithyroid agents, warfarin, lithium, and angiotensin-converting enzyme inhibitors (eg, captopril and enalapril). Anticonvulsants, especially high-dose or multiple drug therapy, may be associated with craniofacial abnormalities. The use of selective serotonin reuptake inhibitors, benzodiazepines, and antipsychotic medications appears to be generally safe, and risk should be balanced against the risk of untreated psychiatric conditions in the mother. However, up to 33% of infants exposed to SSRI medications in utero experience signs of NAS during the first days of life. Paroxetine seems to have the greatest propensity to cause abstinence symptoms. Phenobarbital may be used for severe irritability.
In the second category are drugs transmitted to the infant in breast milk. Most drugs taken by the mother achieve some concentration in breast milk, although they usually do not present a problem to the infant. If the drug is one that could have adverse effects on the infant, timing breast-feeding to coincide with trough concentrations in the mother may be useful.
ML: Infants of drug dependent mothers. Pediatr Rev 2011;32:5
J: Neonatal abstinence syndrome. NEJM 2016;375:2468
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Always monozygous (identical twins) and same sex.
Can be diamniotic or monoamniotic.
Risk for twin-to-twin transfusion and higher risk of congenital anomalies, neurodevelopmental problems, and cerebral palsy.
Either dizygous (fraternal twins) or monozygous (identical twins); same sex or different sex.
Can have growth restriction due to abnormal placental implantation.
Not at risk for twin transfusion syndrome; less risk for anomalies and neurodevelopmental problems than monochorial twins.
Historically, twinning occurred at a rate of 1 in 80 pregnancies (1.25%). The incidence of twinning and higher-order multiple births in the United States has increased because of assisted reproductive technologies. In 2014, twins occurred in 3.4% of live births in the United States, a greater than 70% increase since 1980.
A distinction should be made between dizygous (fraternal) and monozygous (identical) twins. Race, maternal parity, and maternal age affect the incidence of dizygous, but not monozygous, twinning. Drugs used to induce ovulation, such as clomiphene citrate and gonadotropins, increase the incidence of dizygotic or polyzygotic twinning. Monozygous twinning also seems to be more common after assisted reproduction. The incidence of malformations is also increased in identical twins and may affect only one of the twins. If a defect is found in one twin, the other should be examined carefully for lesser degrees of the same defect.
Early transvaginal ultrasound and examination of the placenta after birth can help establish the type of twinning. Two amnionic membranes and two chorionic membranes are found in all dizygous twins and in one-third of monozygous twins even when the placental disks appear to be fused into one. A single chorionic membrane always indicates monozygous twins. The rare monochorial, monoamniotic situation (1% of twins) is especially dangerous, with a high risk of antenatal cord entanglement and death of one or both twins. Close fetal surveillance is indicated, and preterm delivery is often elected.
Complications of Multiple Births
A. Intrauterine Growth Restriction
There is some degree of IUGR in most multiple pregnancies, especially after 32 weeks, although it is usually not clinically significant with two exceptions. First, in monochorial twin pregnancy an arteriovenous shunt may develop between the twins (twin-twin transfusion syndrome). The twin on the venous side (recipient) becomes plethoric and larger than the smaller anemic twin (donor), who may ultimately die or be severely growth restricted. The occurrence of polyhydramnios in the larger twin and severe oligohydramnios in the smaller may be the first sign of this problem. Second, discordance in size (birth weights that are significantly different) can also occur when separate placentas are present if one placenta develops poorly, because of a poor implantation site. In this instance, no fetal exchange of blood takes place but the growth rates of the two infants are different.
Length of gestation tends to be inversely related to the number of fetuses. The mean age at delivery for singletons is 38.8 weeks, for twins 35.3 weeks, for triplets 32.2 weeks, and for quadruplets 29.9 weeks. The prematurity rate in multiple gestations is 5–10 times that of singletons, with 50% of twins and 90% of triplets born before 37 weeks. There is an increased incidence of cerebral palsy in multiple births, more so with monochorial than dichorial infants. Prematurity is the main cause of increased mortality and morbidity in twins, although in the case of monochorial twins, intravascular exchange through placental anastomoses, particularly after the death of one twin, also increases the risk substantially.
C. Obstetric Complications
Polyhydramnios, pregnancy-induced hypertension, premature rupture of membranes, abnormal fetal presentations, and prolapsed umbilical cord occur more frequently in women with multiple fetuses. Multiple pregnancies should always be identified prenatally with ultrasound examinations; doing so allows the obstetrician and pediatrician or neonatologist to plan management jointly. Because neonatal complications are usually related to prematurity, prolongation of pregnancy significantly reduces neonatal morbidity.