Pregnancy and its disorders

Function

The placenta (1) keeps the maternal and fetal circulation systems separate, (2) nourishes the fetus, (3) eliminates fetal wastes, and (4) produces hormones vital to pregnancy. It is composed of large collections of fetal vessels called villi. These villi are finger-like projections that insert into blood-filled spaces called the intervillous spaces. Each intervillous space contains maternal blood that bathes the fetal villi and facilitates bidirectional exchange between mother and fetus. For substances to move from the maternal circulation to the fetal circulation, they must cross through the trophoblasts and several membranes. The transfer of any substance depends largely on the (1) concentration gradient between the maternal and fetal circulatory systems, (2) presence or absence of circulating binding proteins, (3) lipid solubility of the substance, and (4) presence of facilitated transport, such as ion pumps or receptor-mediated endocytosis ( Box 59.1 ). The placenta is an effective barrier to the movement of large proteins and hydrophobic compounds bound to plasma proteins. Maternal immunoglobulin (Ig)G crosses the placenta via receptor-mediated endocytosis. Because of its long half-life, maternally produced IgG protects a newborn through passive immunity for the first 6 months of life. Antibody assays with low limits of detection may be positive in infants up to age 18 months because of the persistence of maternal antibodies.

Placental hormones

The placenta produces several protein and steroid hormones ( Fig. 59.1 ). The major protein hormones are human chorionic gonadotropin (hCG) and human placental lactogen (hPL). Steroid hormones including progesterone, estradiol, estriol, and estrone are synthesized in complex joint pathways involving maternal, placental, and fetal contributions. Generally, hormone production by the placenta increases in proportion to the increase in placental mass. Therefore concentrations of hormones derived from the placenta, such as hPL, increase in maternal peripheral blood as the placenta increases in size. The hormone hCG, which peaks at the end of the first trimester, is an exception.

Volume and dynamics

The volume of amniotic fluid increases progressively until 34 weeks’ gestation, when it decreases slightly through the 40th week and then more sharply declines until the 42nd week. The volume is 200 to 300 mL at 16 weeks, 400 to 1400 mL at 26 weeks, 300 to 2000 mL at 34 weeks, and 300 to 1400 mL at 40 weeks. The volume at any given moment is a function of several inter-related fluid fluxes. Direct measurements in primates and indirect measurements in humans have been used to derive a mathematical model of amniotic fluid volume. At term, total fluid fluxes into and out of the amniotic cavity are large (≈60 mL/h) and result in complete exchange of the amniotic fluid volume twice per day. Gross unidirectional fluid volume shifts occur episodically: into the amniotic cavity by fetal urination and out of the cavity by fetal swallowing. These unidirectional shifts begin at the end of the first trimester and increase linearly until approximately 30 weeks. Fetal swallowing and urination then exponentially increase, peaking at term at about 1000 mL/day. Bidirectional water exchanges—so-called intramembranous fluxes—occur across the following surfaces: (1) placenta (mother-fetus), (2) umbilical vessels, through the substance of the umbilical cord (fetus–amniotic fluid), (3) fetal skin (fetus–amniotic fluid), and (4) fetal membranes (amniotic fluid–mother). These exchanges increase in a linear fashion throughout pregnancy. At term, they are approximately 400 mL/day. The fetal tracheobronchial tree is filled with amniotic fluid. Although lung fluid transport contributes a small volume, fetal inhalation is required for normal fetal lung development and is the mechanism of surfactant transport from the fetal lungs into the amniotic fluid.

Pathologic decreases and increases in amniotic fluid volume are encountered frequently in clinical practice. Intrauterine growth retardation and anomalies of the fetal urinary tract, such as bilateral renal agenesis or obstruction of the urethra, are associated with oligohydramnios, an abnormally low amniotic fluid volume. Increased fluid volume is known as hydramnios (also termed polyhydramnios ). Conditions associated with hydramnios include (1) maternal diabetes mellitus, (2) severe Rh isoimmune disease, (3) fetal esophageal atresia, (4) multifetal pregnancy, (5) anencephaly, and (6) spina bifida.

Composition

Early in gestation, the composition of the amniotic fluid resembles a complex dialysate of the maternal serum. As a fetus grows, the amniotic fluid changes in several ways ( Table 59.1 ). Most notably, the sodium concentration and osmolality decrease and concentrations of urea, creatinine, and uric acid increase. The activities of many enzymes in amniotic fluid have been studied with respect to both gestational age and fetal status but have not been found to be clinically useful. The major lipids of interest are the phospholipids (PL), whose type and concentrations reflect fetal lung maturity (FLM) (discussed further later). Numerous steroid and protein hormones are also present in amniotic fluid. The rare syndrome of congenital adrenal hyperplasia has been diagnosed antenatally by measuring 17-hydroxyprogesterone and pregnanetriol in the amniotic fluid near term. Measurements of thyroid-stimulating hormone (TSH) and thyroxine in amniotic fluid may be useful in cases of fetal thyroid disease. No other diagnostic uses for amniotic fluid hormone measurements are in common use. Prostaglandins (PGs) E ₁ , E ₂ , F ₁ α, and F ₂ α all are found in low concentrations in amniotic fluid and increase gradually during pregnancy. PGE ₂ and PGF ₂ α concentrations are very high during active labor. Attempts to demonstrate an acute rise in PGE ₂ or PGF ₂ α immediately before the onset of labor, at the initiation of parturition, have been unsuccessful.

Early in pregnancy, little or no particulate matter is found in the amniotic fluid. By 16 weeks’ gestation, large numbers of cells are present, having been shed from the surfaces of the amnion, skin, and tracheobronchial tree. These cells have proved to be of great utility in antenatal diagnosis and are the cellular source for DNA used for karyotype analysis after amniocentesis. As pregnancy continues to progress, scalp hair and lanugo (fine hair on the body of the fetus) are shed into the fluid and contribute to its turbidity. Production of surfactant particles in the lung, termed lamellar bodies, greatly increases the haziness of the fluid. At term, amniotic fluid contains gross particles of vernix caseosa, the oily substance composed of sebum and desquamated epithelial cells covering the fetal skin.

Normal fetuses do not defecate during pregnancy. If severely stressed, a fetus may pass stool that is called meconium. This heterogeneous material contains many bile pigments and therefore stains the amniotic fluid green. Meconium-stained amniotic fluid is a sign of fetal stress.

Hematologic changes

The maternal blood volume increases during pregnancy by an average of 45%. The plasma volume increases more than the red blood cell mass; Therefore despite augmented erythropoiesis, the hemoglobin concentration, erythrocyte count, and hematocrit decrease during normal pregnancy, producing the so-called physiologic anemia of pregnancy. Hemoglobin concentrations at term average 12.6 g/dL (126 g/L), compared with 13.3 g/dL (133 g/L) for the nonpregnant state. The leukocyte count varies considerably during pregnancy, from 4000 to 13,000/μL. During labor and puerperium (the interval immediately after delivery), leukocyte counts may be markedly increased.

The concentrations of several blood coagulation factors are increased during pregnancy. For example, plasma fibrinogen increases by approximately 65%, from 275 to 450 mg/dL (8.1 to 13.2 μmol/L); this increase contributes to the increase in sedimentation rate. Other clotting factors also increase, including factors VII, VIII, IX, and X. Prothrombin and factors V and XII do not change, whereas factors XI and XIII decrease slightly. Even though the platelet count remains unchanged in most women and the prothrombin time and activated partial thromboplastin time shorten slightly (see Table 59.2 ), pregnancy increases the risk of thromboembolism up to five times that of nonpregnant women.

General biochemical changes

During pregnancy, electrolytes show little change, but an approximately 40% increase in cholesterol, PL, and free fatty acids is seen. Triglycerides increase by about threefold over the course of gestation. In rare cases, this may progress to chylomicronemia in patients with certain genetic variants that affect lipid metabolism. Plasma albumin is decreased to an average of 3.4 g/dL (34 g/L) in late pregnancy; plasma globulin concentrations increase slightly. Serum cholinesterase activity is reduced, whereas alkaline phosphatase activity in serum is tripled, mainly as the result of an increase in very heat-stable alkaline phosphatase of placental origin. In addition, creatine kinase can markedly increase upon delivery.

Renal function

Pregnancy increases the glomerular filtration rate to about 170 mL/min/1.73 m ² by 20 weeks, and therefore increases the clearance of urea, creatinine, and uric acid. Concentrations of these three analytes are slightly decreased in serum for much of pregnancy. As term approaches, the glomerular filtration rate begins to return to the nonpregnant rate. Urea and creatinine concentrations rise slightly during the last 4 weeks. During this time, tubular reabsorption of uric acid increases dramatically, which increases the serum uric acid compared with the nonpregnant state. Glucosuria up to 1000 mg/day (5.55 mmol/day) may be present due to the increased glomerular filtration rate, which presents more fluid to the tubules and therefore lowers the renal glucose threshold. Protein loss in the urine can increase to up to 300 mg/day.

Endocrine changes

The action of progesterone prevents menses and thus allows pregnancy to continue. In early pregnancy, progesterone is produced by the corpus luteum of the maternal ovary in response to hCG. In later stages the placenta directly produces enough progesterone to maintain the pregnancy.

Throughout pregnancy, plasma parathyroid hormone is increased by approximately 40%, with almost no change in the plasma free ionized calcium fraction, thus suggesting a new set point for the secretion of parathyroid hormone. Calcitonin does not increase predictably during pregnancy, whereas 1,25-dihydroxyvitamin D is increased during pregnancy and promotes increased intestinal calcium absorption to support the calcium requirements for fetal skeletal development.

An increased estrogen concentration stimulates increased hepatic production of cortisol-binding globulin. The hepatic clearance of cortisol decreases. Thus the absolute plasma concentrations of both total and free cortisol are several times higher during pregnancy. The diurnal rhythm of cortisol, higher in the morning and lower in the evening, is maintained. Increased plasma aldosterone and deoxycorticosterone concentrations are observed.

Increasing estrogen concentrations throughout pregnancy increase the secretion of prolactin up to tenfold and markedly increase concentrations of sex hormone-binding globulin. Conversely, high estrogen concentrations during pregnancy suppress the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) below the detection limit. Baseline concentrations of other pituitary hormones such as TSH remain nearly unchanged (see Table 59.2 ), but the GH response to provocative stimuli is blunted.

Although normal pregnancy is a euthyroid state, as evidenced by free T4 concentrations that remain within the nonpregnant reference interval for much of pregnancy, dramatic changes are observed in other thyroid-related analytes. High concentrations of estrogens increase the concentration of thyroxine-binding globulin, which in turn causes a corresponding increase in total thyroxine and triiodothyronine. A slight decrease in free thyroxine concentration occurs at the end of the third trimester. A slight reciprocal increase in TSH was reported by Lockitch. Thyroglobulin is significantly increased, especially in the third trimester. Very few (<0.2% of) pregnant individuals develop hyperthyroidism, and hypothyroidism is very rare. Postpartum thyroiditis, caused by lymphocytic infiltration following rebound from the partial immunosuppression of pregnancy, affects an estimated 8% of pregnant women but is frequently unrecognized and misdiagnosed as routine postpartum symptoms of fatigue and weight changes. However, 25 to 30% of women with postpartum thyroiditis develop permanent hypothyroidism within 5 to 10 years, highlighting the importance of an early and accurate diagnosis.

Lungs and pulmonary surfactant

In normal air-breathing lungs, a substance called pulmonary surfactant coats the alveolar epithelium and responds to alveolar volume changes by reducing surface tension in the alveolar wall during expiration. Surfactant is needed because the surface tension is an inverse function of the radius of the airway. Thus small alveoli have a higher collapsing force than larger alveoli. Surfactant opposes the force and keeps the small alveoli from collapsing. Specialized alveolar cells called type II granular pneumocytes synthesize pulmonary surfactant and package it into laminated storage granules called lamellar bodies . ^, These storage granules are 1 to 5 μm in diameter and contain PL, cholesterol, and protein. After exocytosis into the alveolar space, lamellar bodies unfold into a structure known as tubular myelin, which supplies the lipids necessary for regulation of surface tension in the lungs. Pulmonary surfactant production starts as early as 20 weeks’ gestation, but adequate amounts do not accumulate until about 36 weeks. Exudation of pulmonary fluid (via the trachea) and fetal breathing movements transport lamellar bodies into the amniotic fluid.

The newborn lung contains 100 times more surfactant per cm ³ than the adult lung. Excessive surfactant is needed at birth as the newborn transitions from breathing water to breathing air. Surfactant overcomes the surface tension produced in water-filled alveoli that are admitting air for the first time.

Pulmonary surfactant is a complex mixture of lipids and proteins; less than 5% is composed of carbohydrates. The principal PLs present in surfactant are phosphatidylcholine (lecithin) and phosphatidylglycerol, while phosphatidylinositol and sphingomyelin are present in much lower abundance. Importantly, the predominant phosphatidylcholine species in pulmonary surfactant is dipalmitoylphosphatidylcholine, which is otherwise rarely encountered. The synthesis of phosphatidylcholine gradually increases from 28 weeks’ gestation until birth, with the highest production occurring at week 36. Similarly, phosphatidylinositol first appears at 28 weeks’ gestation, but reaches peak production at between 32 and 35 weeks. Phosphatidylglycerol is the last PL to be produced, appearing in surfactant at 36 weeks and continuing to rise until birth (see Chapter 45 ). The protein fraction of lamellar bodies is approximately 4% and is composed of four surfactant-specific proteins, SP-A, SP-B, SP-C, and SP-D.

Liver

The liver is responsible for production of specific proteins (such as albumin and clotting factors), metabolism and detoxification of many compounds, and secretion of substances such as bilirubin. Alpha-fetoprotein (AFP), produced by the fetal liver, is measured in maternal serum to evaluate the presence of neural tube defects and certain aneuploidies (see subsequent section on maternal serum screening for fetal defects). Bilirubin secretion and detoxification mechanisms are immature until late in pregnancy and even in the first few months after birth. Thus premature infants often have high serum bilirubin concentrations and metabolize drugs poorly. As described below, hematopoiesis occurs in the liver during the first two trimesters and is transferred to the fetal bone marrow during the third trimester.

Kidneys

Toward the end of the first trimester, the fetal kidneys begin to produce urine, which becomes the main component of amniotic fluid. Early nephrons cannot produce concentrated urine, and pH regulation is also limited. Complete maturation occurs after birth. Although kidneys are not required for fetal survival, amniotic fluid is required for normal lung development. Without fluid to breathe, the fetal lungs fail to properly develop. Thus newborns without kidneys die of pulmonary failure.

Fetal blood development

Fetal blood is produced first by the embryonic yolk sac, then by the liver, and finally by the fetal bone marrow. The yolk sac produces three embryonic hemoglobins: Portland (ζ ₂ γ ₂ ), Gower-1 (ζ ₂ ε ₂ ), and Gower-2 (α ₂ ε ₂ ). These normal embryonic hemoglobins are of little importance in clinical chemistry because they are present in fetal blood only in the first trimester.

With the switch of erythropoiesis to the fetal liver and spleen, fetal hemoglobin (HbF) production begins. HbF consists of two α- and two γ-chains (α ₂ γ ₂ ). Small amounts of adult hemoglobin, HbA (α ₂ β ₂ ), are also produced, but HbF predominates during the remainder of fetal life.

As the fetal bone marrow begins red cell production, HbA production increases. At birth, fetal blood contains 75% HbF and 25% HbA. HbF production rapidly diminishes during the first year of postnatal life. In normal adults, less than 1% of hemoglobin is HbF. The difference between fetal and adult hemoglobin is very significant because HbF has a higher affinity for oxygen than does HbA. Thus in the placenta, oxygen is released from the maternal HbA, diffuses into the chorionic villi, and preferentially binds to the fetal HbF. In addition, 2,3-diphosphoglycerate (2,3-DPG) does not bind HbF and therefore cannot decrease its affinity for oxygen.

Ectopic pregnancy and threatened abortion

When a fertilized egg implants in a location other than the body of the uterus, the condition is called an ectopic pregnancy. Most abnormal implantations occur in the fallopian tube; they can also occur in the abdomen, although this is rare. Common symptoms of ectopic pregnancy include abdominal pain, vaginal bleeding, and adnexal mass. Tubal rupture from the expanding nondistensible fallopian tube can cause a life-threatening hemorrhage and is a common cause of maternal death from ectopic pregnancy. From 2006 to 2010 there were 16.0 pregnancy-related deaths per 100,000 live births in the United States; 3% were due to ectopic pregnancy. Management of ectopic pregnancy can be surgical or medical (with methotrexate). ^, Early detection and proper management of ectopic pregnancy are the most effective means of preventing maternal morbidity and mortality.

Ultrasound examination is used to evaluate women with symptoms. When ultrasound is nondiagnostic, quantitative measurements of serum hCG are used to identify women with ectopic pregnancy or abnormal intrauterine pregnancy. These conditions frequently produce abnormal hCG concentrations and slow rates of increase (see At a Glance: Evaluation of Ectopic Pregnancy).

An accurate gestational age is the best predictor of when an intrauterine pregnancy should be detected with transvaginal ultrasound. Failure to detect a gestational sac by sonography 24 days or longer after conception is presumptive evidence of an ectopic pregnancy or fetal demise. An intrauterine pregnancy should be visible by ultrasonography at an hCG concentration of 1500 to 2000 IU/L, but this concentration has a clinical sensitivity of only 42% and a clinical specificity of 81% for the detection of ectopic pregnancy when no intrauterine gestational sac is visualized.

When hCG concentrations are less than 1500 IU/L and ultrasonography is nondiagnostic, serial testing of hCG is used clinically. In normal intrauterine pregnancy, during the second through fifth weeks, serum hCG doubles every 48 hours. After 5 weeks’ gestation, the doubling time gradually lengthens to 2 to 3 days. In a study of 287 women with pain and vaginal bleeding with nondiagnostic ultrasound who were later confirmed to have a viable, intrauterine pregnancy, the smallest increase in hCG over 48 hours was 53%, but as many as 35% of ectopic gestations produce an increase greater than this. In a follow-up study using the minimal rise in hCG over 48 hours of 35% (low limit of 99.9% confidence interval for viable, intrauterine pregnancy) and minimal fall over 48 hours of 21 to 35% (high limit of 90% confidence interval for spontaneous abortion), these authors demonstrated a sensitivity of 83% and specificity of 95% for the detection of ectopic pregnancy. hCG can be followed if rising appropriately until the discriminatory zone of 1500 to 2000 IU/L is reached, at which point ultrasonography can be repeated. If hCG does not increase appropriately, the differential diagnosis includes pregnancy failure and ectopic pregnancy, and repeat ultrasonographic examinations to rule out ectopic pregnancy should be undertaken.

The serum progesterone concentration is often low in mothers with an abnormal pregnancy. For example, a serum progesterone level of less than 6 ng/mL (19.1 nmol/L) predicts an abnormal pregnancy outcome with 81% confidence for asymptomatic women within 8 weeks of their last menses, but an average serum progesterone level in nonviable pregnancies was 10 ng/mL (31.8 nmol/L). For women with clinical symptoms of abnormal pregnancy, measurement of both hCG and progesterone is more predictive of abnormal pregnancy than a single hCG measurement. In a large outcome study, 97% of the patients with hCG of less than 3000 IU/L and progesterone of less than 12.6 ng/mL (40.1 nmol/L) had an abnormal pregnancy outcome, whereas those with hCG greater than 3000 IU/L or progesterone greater than 12.6 ng/mL (40.1 nmol/L) had a normal pregnancy. McCord and associates reported that in women at risk for ectopic pregnancy, a progesterone cutoff of 17.5 ng/mL (55.7 nmol/L) detected 92% of ectopic cases (clinical sensitivity), but had a very poor clinical specificity of about 14%. Investigators concluded that patients with progesterone levels greater than 17.5 ng/mL (55.7 nmol/L) needed no additional laboratory tests. A progesterone cutoff above 8 ng/mL (25.4 nmol/L) had a clinical sensitivity of 81% and a clinical specificity of 88%. In general, progesterone concentrations of 25 ng/mL (79.5 nmol/L) or more are associated with a viable intrauterine pregnancy.

(Modified from Gala RB. Ectopic pregnancy. In: Hoffman BL, Schorge JO, Schaffer JI, et al (eds). Williams Gynecology , 2nd ed. New York: McGraw-Hill; 2012.)

AT A GLANCE

Evaluation of Ectopic Pregnancy

Preeclampsia and eclampsia

Preeclampsia is a condition specific to pregnancy characterized by hypertension and other end-organ involvement, including proteinuria, cerebral vasospasm, hematologic abnormalities such as hemolysis and thrombocytopenia, and transaminitis. It can occur any time after 20 weeks (although there are cases of preeclampsia occurring at less than 20 weeks in abnormal pregnancies such as molar pregnancies). It affects 3 to 5% of pregnancies and continues to be a major cause of maternal and perinatal mortality. ^, If the mother develops generalized seizures, the condition is called eclampsia.

The disorder manifests with placental ischemia and endothelial dysfunction that leads to intravascular deposition of fibrin with subsequent end-organ damage. Most maternal deaths are due to central nervous system complications, but ischemic liver damage may also occur. The only cure for preeclampsia is delivery of the placenta. Importantly, aspirin has proven effective in preventing preeclampsia but only when initiated prior to 16 weeks gestation and at a daily dose of ≥ 100 mg. A 2018 ACOG Committee Opinion recommends the use of low-dose aspirin in high-risk women (as defined by a personal history of preeclampsia or other medical conditions) to prevent or delay the onset of preeclampsia

The cause of preeclampsia has not been elucidated, but many biomarkers have been examined in an attempt to predict its onset. The most promising of these are angiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin. Several studies have shown that aberrant expression of these angiogenic factors precedes the onset of preeclampsia. A systematic review of 34 studies on these markers found significant differences in marker concentrations before 30 weeks’ gestation between women who developed preeclampsia and women who did not. However, little difference was seen prior to 16 weeks’ gestation and the poor sensitivity and specificity of individual factors suggested that these markers are not clinically useful for early prediction of preeclampsia, limiting their utility in the identification of women who would benefit from early initiation of low-dose aspirin. Subsequent work evaluated the performance of a sFlt-1/PlGF ratio of ≤38 (Roche Elecsys) to rule out preeclampsia in 550 women with suggestive signs and symptoms between 24+0 and 36+6 weeks gestation. Negative predictive values (NPVs) for preeclampsia within 1, 2, 3, or 4 weeks were 99.3, 97.9, 95.7, and 94.3, respectively. However, as the prevalence of preeclampsia at each of these time points was 2.7, 7.5, 10.9, and 12.9%, respectively, incorporation of the sFlt-1/PlGF ratio only modestly decreased the pre-test probability of disease. (NPVs in the absence of biomarker measurement were 97.3, 92.5, 89.1, and 87.1%, respectively). This study also found a statistically significant increase in the median change in the sFlt1-PlGF ratio (week 3 sFlt-1/PlGF − week 1 sFlt-1/PlGF) between women who developed preeclampsia and those who did not. However, the range of values in the preeclampsia group overlapped completely with the group of women who did not experience preeclampsia, limiting the effectiveness of this measure in the evaluation of individual women. A later study of 1035 women with suspected preeclampsia found that knowledge of PlGF concentrations reduced the time to preeclampsia diagnosis but had no effect on gestational age at delivery or other maternal or fetal outcomes.

Professional societies differ in their recommendations regarding the clinical use of PlGF in the evaluation of suspected preeclampsia. The 2019 National Institute for Health and Care Excellence (NICE) guideline recommends a single PlGF measurement between 20 and 35 weeks to rule out preeclampsia in women with suggestive signs and symptoms but recommends against the use of PlGF to rule in preeclampsia. The 2020 ACOG practice bulletin on gestational hypertension and preeclampsia notes that biomarkers cannot accurately predict preeclampsia and recommends that they remain investigational.

HELLP syndrome

The HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow platelet counts in association with p reeclampsia) is a life-threatening obstetric complication that occurs in 0.1% of pregnancies. Its most prominent features are thrombocytopenia and disseminated intravascular coagulation (see Chapter 81 ). Most cases occur between 27 and 36 weeks’ gestation, but the syndrome also may occur postpartum. Women typically present with epigastric or right upper quadrant pain, malaise, nausea, vomiting, and headache. ^, Jaundice occurs in 5% of patients. Lactate dehydrogenase values may be very high, reflecting high levels of red blood cell hemolysis, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually 2 to 10 times their upper reference limits. Treatment is delivery. Recurrence rates are 3 to 27%.

Liver disease

Several liver disorders are unique to pregnancy. ^, These include (1) hyperemesis gravidarum, (2) cholestasis of pregnancy, and (3) fatty liver of pregnancy. These disorders must be distinguished from the normal physiologic changes of pregnancy (see Table 59.2 ). Significant changes normally seen in pregnancy include a dilutional decrease in serum albumin and an increase of alkaline phosphatase (from the placenta). Notably, total bilirubin, 5′-nucleotidase, gamma-glutamyl transpeptidase, ALT, and AST are unchanged in mothers with a normal pregnancy. Changes in these analytes reflect hepatobiliary disease. Also discussed in this section are (1) non–pregnancy-related liver disease in pregnancy, (2) differential diagnosis, and (3) effect of pregnancy on preexisting liver disease.

Neonatal thyroid function

During the first trimester of pregnancy, the fetus is dependent on the mother for its supply of thyroid hormone. Low maternal thyroid hormone concentrations (overt or subclinical hypothyroidism) have been associated with adverse outcomes, such as preterm delivery, fetal death, and a reduced IQ in children. ^, Women with untreated thyroid deficiency in pregnancy are also more likely to have permanent hypothyroidism after pregnancy (64%) than are euthyroid mothers.

Later in pregnancy, the fetal thyroid–pituitary axis functions independently from the mother’s axis in most cases. However, if the mother has preexisting Graves disease (see Chapter 57 ), her IgG autoantibodies can cross the placenta and stimulate the fetal thyroid gland. Thus the fetus can develop hyperthyroidism. Measurement of TSH-receptor antibodies by thyroid-stimulating Ig assay is useful for assessing the risk of fetal or neonatal Graves disease.

An association between an underactive thyroid gland during pregnancy and delayed neurodevelopment in the offspring is well known. In 1999, Haddow and colleagues suggested that even subclinical hypothyroidism could result in a lower IQ in the offspring of affected women. For this reason, there has been discussion about routine screening of pregnant women for thyroid function. The American Association of Clinical Endocrinologists guidelines indicate that TSH screening should be routine before pregnancy or during the first trimester, and if the TSH is more than 10 mIU/L or if the TSH is 5 to 10 mIU/L and the patient has goiter or positive anti–thyroid peroxidase antibodies, then thyroid hormone replacement therapy should be initiated. In contrast, the American Thyroid Association and the Endocrine Society only recommend screening pregnant women who are at high risk of overt hypothyroidism (e.g., history of thyroid dysfunction, thyroid peroxidase antibodies positive, goiter). ^, If the TSH is more than 10 mIU/L, the guidelines suggest that thyroid hormone replacement therapy be initiated. The American College of Obstetricians and Gynecologists (ACOG) has recommended against screening all pregnant women for hypothyroidism, as there is lack of evidence that treatment of women with subclinical hypothyroidism will improve maternal or infant outcomes. Regardless, when thyroid hormone is tested, the results should be interpreted using pregnancy-specific reference intervals.

Hemolytic disease of the newborn

HDN is a fetal hemolytic disorder caused by maternal antibodies directed against antigen on fetal erythrocytes. Commonly used synonyms for this disorder are isoimmunization disease, Rh isoimmune disease, Rh disease, or D isoimmunization. Any of a large number of erythrocyte surface antigens—Rh (CcDEe), A, B, Kell, Duffy, Kidd, and others—may be responsible for isoimmune hemolysis. When severe, the disorder is known as erythroblastosis fetalis and is life-threatening to the fetus and newborn. In the past, disease severity was assessed by measuring the amount of bilirubin in the amniotic fluid, and a description of methods for measurement of amniotic fluid bilirubin is available in previous editions of this textbook. This method is no longer widely practiced, however. Presently, the noninvasive ultrasonographic determination of middle fetal cerebral artery velocity has replaced amniotic fluid bilirubin measurements. ^,