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, which are surrounded by intervillous spaces in which maternal blood flows. 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 57-1). 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 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 maternal antibodies.

Placental Hormones

The placenta produces several protein and steroid hormones (Figure 57-1). The major protein hormones are CG and placental lactogen (PL). The steroids include progesterone, estradiol, estriol, and estrone. The placenta secretes most of its products into the maternal circulation; only small amounts reach the fetal circulation. Close proximity of the maternal blood vessels to the site of placental hormone production may explain some of this preferential accumulation of hormones in the maternal blood circulation. 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 PL, increase in maternal peripheral blood as the placenta increases in size. CG, 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.³¹² 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 interrelated fluid fluxes. Direct measurements in primates and indirect measurements in humans have been used to derive a mathematical model of amniotic fluid volume.²³⁹ 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/d. 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/d. The fetal tracheobronchial tree is filled with amniotic fluid. Although lung fluid transport contributes a small volume, fetal breathing of this fluid 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 57-1). Most notably, sodium concentration and osmolality decrease and concentrations of urea, creatinine, and uric acid increase.³⁹ 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, whose type and concentrations reflect fetal lung maturity (discussed further later). Numerous steroid and protein hormones are also present in amniotic fluid.⁴¹⁸ Concentrations of androgens and estrogens have been measured in futile attempts to predict fetal sex. The rare syndrome of congenital adrenal hyperplasia (CAH) has been diagnosed antenatally by measuring 17-hydroxyprogesterone and pregnanetriol in the amniotic fluid near term.¹⁹⁰ Measurements of thyroid-stimulating hormone (TSH) and thyroxine in amniotic fluid may be useful in cases of fetal thyroid disease.³⁴⁸ No other diagnostic uses for amniotic fluid hormone measurements are in common use. Prostaglandins E₁, E₂, F_1α, and F_2α all are found in low concentrations in amniotic fluid and increase gradually during pregnancy. PGE₂ and PGF_2α concentrations are very high during active labor.¹⁰⁹ Attempts to demonstrate an acute rise in PGE₂ or PGF_2α 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 of 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. 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

Maternal blood volume increases during pregnancy by an average of 45%. Plasma volume increases more rapidly than red blood cell mass; therefore, despite augmented erythropoiesis, hemoglobin concentration, erythrocyte count, and hematocrit decrease during normal pregnancy. Hemoglobin concentrations at term average 12.6 g/dL, compared with 13.3 g/dL 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 elevated.

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; 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 prothrombin time and activated partial thromboplastin time shorten slightly (see Table 57-2), pregnancy increases the risk of thromboembolism to up to five times that of nonpregnant women.

Biochemical Changes

During pregnancy, electrolytes show little change, but an approximately 40% increase in serum triglycerides, cholesterol, phospholipids, and free fatty acids is seen. Plasma albumin is decreased to an average of 3.4 g/dL in late pregnancy; plasma globulin concentrations increase slightly. Several of the plasma transport proteins, including thyroxine-binding globulin (TBG), cortisol-binding globulin (CBG), and sex hormone-binding globulin (SHBG), increase markedly. 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 (GFR) to about 170 mL/min/1.73 m² 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 the pregnancy. As term approaches, GFR begins to return to nonpregnant values. Urea and creatinine concentrations rise slightly during the last 4 weeks. During this time, tubular reabsorption of uric acid increases dramatically, which increases serum uric acid compared with the nonpregnant state. Glucosuria, up to 1000 mg/d, may be present owing to increased GFR, 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/d.

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 CG. In later stages, the placenta directly produces enough progesterone to maintain the pregnancy.

Throughout pregnancy, the plasma parathyroid hormone (PTH) 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 PTH. Calcitonin does not increase predictably during pregnancy, whereas 1,25-dihydroxyvitamin D is increased during pregnancy and promotes increased intestinal calcium absorption. These changes permit the transfer of large amounts of calcium to the developing fetus.

Elevated estrogen concentration stimulates increased hepatic production of CBG. 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. 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 57-2), but the GH response to provocative stimuli is blunted.

Although normal pregnancy is a euthyroid state, many changes occur in thyroid function. High concentrations of TBG raise the concentration of total thyroxine (T₄) and triiodothyronine (T₃), but a slight decrease in free T₄ concentration occurs during the second and third trimesters. A slight reciprocal increase in TSH was reported by Lockitch.²²⁹ Thyroglobulin is significantly increased, especially in the third trimester.¹⁵¹ Very few (<0.2%) pregnant individuals develop hyperthyroidism, and hypothyroidism is very rare.⁶⁷ Postpartum thyroid dysfunction is common and is frequently unrecognized. The fetal thyroid-pituitary axis functions independently from the mother’s axis in most cases. However, if the mother has preexisting Graves disease (hyperthyroidism caused by autoantibodies that stimulate the thyroid), those antibodies can cross the placenta, causing hyperthyroidism in the fetus. If the mother has anti-TSH autoantibodies, the infant can develop transient hypothyroidism.²²⁹

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 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.186,351 These storage granules are 1 to 5 µm in diameter and contain phospholipids, cholesterol, and protein.²⁷⁶ Production starts as early as 20 weeks’ gestation,³⁵¹ 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 internal structure of the particles is rearranged into a formation described as tubular myelin by those using electron microscopy.¹⁸⁶ The newborn lung contains 100 times more surfactant per cm³ than the adult lung. Excessive surfactant is needed at birth as the newborn is transformed 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. Most of the lipid is phospholipid, and most of that is lecithin (phosphatidylcholine).⁶⁵ Unlike lecithin from other tissues, pulmonary lecithin has two saturated fatty acids, usually palmitoyl groups. Other lipids present are phosphatidylglycerol (PG), phosphatidylinositol (PI), and phosphatidylethanolamine (see Chapter 27). Sphingomyelin is present in very small amounts (<2%). 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.^177,297

Type II pneumocytes synthesize phosphatidylcholine in a manner quite different from that seen in other cells. Most other cells synthesize phosphatidylserine from cytidine diphosphate diacylglycerol and serine. The phosphatidylserine then is decarboxylated to yield phosphatidyl ethanolamine. The final step is the successive donation of three methyl groups via S-adenosylmethionine to form phosphatidylcholine. The pulmonary biosynthetic pathway is shown in Figure 57-2. The enzyme choline phosphotransferase forms PC directly from cytidine diphosphocholine and diacylglycerol. Phosphatidylinositol formation peaks at about 35 weeks. As PI decreases in concentration, PG begins to increase.

Liver

Hematopoiesis occurs in the liver during the first two trimesters and is transferred to the fetal bone marrow during the third trimester. The liver is also 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. A clinically useful protein produced by the liver is alpha fetoprotein (AFP). Detoxification and bilirubin secretion 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.

Kidneys

Toward the end of the first trimester, the fetal kidneys begin to produce urine, which is 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. 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 (ζ₂γ₂), Gower-1 (ζ₂ε₂), and Gower-2 (α₂ε₂). 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 (Hb F) production begins. Hb F consists of two α- and two γ-chains (α₂γ₂). Small amounts of adult hemoglobin, Hb A (α₂β₂), are also produced, but Hb F predominates during the remainder of fetal life.

As the fetal bone marrow begins red cell production, Hb A production increases. At birth, fetal blood contains 75% Hb F and 25% Hb A. Hb F production rapidly diminishes during the first year of postnatal life. In normal adults, less than 1% of hemoglobin is Hb F. The difference between fetal and adult hemoglobin is very significant as Hb F has a higher affinity for oxygen than does Hb A. Thus in the placenta, oxygen is released from the maternal Hb A, diffuses into the chorionic villi, and binds to the fetal Hb F. In addition, 2,3-diphosphoglycerate (2,3-DPG) does not bind Hb F 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. Tubal rupture and hemorrhage are common serious complications of ectopic pregnancy. About 25% of individuals with an ectopic pregnancy have three classic symptoms: lower abdominal pain, vaginal bleeding, and an adnexal mass.³³² Of all individuals with these symptoms, about 15% have an ectopic pregnancy, and a smaller percentage have incomplete or complete spontaneous abortion. In 2006, the United States had 13.3 pregnancy-related deaths per 100,000 live births²⁵⁷—3% caused by ectopic pregnancy.¹⁸¹ A pregnant patient has about a 1 in 200 chance of dying from an ectopic pregnancy.¹⁵⁵ Management of ectopic pregnancy is surgical (by laparoscopy) or medical (with intramuscular administration of methotrexate).^15,21 Early detection and proper management of ectopic pregnancy are the most effective means of preventing maternal morbidity and mortality. Some have suggested that asymptomatic women at high risk for ectopic pregnancy should be screened with the use of ultrasound and laboratory tests.⁶⁹

Ultrasound examination is used to evaluate women with symptoms. When ultrasound is nondiagnostic, quantitative measurements of serum CG are used to identify women with ectopic pregnancy or abnormal intrauterine pregnancy. These conditions frequently produce abnormal CG concentrations and slow rates of increase.⁵⁸

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 provides presumptive evidence of an ectopic pregnancy or fetal demise.¹⁹³ In the absence of an accurate gestational age, a serum CG concentration is required to assist in interpreting a nondiagnostic ultrasound. An intrauterine pregnancy should be visible by ultrasonography at a CG 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.²⁰⁵

When CG concentrations are less than 1500 IU/L and ultrasonography is nondiagnostic, serial testing of CG may be very helpful. In normal intrauterine pregnancy, during the second through fifth weeks, the CG doubles every 1.5 days. After 5 weeks’ gestation, the doubling time gradually lengthens to 2 to 3 days.³⁰⁵ Before 7 weeks, calculation of the slope of log(CG) versus time in days is useful for identifying normal pregnancies.¹⁹² At least two CG determinations should be obtained from specimens collected 1 to 7 days apart. The log-linear slope, Δlog(CG)/Δtime [in log(IU/L)/d], is greater than 0.11 in the vast majority of normal pregnancies. In cases of ectopic pregnancy or spontaneous abortion, the slope is usually less than 0.11, and the CG concentrations often decrease. An increase in CG of at least 53% over 48 hours is 99% specific for excluding an ectopic pregnancy,³³ but as many as 35% of ectopic gestations produce an increase greater than this.³⁴⁵

Serum progesterone concentration is often low in mothers with abnormal pregnancy.³¹⁴ For example, a serum progesterone less than 6 ng/mL predicts an abnormal pregnancy outcome with 81% confidence for asymptomatic women within 8 weeks of their last menses,¹⁰⁶ but average serum progesterone in nonviable pregnancies is 10 ng/mL. For women with clinical symptoms of abnormal pregnancy, measurement of both CG and progesterone is more predictive of abnormal pregnancy than a single CG measurement. In a large outcome study, 97% of patients with CG less than 3000 IU/L and progesterone less than 12.6 ng/mL had an abnormal pregnancy outcome, whereas those with CG greater than 3000 IU/L or progesterone greater than 12.6 ng/mL had a normal pregnancy.²⁷² McCord and associates²⁴² reported that in women at risk for ectopic pregnancy, a progesterone cutoff of 17.5 ng/mL detected 92% of ectopic cases (clinical sensitivity) but had a very poor clinical specificity of about 14%. Investigators concluded that patients with progesterone greater than 17.5 ng/mL needed no additional laboratory tests. Finally, in symptomatic patients, Stewart and colleagues³⁶² reported a clinical sensitivity of 99% and a clinical specificity of 65% when a Δlog(CG)/Δtime greater than 0.14 is used to distinguish normal intrauterine pregnancy from ectopic pregnancy combined with inevitable abortion. A progesterone cutoff above 8 ng/mL had a clinical sensitivity of 81% and a clinical specificity of 88%.

Preeclampsia and Eclampsia

Preeclampsia is a pregnancy condition characterized by hypertension, proteinuria, and often edema, usually occurring late in the second trimester or early in the third trimester, and affecting 5 to 10% of pregnancies. It is a major cause of maternal and perinatal mortality. If the mother develops convulsions, the condition is called eclampsia. The cause has not been elucidated,³⁵⁹ but research suggests that increased circulating soluble fms-like tyrosine kinase 1 (sFlt-1) may have a role.²²²

The disorder manifests with placental ischemia and endothelial dysfunction that leads to intravascular deposition of fibrin with subsequent end-organ damage.³²⁰ 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.³⁵⁹

HELLP Syndrome

The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet counts in association with preeclampsia) is a life-threatening obstetric complication that occurs in 0.1% of pregnancies. Its most prominent features are thrombocytopenia and disseminated intravascular coagulation (DIC; see Chapter 59). Most cases occur between the 27th and 36th weeks of pregnancy, but the syndrome also may occur postpartum. Women typically present with epigastric or right upper quadrant pain, malaise, nausea, vomiting, and headache.^240,343 Jaundice occurs in 5% of patients. Lactate dehydrogenase (LD) concentrations may be very high, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually 2 to 10 times their upper reference limits. Treatment is delivery. Postpartum management of the patient may require plasmapheresis or organ transplantation. Recurrence rates are 3 to 27%.

Liver Disease

Several liver disorders are unique to pregnancy.191,204 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 57-2). Significant changes normally seen in pregnancy include a dilutional decrease in serum albumin and elevation of alkaline phosphatase (from the placenta). Notably, total bilirubin; 5′-nucleotidase, gamma-glutamyltranspeptidase (GGT), 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.

Stay updated, free articles. Join our Telegram channel

Join