Amy A. Flick, MD
Daniel A. Kahn, MD, PhD
Pregnancy involves a number changes in anatomy, physiology, and biochemistry, which can challenge maternal reserves. A basic knowledge of these adaptations is critical for understanding normal laboratory measurements, knowing the drugs likely to require dose adjustments, and recognizing women who are predisposed to medical complications during pregnancy.
CARDIOVASCULAR SYSTEM
Anatomic Changes
With uterine enlargement and diaphragmatic elevation, the heart rotates on its long axis in a left-upward displacement. As a result of these changes, the apical beat (point of maximum intensity) shifts laterally. Overall, the heart size increases by approximately 12%, which results from both an increase in myocardial mass and intracardiac volume (approximately 80 mL). Vascular changes include hypertrophy of smooth muscle and a reduction in collagen content.
Blood Volume
Blood volume expansion begins early in the first trimester, increases rapidly in the second trimester, and plateaus at about the 30th week (Fig. 8–1). The approximately 50% elevation in plasma volume, which accounts for most of the increment, results from a cascade of effects triggered by pregnancy hormones. For example, increased estrogen production by the placenta stimulates the renin–angiotensin system, which, in turn, leads to higher circulating levels of aldosterone. Aldosterone promotes renal Na+ reabsorption and water retention. Progesterone also participates in plasma volume expansion through a poorly understood mechanism; increased venous capacitance is another important factor. Human chorionic somatomammotropin, progesterone, and perhaps other hormones promote erythropoiesis, resulting in the approximately 30% increase in red cell mass.
Figure 8–1. Increases in maternal hormones (A, B), blood volume (C), and cardiac output (D) over gestation. % control represents the increment relative to nonpregnant values. (Modified, with permission, from Longo LD. Maternal blood volume and cardiac output during pregnancy: A hypothesis of endocrinologic control. Am J Physiol 1983;245:R720.)
The magnitude of the increase in blood volume varies according to the size of the woman, the number of prior pregnancies, and the number of fetuses she is carrying. This hypervolemia of pregnancy compensates for maternal blood loss at delivery, which averages 500–600 mL for vaginal and 1000 mL for caesarean delivery.
Cardiac Output
Cardiac output increases approximately 40% during pregnancy, with maximum values achieved at 20–24 weeks’ gestation. This rise in cardiac output is thought to result from the hormonal changes of pregnancy, as well as the arteriovenous-shunt effect of uteroplacental circulation.
Stroke volume increases 25–30% during pregnancy, reaching peak values at 12–24 weeks’ gestation (Fig. 8–2). Thus elevations in cardiac output after 20 weeks of gestation depend critically on the rise in heart rate. Maximum cardiac output is associated with a 24% increase in stroke volume and a 15% rise in heart rate. Cardiac output increases in labor in association with painful contractions, which increase venous return and activate the sympathetic nervous system. Cardiac output is further increased, albeit transiently, at delivery.
Figure 8–2. Increases in maternal stroke volume and heart rate. The % control represents increment relative to measurements in patients who are not pregnant. (Reproduced, with permission, from Koos BJ. Management of uncorrected, palliated, and repaired cyanotic congenital heart disease in pregnancy. Prog Ped Cardiol 2004;19:250.)
Stroke volume is sensitive to maternal position. In lateral recumbency, stroke volume remains roughly the same from 20 weeks’ gestation until term, but in the supine position stroke volume decreases after 20 weeks and can even decrease to nonpregnant levels by 40 weeks’ gestation.
The resting maternal heart rate, which progressively increases over the course of gestation, averages at term approximately 15 beats/min more than the nonpregnant rate (Fig. 8–2). Of course, exercise, emotional stress, heat, drugs, and other factors can further increase heart rate.
Multiple gestations have even more profound effects on the maternal cardiovascular system. In twin pregnancies, cardiac output is approximately 20% greater than for singletons, because of greater stroke volume (15%) and heart rate (3.5%). Other differences include greater left ventricular end-diastolic dimensions and muscle mass.
Cardiac output is generally resistant to postural stress. For example, the decrease in cardiac output that develops immediately after standing does not occur in the middle of the third trimester, although some reduction can occur earlier in pregnancy. In the third trimester, the supine position can reduce cardiac output and arterial pressure caused by compression of the vena cava by the gravid uterus with an associated reduction in venous return to the heart. Approximately 10% of gravidas will develop supine hypotensive syndrome, characterized by hypotension, bradycardia, and syncope. These women are particularly sensitive to caval compression because of reduced capacitance in venous collaterals. Shifting the gravida to a right or left lateral recumbent position will alleviate caval compression, increase blood return to the heart, and restore cardiac output and arterial pressure.
Blood Pressure
Systemic arterial pressure declines slightly during pregnancy, reaching a nadir at 24–28 weeks of gestation. Pulse pressure widens because the fall is greater for diastolic than for systolic pressures (Fig. 8–3). Systolic and diastolic pressures (and mean arterial pressure) increase to prepregnancy levels by approximately 36 weeks.
Figure 8–3. Changes in maternal peripheral vascular resistance and arterial pressures over gestation. Pressures were measured in the left lateral recumbent position. The % control represents the relative change from nonpregnant values. (Modified, with permission, from Thornburg KL, Jacobson SL, Giraud GD, Morton MJ. Hemodynamic changes in pregnancy. Semin Perinatol 2000;24:11–14; Wilson M, Morganti AA, Zervoudakis I, et al. Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 1980;68:97–104.)
Venous pressure progressively increases in the lower extremities, particularly when the patient is supine, sitting, or standing. The rise in venous pressure, which can cause edema and varicosities, results from compression of the inferior vena cava by the gravid uterus and possibly from the pressure of the fetal presenting part on the common iliac veins. Lying in lateral recumbency minimizes changes in venous pressure. As expected, venous pressure in the lower extremities falls immediately after delivery. Venous pressure in the upper extremities is unchanged by pregnancy.
Peripheral Vascular Resistance
Vascular resistance decreases in the first trimester, reaching a nadir of approximately 34% below nonpregnancy levels by 14 to 0 weeks of gestation with a slight increase toward term (Fig. 8–3). The hormonal changes of pregnancy likely trigger this fall in vascular resistance by enhancing local vasodilators, such as nitric oxide, prostacyclin, and possibly adenosine. Delivery is associated with nearly a 40% decrease in peripheral vascular resistance, although mean arterial pressure is generally maintained because of the associated rise in cardiac output.
Blood Flow Distribution
In absolute terms, blood flow increases to the uterus, kidneys, skin, breast, and possibly other maternal organs; the total augmented organ flow reflects virtually the entire increment in maternal cardiac output. However, when expressed as a percentage of cardiac output, blood flow in some of these organs may not be elevated compared with the nonpregnant state.
Blood flow to the uterus increases in a gestational age-dependent manner. Uterine blood flow can be as high as 800 mL/min, which is approximately 4 times the nonpregnant value. The increased flow during pregnancy results from the relatively low resistance in the uteroplacental circulation.
Renal blood flow increases approximately 400 mL/min above nonpregnant levels, and blood flow to the breasts increases approximately 200 mL/min. Blood flow to the skin also increases, particularly in the hands and feet. The increased skin blood flow helps dissipate heat produced by metabolism in the mother and fetus.
Strenuous exercise, which diverts blood flow to large muscles, has the potential to decrease uteroplacental perfusion and thus O2 delivery to the fetus. Women who are already adapted to an exercise routine can generally continue the program in pregnancy; however, pregnant women should discuss their exercise plans with the physician managing the pregnancy.
HEART MURMURS & RHYTHM
The physiologic changes of pregnancy alter several clinical findings. For example, systolic ejection murmurs, which result from increased cardiac output and decreased blood viscosity, can be detected in 90% or more gravidas. Thus caution should be exercised in interpreting systolic murmurs in pregnant women.
The first heart sound may be split, with increased loudness of both portions, and the third heart sound may also be louder. Continuous murmurs or bruits may be heard at the left sternal edge, which arise from the internal thoracic (mammary) artery.
Pregnancy decreases the threshold for reentrant supraventricular tachycardia. Normal pregnancy can also be accompanied by sinus tachycardia, sinus bradycardia, and isolated atrial and ventricular premature contractions.
Electrocardiographic changes can include a 15- to 20-degree shift to the left in the electrical axis. Changes in ventricular repolarization can result in ST-segment depression or T-wave flattening. However, pregnancy does not alter the amplitude and duration of the P wave, QRS complex, or T wave.
PULMONARY SYSTEM
Anatomic Changes
Pregnancy alters the circulation of a number of tissues involved in respiration. For example, capillary dilatation leads to engorgement of the nasopharynx, larynx, trachea, and bronchi. Prominent pulmonary vascular markings observed on x-ray are consistent with increased pulmonary blood volume.
As the uterus enlarges, the diaphragm is elevated by as much as 4 cm. The rib cage is displaced upward, increasing the angle of the ribs with the spine. These changes increase the lower thoracic diameter by approximately 2 cm and the thoracic circumference by up to 6 cm. Elevation of the diaphragm does not impair its function. Abdominal muscles have less tone and activity during pregnancy, causing respiration to be more diaphragm dependent.
Lung Volumes and Capacities
Several lung volumes and capacities are altered by pregnancy (Table 8–1). Dead space volume increases because of relaxation of the musculature of conducting airways. Tidal volume and inspiratory capacity increase. Elevation of the diaphragm is associated with reduction in total lung capacity and functional residual capacity. The latter involves a decrease in both expiratory reserve and residual volumes.
Table 8–1. Effects of pregnancy on lung volumes and capacities.
Respiration
Pregnancy has little effect on respiratory rate. Thus the increase in minute ventilation (approximately 50%) results from the rise in tidal volume. This increment in minute ventilation is disproportionately greater than the rise (approximately 20%) in total oxygen consumption in maternal muscle tissues (cardiac, respiratory, uterine, skeletal) and in the products of the fetal genome (placenta, fetus). This hyperventilation, which decreases maternal arterial PCO2 to approximately 27–32 mm Hg, results in a mild respiratory alkalosis (blood pH of 7.4–7.5). The hyperventilation and hyperdynamic circulation slightly increase arterial PO2.
Increased levels of progesterone appear to have a critical role in the hyperventilation of pregnancy, which develops early in the first trimester. As in the luteal phase of the menstrual cycle of nonpregnant women, the increased ventilation appears to be caused by the action of progesterone on central neurons involved in respiratory regulation. The overall respiratory effect appears to be a decrease in the threshold and an increase in the sensitivity of central chemoreflex responses to CO2. Maternal hyperventilation may be protective in that that it prevents the fetus from being exposed to high CO2 tensions, which might adversely affect the development of respiratory control and other critical regulatory mechanisms.
Functional measurement of ventilation can also change according to posture and duration of pregnancy. For example, the peak expiratory rate, which declines throughout gestation in the sitting and standing positions, is particularly compromised in the supine position.
RENAL SYSTEM
Anatomic Changes
During pregnancy, the length of the kidneys increases by 1–1.5 cm, with a proportional increase in weight. The renal calyces and pelves are dilated in pregnancy, with the volume of the renal pelvis increased up to 6-fold compared with the nonpregnant value of 10 mL. The ureters are dilated above the brim of the bony pelvis, with more prominent effects on the right. The ureters elongate, widen, and become more curved. The entire dilated collecting system may contain up to 200 mL of urine, which predisposes to ascending urinary infections. Urinary tract dilatation disappears in virtually all women by postpartum day 4.
Several factors likely contribute to the hydronephrosis and hydroureter of pregnancy: (1) Pregnancy hormones (eg, progesterone) may cause hypotonia of ureteral smooth muscle. Against this possibility is the observation that high progesterone levels in nonpregnant women do not cause hydroureter. (2) Enlargement of the ovarian vein complex in the infundibulopelvic ligament may compress the ureter at the brim of the bony pelvis. (3) Hyperplasia of smooth muscle in the distal one-third of the ureter may cause reduction in luminal size, leading to dilatation in the upper two-thirds. (4) The sigmoid colon and dextrorotation of the uterus likely reduce compression (and dilatation) of the left ureter relative to the right.
Renal Function
Renal plasma flow increases 50–85% above nonpregnant values during the first half of pregnancy, with a modest decrease in later gestation. The changes in renal plasma flow reflect decreases in renal vascular resistance, which achieves lowest values by the end of the first trimester. Elevated renal perfusion is the principal factor involved in rise in glomerular filtration rate (GFR), which is increased by approximately 25% in the second week after conception. GFR reaches a peak increment of 40–65% by the end of the first trimester and remains high until term (Fig. 8–4). The fraction of renal plasma flow that passes through the glomerular membrane (filtration fraction) decreases during the first 20 weeks of gestation, which subsequently rises toward term.
Figure 8–4. Increases in glomerular filtration over gestation as reflected by changes in inulin and endogenous creatinine clearances. The % control represents relative change from postpartum values. (Data from Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974;81:558.)
Hormones involved in these changes in renal vascular resistance may include progesterone and relaxin (via upregulation of vascular matrix metalloproteinase-2). Agents elaborated by the endothelium, such as endothelin (ET) (via activation of ETB receptor subtype) and nitric oxide (via increased cyclic guanosine –3’,5’-monophosphate), are likely to be critically involved in the reduction of renal vascular resistance. An additional factor is the increased cardiac output, which permits increased renal perfusion without depriving other organs of blood flow.
Urinary flow and sodium excretion rates in late pregnancy are increased 2-fold in lateral recumbency compared with the supine position. Thus measurements of urinary function must take into account maternal posture. Collection periods should be at least 12–24 hours to allow for errors caused by the large urinary dead space. However, reasonable estimates of urinary excretion of a particular substance over shorter time periods generally can be calculated by referencing the level to the creatinine concentration in the same sample of urine (substance/creatinine ratio) with the assumption that a pregnant woman excretes 1 g of creatinine per day. Creatinine production (0.7–1.0 g/day) by skeletal muscle is virtually unchanged by pregnancy.
Up to 80% of the glomerular filtrate is reabsorbed by the proximal tubules, a process that is independent of hormonal control. Aldosterone regulates sodium reabsorption in the distal tubules, whereas arginine vasopressin activity, which regulates free water clearance, determines the ultimate urine concentration. Pregnancy is associated with increased circulating concentrations of aldosterone. Even though the GFR increases dramatically during gestation, the volume of urine excreted per day is unchanged.
Renal clearance of creatinine increases as the GFR rises, with maximum clearances approximately 50% more than nonpregnant levels. The creatinine clearance decreases somewhat after approximately 30 weeks of gestation. The rise in GFR lowers mean serum creatinine concentrations (pregnant, 
; nonpregnant, 
) and blood urea nitrogen (pregnant, 
; nonpregnant, 
mg/100 mL) concentrations.
Increased GFR with saturation of tubular resorption capacity for filtered glucose can result in glucosuria. In fact, more than 50% of women have glucosuria sometime during pregnancy. Increased urinary glucose levels contribute to increased susceptibility of pregnant women to urinary tract infection.
Urinary protein loss normally does not exceed 300 mg over 24 hours, which is similar to the nonpregnant state. Thus proteinuria of more than 300 mg over 24 hours suggests a renal disorder.
Renin activity increases early in the first trimester and continues to rise until term. This enzyme is critically involved in the conversion of angiotensinogen to angiotensin I, which subsequently forms the potent vasoconstrictor angiotensin II. Angiotensin II levels also increase in pregnancy, but the vasoconstriction and hypertension that might be expected do not occur. In fact, normal pregnant women are very resistant to the pressor effects of elevated levels of angiotensin II and other vasopressors; this effect is likely mediated by increased vascular synthesis of nitric oxide and other vasodilators.
Angiotensin II is also a potent stimulus for adrenocortical secretion of aldosterone, which, in conjunction with arginine vasopressin, promotes salt and water retention in pregnancy. The net effect is a decrease in plasma sodium concentrations by approximately 5 mEq/L and a fall in plasma osmolality by nearly 10 mOsm/kg. These effects on electrolyte homeostasis likely involve a resetting of the pituitary osmostat. In pregnancy, the increased pituitary secretion of vasopressin is largely balanced by placental production of vasopressinase. Pregnant women who are unable to sufficiently augment vasopressin secretion can develop a diabetes insipidus–like condition characterized by massive diuresis and profound hypernatremia. Cases have been described with maternal sodium levels reaching 170 mEq/L.
Bladder
As the uterus enlarges, the urinary bladder is displaced upward and flattened in the anteroposterior diameter. One of the earliest symptoms of pregnancy is increased urinary frequency, which may be related to pregnancy hormones. In later gestation, mechanical effects of the enlarged uterus may contribute to the increased frequency. Bladder vascularity increases and muscle tone decreases, which increases bladder capacity up to 1500 mL.
GASTROINTESTINAL SYSTEM
Anatomic Changes
As the uterus grows, the stomach is pushed upward and the large and small bowels extend into more rostrolateral regions. Historically, it has been believed that the appendix is displaced superiorly in the right flank area. Recent literature has called this, and other common assumptions regarding pregnancy-associated changes, in to question. It is clear that organs return to their normal positions in the early puerperium.
Oral Cavity
Salivation appears to increase, although this may be caused in part by swallowing difficulty associated with nausea. Pregnancy does not predispose to tooth decay or to mobilization of bone calcium.
The gums may become hypertrophic and hyperemic; often, they are so spongy and friable that they bleed easily. This may be caused by increased systemic estrogen because similar problems sometimes occur with the use of oral contraceptives.
Esophagus & Stomach
Reflux symptoms (heartburn) affect 30–80% of pregnant women. Gastric production of hydrochloric acid is variable and sometimes exaggerated but more commonly reduced. Pregnancy is associated with greater production of gastrin, which increases stomach volume and acidity of gastric secretions. Gastric production of mucus also may be increased. Esophageal peristalsis is decreased. Most women first report symptoms of reflux in the first trimester (52% vs. 24% in the second trimester vs. 8.8% in the third trimester), although the symptoms can become more severe with advanced gestation.
The underlying predisposition to reflux in pregnancy is related to hormone-mediated relaxation of the lower esophageal sphincter (Fig. 8–5). With advancing gestation, the lower esophageal sphincter has decreased pressure as well as blunted responses to sphincter stimulation. Thus decreased motility, increased acidity of gastric secretions, and reduced function of the lower esophageal sphincter contribute to the increased gastric reflux. The increased prevalence of gastric reflux and delayed gastric emptying of solid food make the gravida more vulnerable to regurgitation and aspiration with anesthesia. The rate of gastric emptying of solid foods is slowed in pregnancy, but the rate for liquids remains generally the same as in the nonpregnant state.
Figure 8–5. Lower esophageal sphincter pressures for 3 periods of pregnancy and the postpartum state. The shaded area represents the normal range in nonpregnant women. The horizontal bars show the mean ± SE for measurements in 4 women. The rectangles show the mean ± SE for each gestational age. (Modified, with permission, from Van Theil DH, Gravaler JS, Joshi SN, et al. Heartburn in pregnancy. Gastroenterology 1977;72:666.)
Intestines
Intestinal transit times are decreased in the second and third trimesters (Fig. 8–6), whereas first-trimester and postpartum transit times are similar. Transit times return to normal within 2–4 days postpartum.
Figure 8–6. Small-bowel transit times measured by the lactulose hydrogen breath method in a single woman in the third trimester and postpartum. Hydrogen concentrations in maternal breath were determined after administration of a lactulose meal. Hydrogen is released when bacteria in the colon break down lactulose. (Modified, with permission, from Wald A, Van Thiel DH, Hoeschstetter L, et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci1982;27:1015.)
The reduced gastrointestinal motility during pregnancy has been thought to be caused by increased circulating concentrations of progesterone. However, experimental evidence suggests that elevated estrogen concentrations are critically involved through an enhancement of nitric oxide release from the nonadrenergic, noncholinergic nerves that modulate gastrointestinal motility. Other factors may also be involved.
The slow transit time of food through the gastrointestinal tract potentially enhances water absorption, predisposing to constipation. However, diet and cultural expectations may be more important factors in this disorder.
Gallbladder
The emptying of the gallbladder is slowed in pregnancy and often incomplete. When visualized at caesarean delivery, the gallbladder commonly appears dilated and atonic. Bile stasis of pregnancy increases the risk for gallstone formation, although the chemical composition of bile is not appreciably altered.
Liver
Liver morphology does not change in normal pregnancy. Plasma albumin levels are reduced to a greater extent than the slight decrease in plasma globulins. This fall in the albumin/globulin ratio mimics liver disease in nonpregnant individuals. Serum alkaline phosphatase activity can double as the result of alkaline phosphatase isozymes produced by the placenta.
HEMATOLOGIC SYSTEM
Red Blood Cells
The red cell mass expands by approximately 33%, or by approximately 450 mL of erythrocytes for the average pregnant woman (Fig. 8–1). The increase is greater with iron supplementation. The greater increase in plasma volume accounts for the anemia of pregnancy. For example, maternal hemoglobin levels average 10.9 ± 0.8 (SD) g/dL in the second trimester and 12.4 ± 1.0 g/dL at term.
Iron
The enhanced erythropoiesis of pregnancy increases utilization of iron, which can reach 6–7 mg per day in the latter half of pregnancy. Many women begin pregnancy in an iron-deficient state, making them vulnerable to iron deficiency anemia. Thus supplemental iron is commonly given to pregnant women. Because the placenta actively transports iron from the mother to the fetus, the fetus generally is not anemic even when the mother is severely iron deficient.
White Blood Cells
The total blood leukocyte count increases during normal pregnancy from a prepregnancy level of 4300–4500/μL to 5000–12,000/μL in the last trimester, although counts as high as 16,000/μL have been observed in the last trimester. Counts in the 20,000–25,000/μL range can occur during labor. The cause of the rise in the leukocyte count, which primarily involves the polymorphonuclear forms, has not been established.
Polymorphonuclear leukocyte chemotaxis may be impaired in pregnancy, which appears to be a cell-associated defect. Reduced polymorphonuclear leukocyte adherence has been reported in the third trimester. These observations may predispose pregnant women to infection. Basophil counts decrease slightly as pregnancy advances. Eosinophil counts, although variable, remain largely unchanged.
Platelets
Some studies have reported increased production of platelets (thrombocytopoiesis) during pregnancy that is accompanied by progressive platelet consumption. Platelet counts fall below 150,000/μL in 6% of gravidas in the third trimester. This pregnancy-associated thrombocytopenia, which appears to be caused by increased peripheral consumption, resolves with delivery and is of no pathologic significance. Levels of prostacyclin (PGI2), a platelet aggregation inhibitor, and thromboxane A2, an inducer of platelet aggregation and a vasoconstrictor, increase during pregnancy.
Clotting Factors
Circulating levels of several coagulation factors increase in pregnancy. Fibrinogen (factor I) and factor VIII levels increase markedly, whereas factors VII, IX, X, and XII increase to a lesser extent.
Plasma fibrinogen concentrations begin to increase from nonpregnant levels (1.5–4.5 g/L) during the third month of pregnancy and progressively rise by nearly 2-fold by late pregnancy (4–6.5 g/L). The high estrogen levels of pregnancy may be involved in the increased fibrinogen synthesis by the liver.
Prothrombin (factor II) is only nominally affected by pregnancy. Factor V concentrations are mildly increased. Factor XI decreases slightly toward the end of pregnancy, and factor XIII (fibrin-stabilizing factor) is appreciably reduced, up to 50% at term. The free form of protein S declines in the first and second trimesters and remains low for the rest of gestation.
Fibrinolytic activity is depressed during pregnancy through a poorly understood mechanism. Plasminogen concentrations increase concomitantly with fibrinogen, but there is still a net procoagulant effect of pregnancy.
Coagulation and fibrinolytic systems undergo major alterations during pregnancy. Understanding these physiologic changes is critical for the management of some of the more serious pregnancy disorders, including hemorrhage and thromboembolic disease.
SKIN
Anatomic Changes
Hyperpigmentation is one of the well-recognized skin changes of pregnancy, which is manifested in the linea nigra and melasma, the mask of pregnancy. The latter, which is exacerbated by sun exposure, develops in up to 70% of pregnancies and is characterized by an uneven darkening of the skin in the centrofacial-malar area. The hyperpigmentation is probably because of the elevated concentrations of melanocyte-stimulating hormone and/or estrogen and progesterone effects on the skin. Similar hyperpigmentation of the face can be seen in nonpregnant women who are taking oral contraceptives.
Striae gravidarum consist of bands or lines of thickened, hyperemic skin. These “stretch marks” begin to appear in the second trimester on the abdomen, breasts, thighs, and buttocks. Decreased collagen adhesiveness and increased ground substance formation are characteristically seen in this skin condition. A genetic predisposition appears to be involved because not every gravida develops these skin changes. Effective treatment (preventive or therapeutic) has yet to be found.
Other common cutaneous changes include spider angiomas, palmar erythema, and cutis marmorata (mottled appearance of skin secondary to vasomotor instability). The development or worsening of varicosities accompanies nearly 40% of pregnancies. Compression of the vena cava by the gravid uterus increases venous pressures in the lower extremities, which dilates veins in the legs, anus (hemorrhoids), and vulva.
The nails and hair also undergo changes. Nails become brittle and can show horizontal grooves (Beau’s lines). Thickening of the hair during pregnancy is caused by an increased number of follicles in anagen (growth) phase, and generalized hirsutism can worsen in women who already have hair that is thick or has a male pattern of distribution. The thickening of the hair ends 1–5 months postpartum with the onset of the telogen (resting) phase, which results in excessive shedding and thinning of hair. Normal hair growth returns within 12 months.
METABOLISM
Pregnancy increases nutritional requirements, and several maternal alterations occur to meet this demand. Pregnant women tend to rest more often, which conserves energy and thereby enhances fetal nutrition. The maternal appetite and food intake usually increase, although some have a decreased appetite or experience nausea and vomiting (see Chapter 6). In rare instances, women with pica may crave substances such as clay, cornstarch, soap, or even coal.
Pregnancy is associated with profound changes in structure and metabolism. The most obvious physical changes are weight gain and altered body shape. Weight gain results not only from the uterus and its contents, but also from increased breast tissue, blood volume, and water volume (approximately 6.8 L) in the form of extravascular and extracellular fluid. Deposition of fat and protein and increased cellular water are added to maternal stores. The average weight gain during pregnancy is 12.5 kg (27.5 lb).
Protein accretion accounts for approximately 1 kg of maternal weight gain, which is evenly divided between the mother (uterine contractile protein, breast glandular tissue, plasma protein, and hemoglobin) and the fetoplacental unit.
Total body fat increases during pregnancy, but the amount varies with the total weight gain. During the second half of pregnancy, plasma lipids increase (plasma cholesterol increases 50%, plasma triglyceride concentration may triple), but triglycerides, cholesterol, and lipoproteins decrease soon after delivery. The ratio of low-density lipoproteins to high-density lipoproteins increases during pregnancy. It has been suggested that most fat is stored centrally during midpregnancy and that as the fetus extracts more nutrition in the latter months, fat storage decreases.
Metabolism of carbohydrates and insulin during pregnancy is discussed in Chapter 31. Pregnancy is associated with insulin resistance, which can lead to hyperglycemia (gestational diabetes) in susceptible women. This metabolic disorder usually disappears after delivery, but may arise later in life as type 2 diabetes.
Maternal–Placental–Fetal Unit
Fetal genetics, physiology, anatomy, and biochemistry can now be studied with ultrasonography, fetoscopy, chorionic villus sampling, amniocentesis, and fetal cord and scalp blood sampling. Embryology and fetoplacental physiology must now be considered when providing direct patient care. Currently, some medical centers measure fetal pulse oximetry, fetal electroencephalograms, and fetal heart rate monitoring in determining the oxygenation status of the fetus. As the technology improves, we are reaching further into the early perinatal period to determine abnormal physiology and growth.
THE PLACENTA
A placenta may be defined as any intimate apposition or fusion of fetal organs to maternal tissues for physiologic exchange. The basic parenchyma of all placentas is the trophoblast; when this becomes a membrane penetrated by fetal mesoderm, it is called the chorion.
In the evolution of viviparous species, the yolk sac presumably is the most archaic type of placentation, having developed from the egg-laying ancestors of mammals. In higher mammals, the allantoic sacfuses with the chorion, forming the chorioallantoic placenta, which has mesodermal vascular villi. When the trophoblast actually invades the maternal endometrium (which in pregnancy is largely composed of decidua), a deciduate placenta results. In humans, maternal blood comes into direct contact with the fetal trophoblast.
DEVELOPMENT OF THE PLACENTA
Soon after ovulation, the endometrium develops its typical secretory pattern under the influence of progesterone from the corpus luteum. The peak of development occurs at approximately 1 week after ovulation, coinciding with the expected time for implantation of a fertilized ovum.
The first cleavage occurs during the next 36 hours after the cellular union of the egg and sperm. As the conceptus continues to divide and grow, the peristaltic activity of the uterine tube slowly transports it to the uterus, a journey that requires 6–7 days. Concomitantly, a series of divisions creates a hollow ball, the blastocyst, which then implants within the endometrium. Most cells in the wall of the blastocyst are trophoblastic; only a few are destined to become the embryo.
Within a few hours after implantation, the trophoblast invades the endometrium and begins to produce human chorionic gonadotropin (hCG), which is thought to be important in converting the normal corpus luteum into the corpus luteum of pregnancy. As the cytotrophoblasts (Langhans’ cells) divide and proliferate, they form transitional cells that are the likely source of hCG. Next, these transitional cells fuse, lose their individual membranes, and form the multinucleated syncytiotrophoblast. Mitotic division then ceases. Thus the syncytial layer becomes the front line of the invading fetal tissue. Maternal capillaries and venules are tapped by the invading fetal tissue to cause extravasation of maternal blood and the formation of small lakes (lacunae), the forerunners of the intervillous space. These lacunae fill with maternal blood by reflux from previously tapped veins. An occasional maternal artery then opens, and a sluggish circulation is established (hemato-tropic phase of the embryo).
The lacunar system is separated by trabeculae, many of which develop buds or extensions. Within these branching projections, the cytotrophoblast forms a mesenchymal core.
The proliferating trophoblast cells then branch to form secondary and tertiary villi. The mesoblast, or central stromal core, also formed from the original trophoblast, invades these columns to form a supportive structure within which capillaries are formed. The embryonic body stalk (later to become the umbilical cord) invades this stromal core to establish the fetoplacental circulation. If this last step does not occur, the embryo will die. Sensitive tests for hCG suggest that at this stage, more embryos die than live.
Where the placenta is attached, the branching villi resemble a leafy tree (the chorion frondosum), whereas the portion of the placenta covering the expanding conceptus is smoother (chorion laeve). When the latter is finally pushed against the opposite wall of the uterus, the villi atrophy, leaving the amnion and chorion to form the 2-layered sac of fetal membranes.
At approximately 40 days after conception, the trophoblast has invaded approximately 40–60 spiral arterioles, of which 12–15 may be called major arteries. The pulsatile arterial pressure of blood that spurts from each of these major vessels pushes the chorionic plate away from the decidua to form 12–15 “tents,” or maternal cotyledons. The remaining 24–45 tapped arterioles form minor vascular units that become crowded between the larger units. As the chorionic plate is pushed away from the basal plate, the anchoring villi pull the maternal basal plate up into septa (columns of fibrous tissue that virtually surround the major cotyledons). Thus at the center of each maternal vascular unit there is 1 artery that terminates in a thin-walled sac, but there are numerous maternal veins that open through the basal plate at random. The human placenta has no peripheral venous collecting system. Within each maternal vascular unit is the fetal vascular “tree,” with the tertiary free-floating villi (the major area for physiologic exchange) acting as thousands of baffles that disperse the maternal bloodstream in many directions.
FUNCTIONS OF THE MATERNAL– PLACENTAL–FETAL UNIT
The placenta is a complex organ of internal secretion, releasing numerous hormones and enzymes into the maternal bloodstream. In addition, it serves as the organ of transport for all fetal nutrients and metabolic products as well as for the exchange of oxygen and CO2. Although fetal in origin, the placenta depends almost entirely on maternal blood for its nourishment.
The arterial pressure of maternal blood (60–70 mm Hg) causes it to pulsate toward the chorionic plate into the low-pressure (20 mm Hg) intervillous space. Venous blood in the placenta tends to flow along the basal plate and out through the venules directly into maternal veins. The pressure gradient within the fetal circulation changes slowly with the mother’s posture, fetal movements, and physical stress. The pressure within the placental intervillous space is approximately 10 mm Hg when the pregnant woman is lying down. After a few minutes of standing, this pressure exceeds 30 mm Hg. In comparison, the fetal capillary pressure is 20–40 mm Hg.
Clinically, placental perfusion can be altered by many physiologic changes in the mother or fetus. When a precipitous fall in maternal blood pressure occurs, increased plasma volume improves placental perfusion. Increasing the maternal volume with saline infusion increases the fetal oxygen saturation. An increased rate of rhythmic uterine contractions benefits placental perfusion, but tetanic labor contractions are detrimental to placental and fetal circulation as they do not allow a resting period in which normal flow resumes to the fetus. An increased fetal heart rate tends to expand the villi during systole, but this is a minor aid in circulatory transfer.
Circulatory Function
A. Uteroplacental Circulation
The magnitude of the uteroplacental circulation is difficult to measure in humans. The consensus is that total uterine blood flow near term is 500–700 mL/min. Not all of this blood traverses the intervillous space. It is generally assumed that approximately 85% of the uterine blood flow goes to the cotyledons and the rest to the myometrium and endometrium. One may assume that blood flow in the placenta is 400–500 mL/min in a patient near term who is lying quietly on her side and is not in labor.
As the placenta matures, thrombosis decreases the number of arterial openings into the basal plate. At term, the ratio of veins to arteries is 2:1 (approximately the ratio found in other mature organs).
Near their entry into the intervillous spaces, the terminal maternal arterioles lose their elastic reticulum. Because the distal portions of these vessels are lost with the placenta, bleeding from their source can be controlled only by uterine contraction. Thus uterine atony causes postpartum hemorrhage.
B. Plasma Volume Expansion & Spiral Artery Changes
Structural alterations occur in the human uterine spiral arteries found in the decidual part of the placental bed. As a consequence of the action of cytotrophoblast on the spiral artery vessel wall, the normal musculoelastic tissue is replaced by a mixture of fibrinoid and fibrous tissue. The small spiral arteries are converted to large tortuous channels, creating low-resistance channels or arteriovenous shunts.
In early normal pregnancy, there is an early increase in plasma volume and resulting physiologic anemia as the red blood cell mass slowly expands. Immediately after delivery, with closure of the placental shunt, diuresis and natriuresis occur. When the spiral arteries fail to undergo these physiologic changes, fetal growth retardation often occurs with preeclampsia. “Evaluating uterine arteries, which serve the spiral arteries and the placenta in the pregnant women, offers an indirect method of monitoring the spiral arteries.” Fleischer and colleagues (1986) reported that normal pregnancy is associated with a uterine artery Doppler velocimetry systolic/diastolic ratio of less than 2:6. With a higher ratio and a notch in the waveform, the pregnancy is usually complicated by stillbirth, premature birth, intrauterine growth retardation, or preeclampsia.
C. Fetoplacental Circulation
At term, a normal fetus has a total umbilical blood flow of 350–400 mL/min. Thus the maternoplacental and fetoplacental flows have a similar order of magnitude.
The villous system is best compared with an inverted tree. The branches pass obliquely downward and outward within the intervillous spaces. This arrangement probably permits preferential currents or gradients of flow and undoubtedly encourages intervillous fibrin deposition, commonly seen in the mature placenta.
Cotyledons (subdivisions of the placenta) can be identified early in placentation. Although they are separated by the placental septa, some communication occurs via the subchorionic lake in the roof of the intervillous spaces.
Before labor, placental filling occurs whenever the uterus contracts (Braxton Hicks contractions). At these times, the maternal venous exits are closed, but the thicker-walled arteries are only slightly narrowed. When the uterus relaxes, blood drains out through the maternal veins. Hence blood is not squeezed out of the placental lake with each contraction, nor does it enter the placental lake in appreciably greater amounts during relaxation.
During the height of an average first-stage contraction, most of the cotyledons are devoid of any flow and the remainder are only partially filled. Thus, intermittently—for periods of up to a minute—maternoplacental flow virtually ceases. Therefore, it should be evident that any extended prolongation of the contractile phase, as in uterine tetany, could lead to fetal hypoxia.
Endocrine Function
A. Secretions of the Maternal– Placental–Fetal Unit
The placenta and the maternal–placental–fetal unit produce increasing amounts of steroids late in the first trimester. Of greatest importance are the steroids required in fetal development from 7 weeks’ gestation through parturition. Immediately after conception and until 12–13 weeks’ gestation, the principal source of circulating gestational steroids (progesterone is the major one) is the corpus luteum of pregnancy.
After 42 days, the placenta assumes an increasingly important role in the production of several steroid hormones. Steroid production by the embryo occurs even before implantation is detectable in utero. Before implantation, production of progesterone by the embryo may assist ovum transport.
Once implantation occurs, trophoblastic hCG and other pregnancy-related peptides are secreted. A more sophisticated array of fetoplacental steroids is produced during organogenesis and with the development of a functioning hypothalamic–pituitary–adrenal axis. Adenohypophyseal basophilic cells first appear at approximately 8 weeks in the development of the fetus and indicate the presence of significant quantities of adrenocorticotropic hormone (ACTH). The first adrenal primordial structures are identified at approximately 4 weeks, and the fetal adrenal cortex develops in concert with the adenohypophysis.
The fetus and the placenta acting in concert are the principal sources of steroid hormones controlling intrauterine growth, maturation of vital organs, and parturition. The fetal adrenal cortex is much larger than its adult counterpart. From midtrimester until term, the large inner mass of the fetal adrenal gland (80% of the adrenal tissue) is known as the fetal zone. This tissue is supported by factors unique to the fetal status and regresses rapidly after birth. The outer zone ultimately becomes the bulk of the postnatal and adult cortex.
The trophoblastic mass increases exponentially through the seventh week, after which time the growth velocity gradually increases to an asymptote close to term. The fetal zone and placenta exchange steroid precursors to make possible the full complement of fetoplacental steroids. Formation and regulation of steroid hormones also take place within the fetus itself.
In addition to the steroids, another group of placental hormones unique to pregnancy are the polypeptide hormones, each of which has an analogue in the pituitary. These placental protein hormones include hCG and human chorionic somatomammotropin. The existence of placental human chorionic corticotropin also has been suggested.
A summary of the hormones produced by the maternal–placental–fetal unit is shown in Table 8–2.
Table 8–2. Summary of maternal–placental–fetal endocrine-paracrine functions.
B. Placental Secretions
1. Human chorionic gonadotropin—hCG was the first of the placental protein hormones to be described. It is a glycoprotein that has biologic and immunologic similarities to the luteinizing hormone (LH) from the pituitary. Recent evidence suggests that hCG is produced by the syncytiotrophoblast of the placenta. hCG is elaborated by all types of trophoblastic tissue, including that of hydatidiform moles, chorioadenoma destruens, and choriocarcinoma. As with all glycoprotein hormones (LH, follicle-stimulating hormone, thyroid-stimulating hormone [TSH]), hCG is composed of 2 subunits, α and β. The α subunit is common to all glycoproteins, and the β subunit confers unique specificity to the hormone.
Antibodies have been developed to the β subunit of hCG. This specific reaction allows for differentiation of hCG from pituitary LH. hCG is detectable 9 days after the midcycle LH peak, which occurs 8 days after ovulation and only 1 day after implantation. This measurement is useful because it can detect pregnancy in all patients on day 11 after fertilization. Concentrations of hCG rise exponentially until 9–10 weeks’ gestation, with a doubling time of 1.3–2 days.
Concentrations peak at 60–90 days’ gestation. Afterward, hCG levels decrease to a plateau that is maintained until delivery. The half-life of hCG is approximately 32–37 hours, in contrast to that of most protein and steroid hormones, which have half-lives measured in minutes. Structural characteristics of the hCG molecule allow it to interact with the human TSH receptor in activation of the membrane adenylate cyclase that regulates thyroid cell function. The finding of hCG-specific adenylate stimulation in the placenta may mean that hCG provides “order regulation” within the cell of the trophoblast.
2. Human chorionic somatomammotropin—Human chorionic somatomammotropin (hCS), previously referred to as designated human placental lactogen, is a protein hormone with immunologic and biologic similarities to the pituitary growth hormone. It is synthesized in the syncytiotrophoblastic layer of the placenta. It can be found in maternal serum and urine in both normal and molar pregnancies. However, it disappears so rapidly from serum and urine after delivery of the placenta or evacuation of the uterus that it cannot be detected in the serum after the first postpartum day. The somatotropic activity of hCS is 3%, which is less than that of human growth hormone (hGH). In vitro, hCS stimulates thymidine incorporation into DNA and enhances the action of hGH and insulin. It is present in microgram-per-milliliter quantities in early pregnancy, but its concentration increases as pregnancy progresses, with peak levels reached during the last 4 weeks. Prolonged fasting at midgestation and insulin-induced hypoglycemia are reported to raise hCS concentrations. hCS may exert its major metabolic effect on the mother to ensure that the nutritional demands of the fetus are met.
It has been suggested that hCS is the “growth hormone” of pregnancy. The in vivo effects of hCS owing to its growth hormonelike and anti-insulin characteristics result in impaired glucose uptake and stimulation of free fatty acid release, with resultant decrease in insulin effect.
3. Placental proteins—A number of proteins thought to be specific to the pregnant state have been isolated. The most commonly known are the 4 pregnancy-associated plasma proteins (PAPPs) designated as PAPP-A, PAPP-B, PAPP-C, and PAPP-D. PAPP-D is the hormone hCS (described earlier). All these proteins are produced by the placenta and/or decidua. The physiologic role of these proteins, except for PAPP-D, are at present unclear. Numerous investigators have postulated various functions, ranging from facilitating fetal “allograft” survival and the regulation of coagulation and complement cascades to the maintenance of the placenta and the regulation of carbohydrate metabolism in pregnancy. In vitro studies of PAPP-A in knockout mouse models show it functioning as a regulator of local insulin-like growth factor bioavailability.
C. Fetoplacental Secretions
The placenta may be an incomplete steroid-producing organ that must rely on precursors reaching it from the fetal and maternal circulations (an integrated-maternal–placental–fetal unit). The adult steroid-producing glands can form progestins, androgens, and estrogens, but this is not true of the placenta. Estrogen production by the placenta is dependent on precursors reaching it from both the fetal and maternal compartments. Placental progesterone formation is accomplished in large part from circulating maternal cholesterol.
In the placenta, cholesterol is converted to pregnenolone and then rapidly and efficiently to progesterone. Production of progesterone approximates 250 mg per day by the end of pregnancy, at which time circulating levels are on the order of 130 mg/mL. To form estrogens, the placenta, which has an active aromatizing capacity, uses circulating androgens obtained primarily from the fetus but also from the mother. The major androgenic precursor is dehydroepiandrosterone sulfate (DHEAS). This compound comes from the fetal adrenal gland. Because the placenta has an abundance of sulfatase (sulfate-cleaving) enzyme, DHEAS is converted to free unconjugated DHEA when it reaches the placenta, then to androstenedione, testosterone, and finally estrone and 17β-estradiol.
The major estrogen formed in pregnancy is estriol; however, its functional value is not well understood. It appears to be effective in increasing uteroplacental blood flow, as it has a relatively weak estrogenic effect on other organ systems. Ninety percent of the estrogen in the urine of pregnant women is estriol.
Circulating progesterone and estriol are thought to be important during pregnancy because they are present in such large amounts. Progesterone may play a role in maintaining the myometrium in a state of relative quiescence during much of pregnancy. A high local (intrauterine) concentration of progesterone may block cellular immune responses to foreign antigens. Progesterone appears to be essential for maintaining pregnancy in almost all mammals examined. This suggests that progesterone may be instrumental in conferring immunologic privilege to the uterus.
Placental Transport
The placenta has a high rate of metabolism, with consumption of oxygen and glucose occurring at a faster rate than in the fetus. Presumably, this high metabolism requirement is caused by multiple transport and biosynthesis activities.
The primary function of the placenta is the transport of oxygen and nutrients to the fetus and the reverse transfer of CO2, urea, and other catabolites back to the mother. In general, those compounds that are essential for the minute-by-minute homeostasis of the fetus (eg, oxygen, CO2, water, sodium) are transported very rapidly by diffusion. Compounds required for the synthesis of new tissues (eg, amino acids, enzyme cofactors such as vitamins) are transported by an active process. Substances such as certain maternal hormones, which may modify fetal growth and are at the upper limits of admissible molecular size, may diffuse very slowly, whereas proteins such as IgG immunoglobulins probably reach the fetus by the process of pinocytosis. This transfer takes place by at least 5 mechanisms: simple diffusion, facilitated diffusion, active transport, pinocytosis, and leakage.
A. Mechanisms of Transport
1. Simple diffusion—Simple diffusion is the method by which gases and other simple molecules cross the placenta. The rate of transport depends on the chemical gradient, the diffusion constant of the compound in question, and the total area of the placenta available for transfer (Fick’s law). The chemical gradient (ie, the differences in concentration in fetal and maternal plasma) is in turn affected by the rates of flow of uteroplacental and umbilical blood. Simple diffusion is also the method of transfer for exogenous compounds such as drugs.
2. Facilitated diffusion—The prime example of a substance transported by facilitated diffusion is glucose, the major source of energy for the fetus. Presumably, a carrier system operates with the chemical gradient (as opposed to active transport, which operates against the gradient) and may become saturated at high glucose concentrations. In the steady state, the glucose concentration in fetal plasma is approximately two-thirds that of the maternal concentration, reflecting the rapid rate of fetal utilization. Substances of low molecular weight, minimal electric charge, and high lipid solubility diffuse across the placenta with ease.
3. Active transport—Selective transport of specific essential nutrients and amnio acids are accomplished by enzymatic mechanisms.
4. Pinocytosis—Electron microscopy has shown pseudo-podial projections of the syncytiotrophoblastic layer that reach out to surround minute amounts of maternal plasma. These particles are carried across the cell virtually intact to be released on the other side, whereupon they promptly gain access to the fetal circulation. Certain other proteins (eg, foreign antigens) may be immunologically rejected. This process may work both to and from the fetus, but the selectivity of the process has not been determined. Complex proteins, small amounts of fat, some immunoglobulins, and even viruses may traverse the placenta in this way. For the passage of complex proteins, highly selective processes involving special receptors are involved. For example, maternal antibodies of the IgG class are freely transferred, whereas other antibodies are not.
5. Leakage—Gross breaks in the placental membrane may occur, allowing the passage of intact cells. Despite the fact that the hydrostatic pressure gradient is normally from fetus to mother, tagged red cells and white cells have been found to travel in either direction. Such breaks probably occur most often during labor or with placental disruption (abruptio placentae, placenta previa, or trauma), caesarean section, or intrauterine fetal death. It is at these times that fetal red cells can most often be demonstrated in the maternal circulation. This is the mechanism by which the mother may become sensitized to fetal red cell antigens such as the D (Rh) antigen.
B. Placental Transport of Drugs
The placental membranes are often referred to as a “barrier” to fetal transfer, but there are few substances (eg, drugs) that will not cross the membranes at all. A few compounds, such as heparin and insulin, are of sufficiently large molecular size or charge that minimal transfer occurs. This lack of transfer is almost unique among drugs. Most medications are transferred from the maternal to the fetal circulation by simple diffusion, the rate of which is determined by the respective gradients of the drugs.
These diffusion gradients are influenced in turn by a number of serum factors, including the degree of drug-protein binding (eg, sex hormone binding globulin). Because serum albumin concentration is considerably lower during pregnancy, drugs that bind almost exclusively to plasma albumin (eg, warfarin, salicylates) may have relatively higher unbound concentrations and, therefore, an effectively higher placental gradient. By contrast, a compound such as carbon monoxide may attach itself so strongly to the increased total hemoglobin that there will be little left in the plasma for transport.
The placenta also acts as a lipoidal resistance factor to the transfer of water-soluble foreign organic chemicals; as a result, chemicals and drugs that are readily soluble in lipids are transferred much more easily across the placental barrier than are water-soluble drugs or molecules. Ionized drug molecules are highly water soluble and are therefore poorly transmitted across the placenta. Because ionization of chemicals depends in part on their pH-pK relationships, multiple factors determine this “simple diffusion” of drugs across the placenta. Obviously, drug transfer is not simple, and one must assume that some amount of almost any drug will cross the placenta.
ANATOMIC DISORDERS OF THE PLACENTA
Observation of structural alterations within the placenta may indicate fetal and maternal disease that otherwise might go undetected.
Twin-Twin Transfusion Syndrome
Nearly all monochorionic twin placentas show an anastomosis between the vessels of the 2 umbilical circulations, but differ in number, direction, and size of the anastomoses. These usually involve the major branches of the arteries and veins in the placental surface. Artery-to-artery communications are found in 75% of the monochorionic twin placentas. Less frequently found are vein-to-vein and artery-to-vein anastomoses. Of great pathologic significance are deep arteriovenous communications between the 2 circulations. This occurs when there are shared lobules supplied by an umbilical arterial branch from one fetus and drained by an umbilical vein branch of the other fetus. This is found in approximately half of all monochorionic twin placentas. Fortunately, one-way flow to the shared lobule may be compensated for by reverse flow through a superficial arterioarterial or venovenous anastomosis, if they coexist.
Twin-twin transfusion syndrome (TTS) arises when shared lobules causing blood flow from one twin to the other are not compensated for by the presence of superficial anastomosis or by shared lobules, causing flow in the opposite direction. This syndrome occurs in 15–20% of cases of monochorial placentation The twin receiving the transfusion is plethoric and polycythemic and may show cardiomegaly. The donor twin is pale and anemic and may have organ weights similar to those seen in the intrauterine malnutrition form of small for gestational age.
Placental Infarction
A placental infarct is an area of ischemic necrosis of placental villi resulting from obstruction of blood flow through the spiral arteries as a result of thrombosis. The lesions have a lobular distribution. However, the spiral arteries are not true end arteries, and if there is adequate flow through the arteries supplying adjacent lobules, sufficient circulation will be maintained to prevent necrosis. Thus ischemic necrosis of one placental lobule probably indicates not only that the spiral artery supplying the infarcted lobule is thrombosed, but that flow through adjacent spiral arteries is severely impaired. Placental infarction may serve as a mechanism allowing the fetus to redistribute blood flow to those placental lobules that are adequately supplied by the maternal circulation. Although often seen in mature placentas at low levels, the infarct must be extensive before the fetus is physiologically impaired.
Chorioangioma of the Placenta
A benign neoplasm occurring in approximately 1% of placentas and composed of fetoplacental capillaries may occur within the placenta. It is grossly visible as a purplered, apparently encapsulated mass, variable in size, and occasionally multicentered. Placental hemangiomas, or “chorioangiomas,” that measure 5 cm or more may be linked with maternal, fetal, and neonatal complications due to arteriovenous shunting of blood away from the fetus. Many placental tumors are accompanied by hydramnios, hemorrhage, preterm delivery, and fetal growth restriction.
Amniotic Bands
Close inspection of the fetal membranes, particularly near the umbilical cord insertion, may reveal band or stringlike membrane segments that are easily lifted above the placental surface. The origin of amniotic bands is unclear. Proposed mechanism include tearing in the amnion early in pregnancy as well as inherited developmental abnormality. They may cause constriction of the developing limbs or other digits. Amputation has been known to result. Syndactyly, clubfoot, and fusion deformities of the cranium and face may also be explained in certain instances on the basis of amniotic bands.
Placental Pathology
Any infant born with a complication may benefit from histologic evaluation of the placenta and umbilical cord. Histopathologic features of a placenta with uteroplacental insufficiency include nonmarginal infarcts, shrunken placental villi, increased syncytial knots, increased perivillous fibrin, and multifocal and diffuse fibrin deposition. Similarly, if the ratio of nucleated red blood cells to leukocytes exceeds 2:3, this indicates fetal hypoxic stress. Chorangiosis is a pathologic change that indicates long-standing placental hypoperfusion or low-grade tissue hypoxia.
The presence of meconium and its location can also give insight into the possible time of the presumed insult. Under gross observation, meconium will stain the placenta and cord after 1–3 hours of exposure. Stained infant fingernails indicate meconium exposure for at least 6 hours. Stained vernix equates with exposure of meconium for 15 hours or longer.
Microscopic evaluation also sheds light on the timing of the release of meconium. Meconium-laden macrophages at the chorionic surface of the placenta can be seen when meconium has been present for 2–3 hours. When these macrophages are found deep within the extraplacental membranes, meconium has been present for at least 6–12 hours.
Lastly, when evaluation of the umbilical cord demonstrates necrobiotic and necrotic arterial media with surrounding meconium-laden macrophages, the release of meconium occurred more than 48 hours before delivery.
Abnormalities of Placental Implantation
Normally the placenta selects a location on the endometrium that benefits the growing fetus. However, there are numerous instances when the placental implantation site is not beneficial.
Placenta previa, or the implantation of the placenta over the cervical os, is the most common. The incidence at 12 weeks’ gestation is approximately 6% because of the advancement of transvaginal imaging. Fortunately, most cases of placenta previa resolve by the time of delivery (reported incidence of 5/1000 births). A marginal placenta previa occurs when the edge of the placenta lies within 2–3 cm of the cervical os; the prevalence ranges from 10–45% when the less accurate abdominal ultra-sonogram is used.
Associated consequences of these abnormal placentation sites include increased risk for bleeding, both for the mother and the fetus, increased need for caesarean delivery, and possible risk of placenta accreta and increta or percreta, abruption, and growth restriction. Once the placental edge moves beyond 2–3 cm from the cervical os, these risks are minimized.
Placenta accreta is the most dangerous consequence of placenta previa. It involves abnormal trophoblastic invasion beyond the Nitabuch’s layer. Placenta increta is the term used to describe invasion into the myometrium. Placenta percreta describes invasion through the serosa with possible invasion into surrounding tissues such as the bladder. Placenta accreta is associated with life-threatening postpartum hemorrhage and increased need for immediate hysterectomy.
The risk factors for placenta previa and placenta accreta are similar. Advanced maternal age, increased parity, and prior uterine surgery are common risk factors for both entities. The strongest correlation appears to exist with prior uterine surgeries. The prevalence of placenta previa after 1 prior caesarean delivery reaches 0.65% versus 0.26% in the unscarred uterus. However, after 4 or more caesarean deliveries the prevalence reaches 10%. Similarly, the frequency of accreta in the presence of placenta previa increases as the number of uterine surgeries increases. In patients with 1 prior uterine surgery, accreta occurs in 24% of placenta previas, whereas after 4 or more surgeries, the frequency of placenta accreta may be as high as 67%.
Placenta accreta may be suspected with certain ultrasound findings such as loss of the hypoechoic retroplacental myometrial zone, thinning or disruption of the hyperechoic uterine serosa-bladder interface, or with visualization of an exophytic mass. In all cases of placenta previa, and especially if placenta accreta is suspected, the patient must be counseled that hysterectomy may be needed to control excessive bleeding after delivery. Blood products must be available before delivery of the infant to ensure prompt replacement.
THE UMBILICAL CORD
Development
In the early stages, the embryo has a thick embryonic stalk containing 2 umbilical arteries, 1 large umbilical vein, the allantois, and the primary mesoderm. The arteries carry blood from the embryo to the chorionic villi, and the umbilical vein returns blood to the embryo. The umbilical vein and 2 arteries twist around one another.
In the fifth week of gestation, the amnion expands to fill the entire extraembryonic coelom. This process forces the yolk sac against the embryonic stalk and covers the entire contents with a tube of amniotic ectoderm, forming the umbilical cord. The cord is narrower in diameter than the embryonic stalk and rapidly increases in length. The connective tissue of the umbilical cord is called Wharton’s jelly and is derived from the primary mesoderm. The umbilical cord can be found in loops around the baby’s neck in approximately 23% of normal spontaneous vertex deliveries.
At birth, the mature cord is approximately 50–60 cm in length and 12 mm in diameter. A long cord is defined as more than 100 cm, and a short cord as less than 30 cm. There may be as many as 40 spiral twists in the cord, as well as false knots and true knots. When umbilical blood flow is interrupted at birth, the intraabdominal sections of the umbilical arteries and vein gradually become fibrous cords. The course of the umbilical vein is discernible in the adult as a fibrous cord from the umbilicus to the liver (ligamentum teres) contained within the falciform ligament. The umbilical arteries are retained proximally as the internal iliac arteries and give off the superior vesicle arteries and the medial umbilical ligaments within the medial umbilical folds to the umbilicus. When the umbilical cord is cut and the end examined at the time of delivery, the vessels ordinarily are collapsed.
Analysis of the Umbilical Cord in Fetal Abnormalities
A segment of umbilical cord should be kept available as a source of umbilical cord blood for blood gas measurements at the time of delivery. Cord blood gases are a more objective measure of oxygenation than Apgar scores.
ABNORMALITIES OF THE UMBILICAL CORD
Velamentous Insertion
In velamentous insertion, the umbilical vessels divide to course through the membranes before reaching the chorionic plate. Velamentous insertion occurs in approximately 1% of placentas in singleton pregnancies, with multiple gestations having a 6–9 times higher incidence. When these vessels present themselves ahead of the fetus (vasa previa), they may rupture during labor or before to cause fetal exsanguination. When painless vaginal bleeding occurs, the blood may be tested to determine whether it is of fetal origin (Apt test). In practical terms, a high index of suspicion for vasa previa is needed because the time to fetal collapse with bleeding from vasa previa is often too rapid to allow test interpretation.
Short Umbilical Cord
It appears from indirect evidence in the human fetus that the length of the umbilical cord at term is determined by the amount of amniotic fluid present during the first and second trimesters and by the mobility of the fetus. If oligohydramnios, amniotic bands, or limitation of fetal motion occur for any reason, the umbilical cord will not develop to an average length. Amniocentesis performed to produce oligohydramnios in pregnant rats at 14–16 days results in significant reduction of umbilical cord length. The length of the umbilical cord does not vary with fetal weight, presentation, or placental size. Simple mechanical factors may determine the eventual length of the cord.
Knots in the Umbilical Cord
True knots occur in the cord in 1% of deliveries, leading to a perinatal loss of 6.1% in such cases. False knots are developmental variations with no clinical importance.
Loops of the Umbilical Cord
Twisting of the cord about the fetus may be the reason for excessive cord length. One loop of cord is present about the neck in 21% of deliveries, 2 loops in 2.5%, and 3 loops in 0.2%. The presence of loops increases as the amount of amniotic fluid increases, as the length of the umbilical cord increases and as fetal movement increases. When 3 loops are present, the cord is usually longer than 70 cm. One study of 1000 consecutive deliveries found 1 or more loops of cord around the neck in approximately 24% of cases. Retrospective studies suggest that neither single nor multiple loops are associated with adverse fetal outcomes.
Torsion of the Umbilical Cord
Torsion of the cord occurs counterclockwise in most cases. If twisting is extreme, fetal asphyxia may result.
Single Artery
A 2-vessel cord (absence of 1 umbilical artery) occurs in approximately 0.2–11% pregnancies, with risks depending on multiple gestation, ethnicity, maternal age, fetal sex, and smoking. The cause may be aplasia or atrophy of the missing vessel. The presence of single umbilical artery increases the risk for congenital and chromosomal anomalies. Associated malformations include neural tube defects, cardiac defects, genitourinary malformations, gastrointestinal malformations, and respiratory malformations. Acardiac twinning has also been documented. Level III ultrasound should be preformed.
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