Prenatal Environment

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2. Prenatal Environment

Effect on Neonatal Outcome *
*Please note that the PURPLE type in each chapter is intended to make it easier to identify clinically applicable material.
Priscilla M. Nodine, Jaime Arruda and Marie Hastings-Tolsma
The human fetus develops within a complex maternal environment. Structurally defined by the intrauterine/intraamniotic compartment, the character of the prenatal environment is determined largely by maternal variables. The fetus depends totally on the maternal host for respiratory and nutritive support and is significantly influenced by maternal metabolic, cardiovascular, and environmental factors. In addition, the fetus is limited in its ability to adapt to stress or modify its surroundings. This creates a situation in which the prenatal environment exerts a tremendous influence on fetal development and well-being. This influence lasts well beyond the period of gestation, often affecting the newborn in ways that have profound significance for both immediate and long-term outcome.
There is great utility in identifying maternal factors that adversely affect the condition of the fetus. Providers of obstetric care have long used this information to identify the “at-risk” population and design interventions that prevent or reduce the occurrence of fetal and neonatal complications. It is equally important that neonatal care providers obtain a clear picture of the prenatal environment and use this information before birth to anticipate the newborn’s immediate needs and make appropriate preparations for resuscitation and initial nursery care. After birth, an awareness of the likely sequelae of environmental compromise helps focus ongoing assessment and aids in clinical problem solving.
The purpose of this chapter is to help neonatal care providers evaluate maternal influences on the prenatal environment, identify significant environmental risk factors, and anticipate the associated neonatal problems. Information on the assessment and treatment of specific neonatal problems is provided throughout this text and is not repeated here. For a more extensive discussion of perinatal physiology and complicated pregnancies, refer to the references cited at the end of this chapter.

PHYSIOLOGY

Two variables have a critical influence on fetal well-being throughout gestation: utero-placental functioning and inherent maternal resources. The interplay of these factors is a major determinant of fetal oxygenation, metabolism, and growth. Alterations in the development and function of the placenta also influence fetal growth and development. The fetus may be affected to the point that survival is threatened. Likewise, extrauterine well-being may be compromised.
The placenta has a dual role in providing nutrients and metabolic fuels to the fetus. First, placental secretion of endocrine hormones, chiefly human chorionic somatomammotropin (HCS), increases throughout pregnancy, causing progressive changes in maternal metabolism. The net effect of these changes is an increase in maternal glucose and amino acids available to the fetus, especially in the second half of pregnancy. Second, the placenta is instrumental in the transfer of these (and other) essential nutrients from the maternal to the fetal circulation and, conversely, of metabolic wastes from the fetal to the maternal system. Adequate maternal and fetal blood flow through the placenta is essential throughout the entire pregnancy.
Fetal respiration also depends on adequate placental function. Respiratory gases (oxygen and carbon dioxide) readily cross the placental membrane by simple diffusion, with the rate of diffusion determined by the P o2 (or P co2) differential between maternal and fetal blood.
Although the placenta mediates the transport of respiratory gases, carbohydrates, lipids, vitamins, minerals, and amino acids, the maternal reservoir is their source. Maternal-fetal transfer depends on the characteristics and absolute content of substances within the maternal circulation, the relative efficiency of the maternal cardiovascular system in perfusing the placenta, and the function of the placenta itself. 155 The fetal environment can be disrupted by inappropriate types or amounts of substances (e.g., ethanol) in the maternal circulation, decreases or interruptions in placental blood flow (e.g., placental abruption), or abnormalities in placental function (e.g., small placenta). Maternal nutrition, exercise, and disease can impair placental uptake and transfer of substances across the placenta to the fetus.

COMPROMISED FETAL ENVIRONMENT

Maternal Disease

DIABETES

The prevalence of diabetes mellitus and gestational diabetes mellitus (GDM) is increasing worldwide. Diabetes is the most common endocrine disorder affecting pregnancy, and approximately 2% to 7% of pregnant women in the United States are diagnosed with GDM annually. 32 Despite major reductions in mortality over the past several decades, the infant of a diabetic mother (IDM) continues to have a considerable perinatal disadvantage. The physiologic changes in maternal glucose use that accompany pregnancy, coupled with either a preexisting hyperglycemia (as found in types 1 and 2 diabetes) or an inability to mount an appropriate insulin response (as seen in patients with gestational diabetes) result in a significantly abnormal fetal environment. This is because of the increased level of maternal glucose, often in concert with episodic hypoglycemia and ketone exposure. Early in pregnancy, this environment may have a teratogenic effect on the embryo, accounting for the dramatic increase in spontaneous abortions and congenital malformations in the offspring of diabetic women with poor metabolic control. 8 During the second and third trimesters, the mechanics of placental transport dictate that fetal glucose levels depend on, but are slightly less than, maternal levels. 126 Assuming adequate placental function and perfusion, elevations in maternal glucose lead to fetal hyperglycemia and increased fetal insulin production. Repeated or continued elevations in blood glucose result in fetal hyperinsulinism, alterations in the use of glucose and other nutrients, and altered patterns of growth and development. 8,126
Fetal macrosomia (greater than the 90th percentile for weight) occurs in 25% to 42% of diabetic pregnancies because of hyperinsulinemia. These macrosomic infants suffer increased morbidity and mortality from unexplained death in utero, birth trauma, hypertrophic cardiomyopathy, vascular thrombosis, neonatal hypoglycemia, hyperbilirubinemia, erythrocytosis, and respiratory distress. 93 Macrosomic infants have double the risk for shoulder dystocia during vaginal birth and are at greater risk for death during the last 4 to 6 weeks of gestation. 170 Brachial plexus injury and facial nerve palsy also can result from shoulder dystocia. 72 Finally, macrosomic infants are at higher risk for dysfunctional labor patterns and operative vaginal deliveries, which can also contribute to their higher rate of birth trauma.
In addition to the basic metabolic disturbances, diabetes predisposes the pregnant woman to several other complications, including gestational hypertension, preeclampsia, renal disease, and vascular disease. 8 As a consequence, the fetus may be compromised further by chronic hypoxia and other insults, which can lead to intrauterine demise, prematurity, growth restriction, cardiovascular problems, respiratory distress syndrome (RDS), and long-term neurologic problems. 37 In terms of predicting perinatal morbidity and mortality, the “prognostically bad signs of pregnancy,” first identified by Pedersen in the 1960s, are especially significant. The occurrence of any of these signs, which include diabetic ketoacidosis, hypertension, pyelonephritis, and maternal noncompliance, continue to be useful predictors of increased fetal and neonatal risk. 46
In preparing for the delivery of an IDM, the neonatal team should consider the classification of maternal diabetes (type 1 or 2, or gestational). In addition, the quality of metabolic control throughout the pregnancy and labor, maternal complications, and the duration of the pregnancy should be considered, along with indicators of fetal growth and well-being. In cases in which the newer generation sulfonylurea (i.e., glyburide) has been used, an increased incidence of neonatal jaundice may be anticipated.77

THYROID DISEASE

Thyroid disorders are the second most common endocrine disorder seen in pregnancy. 9 The thyroid hormones triiodothyronine (T 3) and thyroxine (T 4) cross the placenta in small amounts, though the significance of the transfer has not been well elucidated. The fetus depends on maternal T 4 in the first trimester of pregnancy. At 8 to 10 weeks’ gestation, the fetal thyroid begins to concentrate iodine and produce T 4. During the second and third trimester, the fetus is independent of maternal status. At approximately 24 weeks, thyroid-stimulating immunoglobulins (TSIs) or thyroid-stimulating hormone (TSH) receptor Abs, which are classes of immunoglobulin G (IgG), cross the placenta and stimulate fetal thyroid. Iodine is readily transferred from mother to fetus. The fetal thyroid gland concentrates iodine and synthesizes its own hormones as early as 10 to 12 weeks’ gestation; this is independent of maternal thyroid function. Maternal thyroid hormones are believed to be important for fetal neurologic development in the first trimester. 3 Significant decreases in intelligence quotient (IQ) of offspring of mothers with untreated hypothyroidism in early gestation have been shown in some studies. 70,96 Whereas subclinical hypothyroidism does not need to be treated, 26 severe maternal hypothyroidism may result in increased neurodevelopmental delay in offspring, pregnancy loss, prematurity, preeclampsia, low birth weight, and abruptio placenta. 25 Treatment with replacement hormone during pregnancy is well tolerated by the fetus and reduces these risks. 3
Maternal hyperthyroidism presents a different situation. Thyroid-stimulating antibodies, commonly found in patients with Graves’ disease, as well as many of the drugs used to treat hyperthyroidism, cross the placenta and can have a significant effect on the fetus. Antibodies, including long-acting thyroid stimulant (LATS) and TSI, can increase fetal thyroid hormone production. High levels are associated with fetal and neonatal hyperthyroidism. Untreated maternal thyrotoxicosis has been linked to preterm delivery, intrauterine growth restriction (IUGR), low birth weight, and stillbirth. In rare cases, the offspring of women with Graves’ disease may themselves have this condition. In fetuses and newborns, this is evidenced by elevations in heart rate, growth restriction, prematurity, goiter, and congestive heart failure. The perinatal mortality rate is high. 26 Administration of antithyroid medication to the mother can decrease thyroid hormone production in both the mother and the fetus but may result in fetal hypothyroidism and goiter. 1
Another maternal antibody, TSH-binding inhibitor immunoglobulin, also crosses the placenta and can prevent the expected fetal thyroid response to TSH. The result is a transient fetal and neonatal hypothyroidism. Iodine deficiency in the mother is another cause of fetal and neonatal hypothyroidism and, in its severe form, leads to cretinism because of the fetus’s dependence on maternal iodine reserves. 1

PHENYLKETONURIA

Phenylketonuria (PKU) is an inherited disorder in which an enzymatic defect precludes conversion of the essential amino acid phenylalanine to tyrosine. This metabolic derangement is evidenced by an accumulation of excessive amounts of phenylalanine and alternative pathway by-products in the blood, and these are toxic to the central nervous system. Historically, PKU resulted in virtually certain mental retardation; affected individuals often were institutionalized and rarely reproduced. With the advent of universal neonatal screening in the United States since the 1960s and effective dietary treatment to prevent hyperphenylalaninemia during infancy and early childhood, genetically affected persons may avoid the devastating effects of this disease, have relatively normal development, and become pregnant. For women who do conceive, PKU poses a significant environmental risk for their developing fetus. The care of these women and their infants presents a unique perinatal challenge.
An estimated 3000 healthy young women of childbearing age with successfully treated PKU are in the United States. 104 However, most discontinued their special diet in childhood because, at the time, most doctors believed it was safe to do so. Unfortunately, their blood phenylalanine levels are very high when they become pregnant if they are eating a normal diet. In up to 90% of such cases, the offspring will be microcephalic and/or have mental retardation. These babies also have an increased incidence of low birth weight, cardiac defects, and characteristic facial features regardless of whether they are themselves affected with PKU. 97,98 They cannot be helped by the PKU diet, or they suffer from brain damage caused entirely by their mothers’ high phenylalanine levels during pregnancy. To prevent such damage, these women should resume their special PKU diets during preconception. Studies have identified improved long-term outcomes when desirable phenylalanine levels (2 to 8 mg/dL) are achieved at least 3 months before pregnancy and maintained throughout gestation. 102 Phenylalanine levels drop quickly once dietary restrictions are instituted, and there is a strong correlation between maternal blood levels and neonatal outcome. 102
About 1 baby in 14,000 inherits PKU when both parents have the PKU gene and both pass it on to their baby. Neonatal blood screening will identify these PKU babies. If this screening is performed within the first 24 hours of life, the American Academy of Pediatrics recommends re-screening at 1 to 2 weeks of age to avoid missed cases of PKU. Once identified, PKU babies should be fed a special formula that contains protein but no phenylalanine, started within the first 7 to 10 days of life, and they must remain on an individualized, restricted diet throughout childhood/adolescence, and generally for life. In some instances, breastfeeding may be possible. 88 When treatment is discontinued too soon, risks include blindness, learning disabilities, behavioral disturbances, and a decrease in IQ. When no treatment is instituted at all, phenylalanine accumulates in the bloodstream and causes brain damage and mental retardation.

RENAL DISEASE

Maternal adaptation to pregnancy involves major changes in renal function and structure. Renal hemodynamic changes begin early in pregnancy and before significant expansion of plasma volume. Renal blood flow increases in the first trimester by 35% to 60% and then decreases from the second trimester to term. Additional changes include an increase in the glomerular filtration rate (GFR) and effective renal plasma flow, a decrease in renal vascular resistance, an activation of the renin-angiotensin-aldosterone system, and increased retention of sodium and water. These changes place unique demands on the renal system. Women with preexisting renal disease may have a successful pregnancy outcome with proper prenatal care; however, some women do experience fetal loss and deterioration in renal function. Furthermore, moderate or severe renal dysfunction complicates pregnancy and increases maternal and fetal risks and adverse outcomes. 16
Renal disease in pregnancy may occur as a result of urinary tract infections, glomerular disease, or severe hypertension or as a complication of systemic diseases including diabetes and systemic lupus erythematosus. 84 Regardless of the underlying etiologic factors, pregnancy outcome relates most closely to these factors: the presence of hypertension and the degree of renal insufficiency before and during pregnancy. 84 Many women with renal disorders are hypertensive before pregnancy, and they often develop a superimposed pregnancy-induced hypertension leading to preeclampsia. 83 Even those with previously normal blood pressures run an increased risk for developing hypertension during pregnancy. The presence of hypertension in these pregnancies represents a significant risk to the fetus and is strongly associated with IUGR, preterm delivery, and perinatal loss.
Drug therapy to control chronic hypertension has been shown to have a beneficial effect on fetal outcome and generally is continued throughout pregnancy. Renal insufficiency, as measured by creatinine clearance or serum creatinine level, also has implications for fetal outcome. Mild to moderate renal insufficiency (serum creatinine less than 1.5 mg/dL) is associated with a generally favorable outcome, whereas severe insufficiency (serum creatinine greater than 1.6 mg/dL) often carries an increased risk for perinatal death. Persistent proteinuria also may increase fetal loss, and a urinary protein excretion rate higher than 0.5 g/24 hr may be an independent predictor of fetal outcome. 112 As a rule, the number of preterm deliveries and growth-restricted infants increases with increasing blood pressure and decreasing renal function.
Bacteriuria occurs in 2% to 7% of pregnancies. If untreated, asymptomatic bacteriuria may lead to pyelonephritis or acute cystitis. Risks for the fetus are preterm birth and IUGR. Fetal death is an additional risk with pyelonephritis. Prophylactic antibiotics (suppressive therapy) should be given to women with persistent or frequent recurrence of bacteriuria or a history of pyelonephritis in pregnancy. 147
Two special circumstances are dialysis during pregnancy and pregnancy after renal transplant. Women undergoing dialysis rarely become pregnant. When pregnancy does occur, it is associated with significant perinatal morbidity and mortality, with spontaneous abortions reaching 50%. Hemodialysis also is associated with numerous complications, including placental abruption, polyhydramnios, IUGR, preterm labor, and pregnancy loss. 56,106 The risk may be lower with ambulatory peritoneal dialysis. 56 Pregnancy after transplantation is more common and has a better prognosis than pregnancy managed by dialysis. 84 A long interval from transplantation to conception and use of a low dose of prednisone are predictive of successful outcome. 16Infants born after maternal transplantation are commonly preterm. A wide range of perinatal problems have been noted, thus requiring specialized care at a tertiary center. Other complications may include growth restriction, RDS, congenital anomalies, adrenocortical insufficiency, hyperviscosity, seizures, and neonatal sepsis.66 Concerns persist about neonatal complications if exposure to immunosuppressive therapy occurred while in utero. The criteria used to predict fetal outcome with other renal patients (i.e., hypertension, renal insufficiency) also have predictive value in post-transplantation pregnancies. Acute renal failure in pregnancy is associated with a maternal mortality rate of 20% and an increased fetal mortality rate. 80

NEUROLOGIC DISORDERS

The risks that accompany pregnancies complicated by maternal neurologic disorders vary according to the individual disease entity and pertain to both the course of the mother’s disease and pregnancy outcome. The physiologic and hormonal changes of pregnancy can influence the course of chronic neuromuscular disorders, such as epilepsy, multiple sclerosis, and myasthenia gravis. The medications used to control these disorders can be particularly problematic for the fetus.
The prevalence of maternal seizure disorders is about 4 in every 1000 pregnancies, and most are treated with antiepileptic drugs (AEDs). The disorders and/or the AEDs have been associated with increased fetal and neonatal risks, including spontaneous abortion, prematurity, small for gestational age, congenital defects, intrauterine demise, neonatal depression, and hemorrhage. Significant numbers of epileptic women experience an increase in seizure activity during pregnancy. This is probably because of decreased compliance with medication regimens, physiologic changes associated with pregnancy, and gestational changes in plasma levels of anticonvulsant drugs. 91,108 There is evidence that maternal seizures may compromise fetal oxygenation, possibly because of diminished placental blood flow or maternal hypoxemia resulting from post-seizure apnea. For these reasons, control of maternal seizure activity with anticonvulsants is one of the primary goals of prenatal care.
Placental transport of anticonvulsants does occur, resulting in fetal levels that approximate or, in some cases, exceed maternal levels. 21 Although the majority of infants born to women with epilepsy are normal, these infants are at increased risk for poor outcomes. 153Many studies have demonstrated an increased incidence of congenital defects in the offspring of epileptic women treated with anticonvulsants. Estimates of risks vary, but studies report a 21/2-fold increased risk over the general population when AED monotherapy is used and a 5-fold increased risk when multiple AEDs are used during pregnancy.108,110 The teratogenic potential of most individual AEDs remains unclear, but valproate seems to be consistently associated with the highest rates of congenital malformations and the use of other AEDs is recommended if possible during pregnancy. 20,160 Although many newer AEDs are listed as class B medications in pregnancy, reports of teratogenicity are just now surfacing, so caution should be used with all anticonvulsants. 53,75The most common major congenital malformations associated with AEDs are neural tube defects (e.g., spina bifida), orofacial defects (e.g., cleft lip, cleft palate), heart malformations (e.g., ventricular septal defect), urogenital defects (e.g., hypospadias), and skeletal abnormalities (e.g., radial ray defects, phalangeal hypoplasias).107 The influence of the seizure disorder itself, as well as genetic makeup, cannot be ignored. Maternal folic acid supplementation has been shown to improve pregnancy outcomes for women taking AEDs. 130,160
Infants born to mothers treated with anticonvulsants, especially barbiturates, may exhibit signs of generalized depression, including decreased respiratory effort, poor muscle tone, and feeding difficulties. They also may have symptoms indicative of drug withdrawal (seeChapter 11). These symptoms are usually present in the first week of life and include tremors, restlessness, hypertonia, and hyperventilation.21In addition, abnormal clotting and hemorrhage in the offspring of women treated with phenytoin, phenobarbital, and primidone have been reported. This appears to be caused by a decrease in vitamin K–dependent clotting factors. Hemorrhage usually starts within the first 24 hours, is often severe, and may result in death. Infants born to these mothers should have cord blood clotting studies done, vitamin K prophylaxis on admission to the nursery, and close observation. Reports of long-term sequelae for the infants of epileptic mothers with AED use during pregnancy, especially the third trimester, include possible cognitive and behavioral deficiencies. 107
Multiple sclerosis (MS) frequently strikes women during their reproductive years. The onset of MS usually is insidious; the course is marked by a seemingly capricious cycle of exacerbation and remission. A wide range of sensory, motor, and functional changes is associated with this disease; the type and severity of symptoms vary dramatically from one individual to another and in any one patient over time. The disease is a T-cell–mediated autoimmune disease of the central nervous system triggered by unknown exogenous agents in individuals with specific genetics. 73 Pregnancy usually is well tolerated and may be associated with MS stability or improvement. The reported effects of the disease on pregnancy outcomes, including risk for malformations, cesarean section rates, newborn birth weight, and rate of preterm delivery, are inconsistent. Some report no increase in adverse pregnancy outcomes, 114,169 whereas other groups report a higher cesarean rate as well as a greater number of low-birth-weight infants in mothers with MS. 45 Alterations in neural function, fatigue, and general weakness may play a role in pregnancy outcomes. During the postpartum period, a higher-than-expected relapse rate has been identified and is associated with hormonal changes. 52,163 However, in women with MS, the disease process itself is not a threat to fetal or neonatal well-being. The priority for neonatal care providers is to determine the extent of the mother’s disability, including her level of fatigue and her ability to care for her infant. The availability of appropriate support systems, both personal and professional, should be assessed, and needed follow-up and referrals should be made.
Even though the prognosis for these infants is excellent, some factors associated with MS are potentially problematic. Bladder dysfunction, common in women with MS, often results in urinary tract infections during pregnancy. Associated fetal and neonatal problems include preterm delivery and sepsis. Early identification and prompt treatment with appropriate antibiotics should minimize these risks. An additional area of concern is the variety of drugs administered to MS patients. Immunosuppressants are frequently used during severe exacerbations. The placental transport and fetal risk vary with the individual agent used. Prednisone and intravenous steroids generally are considered safe for use in pregnancy. 73 Azathioprine also is generally considered safe because the fetal liver lacks the enzyme that converts azathioprine to its active metabolites, thus protecting the fetus from any teratogenic effects from this drug. However, neonatal hematologic and immune impairment have been reported in some exposed infants. 60 Cyclophosphamide has been associated with skeletal defects, growth retardation, and preterm labor19 and is best avoided during pregnancy. Cyclosporine is not teratogenic; however, it may be associated with prematurity and growth restriction. Early in-utero exposure to interferon beta is controversial. 124 Other drug therapies should be evaluated carefully before use because definitive knowledge about safety in pregnancy may be lacking. 60 A final consideration is a long-term one: the incidence of MS in the offspring of a parent with the disease is 4%, compared with 0.1% in the general population. 73
Myasthenia gravis (MG) is a chronic autoimmune disease that causes neuromuscular dysfunction and is encountered rarely in pregnancy; only 1 in 20,000 pregnancies is complicated by MG. 81 Cells of the immune system make proteins called antibodies that block nerve impulses to the muscles. Antibodies to acetylcholine receptor (AchR) have been found in most affected persons. Distinguishing features include generalized weakness and muscle fatigue with activity. Persons with MG also may experience respiratory compromise and difficulty swallowing. 81 The course of MG during pregnancy is unpredictable and may vary in different pregnancies in the same woman. 59 Exacerbations occur in approximately 40% of pregnancies and remission in 30%, with the remaining 30% experiencing no change. During the first trimester and the first month postpartum, exacerbations are more likely. 81 Corticosteroids can be used to maintain the remissions of MG and should be continued on the lowest possible doses throughout the pregnancy and postpartum period. Immunosuppressive agents like methotrexate, cyclophosphamide, and mycophenolate mofetil are contraindicated in pregnancy, but azathioprine and cyclosporine A are sometimes used and plasmapheresis and intravenous immunoglobulins can be effective in the treatment of myasthenic crises during pregnancy. Instrumental delivery may be needed in the second stage as MG mothers are more likely to become exhausted. 81
Infants born to myasthenic mothers may be affected by the drug therapy and the underlying immunologic dysfunction. Increased rates of premature rupture of membranes (PROM), preterm delivery, and cesarean birth have been reported. 59An additional risk stems from transplacentally acquired antiacetylcholine receptor antibodies, which cause approximately 12% of these newborns to experience a transient, self-limited course of MG. It is difficult to predict which pregnancies will result in an affected infant, although infants born to women with very high AChR antibody titers may be at highest risk. 81Affected infants usually present at birth or within the first 24 hours of life with generalized weakness, a feeble cry, diminished suck and swallow, and a decreased respiratory effort that may require mechanical support.59Therefore plans should be made in advance for delivery of the mother with MG, and intensive care facilities for the newborn should be available immediately. Symptoms from neonatal MG generally subside within a few weeks after birth and do not recur.
MG is not a contraindication to pregnancy and can usually be managed well with relatively safe and effective therapies, including maternal rest. Standard therapies for some obstetric complications, such as preeclampsia and preterm labor, may need to be altered in women with MG. 81 Vaginal delivery is recommended if possible. Breast feeding is not contraindicated but depends on maternal medications and infant and maternal health postpartum.

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is an autoimmune disease that presents primarily in women of childbearing age. The pathogenesis involves the production of autoantibodies and immune complexes. The clinical effects of lupus range from mild or subclinical disease to serious illness affecting multiple organ systems. The leading causes of death are infections and renal failure. In pregnancy, SLE is associated with an increased incidence of preeclampsia, thrombotic events, spontaneous abortion, preterm delivery, IUGR, and stillbirths. 113,152 Outcome is best when infections, renal disease, and hypertension do not complicate pregnancy and when pregnancy occurs with prolonged disease remission. 49,137 Reported frequency of SLE flares in pregnancy is 15% to 60%. 2 When necessary, treatments used with pregnancies complicated by SLE include anti-inflammatory, antimalarial, immunosuppressive, and biological drugs and/or anticoagulants. 49
The neonatal manifestations of SLE are rare and are attributed to the placental transfer of maternal antibodies to the fetus. Usual findings of neonatal lupus include a transient lupus-like rash (erythematous lesions of the face, scalp, and upper thorax), thrombocytopenia, and hemolysis.2 These findings generally are transient and clear within a few months. A strong association has been established between maternal antibodies to the anti-Ro/SS-A and anti-La/SS-B antigens and congenital heart block, a rare manifestation of neonatal lupus syndrome.2 The fetal heart block may be detected with antenatal testing; some authors believe that antenatal fetal surveillance with nonstress tests should begin at 28 weeks’ gestation. Infants are treated with cardiac pacemakers after delivery; however, about one third of affected infants die within 3 years.164

HEART DISEASE

Significant changes in cardiovascular function accompany normal pregnancy. Plasma and red blood cell volumes rise, heart rate and cardiac output increase, and peripheral vascular resistance falls. These changes facilitate increased uterine blood flow, placental perfusion, and fetal oxygenation and growth. They also increase maternal oxygen consumption and cardiovascular workload and can further compromise the cardiovascular status of women with preexisting serious heart disease. Approximately 2% to 4% of childbearing-age women have concomitant heart disease. 86 Pregnancy creates a risk for maternal cardiovascular complications, but especially for those with underlying heart disease, and includes an increased incidence of thromboembolism and sudden death. 85,146 In some cases, such as Eisenmenger’s syndrome and primary pulmonary hypertension, the risk to maternal survival is so great that pregnancy is contraindicated. In general, how well the woman with heart disease tolerates pregnancy depends on the specific disease process and the degree to which her cardiac status is compromised. 123
Maternal heart disease also affects the fetus. Fetal risks are the result of genetic factors, alterations in placental perfusion and exchange, and the effect of maternally administered drugs. The genetic risk is demonstrated by the increased incidence of congenital heart defects that occur in the offspring of parents who have such a defect. The exact risk depends on the specific parental lesion, mode of inheritance, and exposure to environmental triggers. 23
Alterations in placental perfusion and gas exchange occur when the mother’s condition involves chronic hypoxemia or a significant decrease in cardiac output. These factors increase the threat to the fetus, with fetal risk increasing as maternal cardiac status declines. Chronic maternal hypoxemia results in a decrease in oxygen available to the fetus and is associated with fetal loss, prematurity, and IUGR. 168 Significant reductions in maternal cardiac output create decreased uterine blood flow and diminished placental perfusion with a resulting impairment in the exchange of nutrients, oxygen, and metabolic wastes. Possible fetal and neonatal consequences include spontaneous abortion, IUGR, neonatal asphyxia, central nervous system (CNS) damage, and intrauterine, intrapartum, or neonatal death. 85
A wide variety of drugs are used in the management of maternal cardiovascular disease. Although sometimes it is difficult to differentiate drug effects from the effects of the underlying disease, some associations between drug administration and fetal outcomes can be made. Anticoagulants are used to decrease the risk for thromboembolism, especially in women with artificial valves, a history of thrombophlebitis, or rheumatic heart disease. Oral anticoagulants, specifically warfarin sodium (Coumadin), have been associated with fetal malformations, including nasal hypoplasia and epiphyseal stippling, when administered during the first trimester. They also have been associated with eye and CNS abnormalities when administered later in pregnancy. The incidence of warfarin embryopathy is estimated to be 15% to 25%. Warfarin also is associated with maternal and fetal hemorrhage. Because of these risks, warfarin is contraindicated in pregnancy except in special circumstances such as pregnancy in women with prosthetic heart valves. 38 Heparin is considered the preferred agent for anticoagulation therapy during pregnancy. Heparin does not cross the placenta; therefore it does not result in fetal anticoagulation or neonatal hemorrhage (although maternal hemorrhage still may occur), nor has it been associated with congenital defects. Low-molecular-weight heparin is another alternative for anticoagulation during pregnancy. 51 In general, patients being treated with low-molecular-weight heparin during pregnancy are converted to unfractionated heparin during the final weeks of pregnancy because of the ease of rapid reversal of anticoagulation for labor and delivery. Some studies, however, did not demonstrate any difference in bleeding complications for gravidas continued on low-molecular-weight heparin versus those who were converted to unfractionated heparin. 89
Antiarrhythmic medications and cardiac glycosides used during pregnancy cross the placenta to varying degrees. They have not been implicated in fetal malformations and, although several have been associated with minor complications, generally are considered safe for use in pregnancy. 136 Reported complications include uterine contractions (quinidine, disopyramide), decreased birth weight (digoxin, disopyramide), and maternal hypotension with a sudden decrease in placental perfusion (verapamil).
Antihypertensives and diuretics also have been used in the treatment of cardiovascular disease during pregnancy. Labetalol and methyldopa are commonly used in pregnant women with chronic hypertension. These medications have been studied in prospective trials that revealed no adverse fetal or maternal outcomes. 58,157 Their use in the first trimester has also demonstrated safety. Atenolol has been associated with fetal growth restriction and abnormal placental growth. 24,54 Calcium channel blockers, such as nifedipine, are also safely used during pregnancy without an increase in major birth defects or adverse neonatal outcomes. 143 Diuretic use in pregnancy remains an area of some controversy. Fetal and neonatal compromise can result from diuretic-induced electrolyte and glucose imbalance and decreased placental perfusion caused by maternal hypovolemia. The use of thiazide diuretics has been linked to neonatal liver damage and thrombocytopenia. In general, diuretic use is restricted to women with pulmonary edema or acute cardiac or renal failure. Antihypertensive medications are not clearly shown to reduce the risk for preeclampsia in the hypertensive patient. 143
Although a great number of complications are possible, remember that, with few exceptions, most of the drugs used in the treatment of maternal heart disease can be used in pregnancy if the maternal condition warrants it. Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy because of an association with fetal injury (renal dysfunction, fetal oliguria, oligohydramnios, fetal skull hypoplasia) and fetal death.

RESPIRATORY DISEASE

Respiratory function is altered even in normal pregnancy. Changes include a decrease in lung volume and increases in oxygen consumption, tidal volume, and minute ventilation. Significant decreases in maternal respiratory function and oxygenation can result in fetal growth restriction and fetal hypoxia with negative outcomes, but careful management of respiratory disease during pregnancy generally results in a favorable outcome.
Asthma is the most common respiratory disease in pregnancy, occurring in 3% to 12% of women, and the prevalence among pregnant women is rising. 115 For about two thirds of pregnant women, the course of asthma changes. 140 Infants born to women whose asthma is well controlled usually do well; unstable or worsening disease, especially status asthmaticus, increases fetal risk. 14 Commonly used asthma medications (e.g., long-acting beta agonists, inhaled corticosteroids, oral corticosteroids, other bronchodilators, and cromones) are generally considered safe for use in pregnancy. However, limited studies have associated maternal bronchodilator use and cromone exposure with an elevated risk for fetal gastroschisis99and a slight increase in fetal musculoskeletal malformation,150respectively. Additional research is needed to help determine whether a real risk exists and to guide asthma treatment during pregnancy. Presently, clinical evidence supports pharmacologic asthma control because the fetus is at greater risk from inadequate control of asthma than from asthma medications. 14
Fetal risks related to maternal asthma depend on the severity of the condition. Controlled asthma carries few risks for the fetus. However, severe or uncontrolled asthma increases the risk for infant death and the incidence of low birth weight, IUGR, preterm birth (possibly influenced by steroid use), and the need for cesarean delivery.82 Risks are higher in poorly controlled asthma patients. 15 Noncompliance with treatment, respiratory tract infections, allergens and irritants, smoking, gastroesophageal reflux, and exercise can lead to asthma exacerbations. 115
Cystic fibrosis (CF) was once considered a lethal childhood disease, but the life expectancy of a person with CF has increased, and is currently at about 35 years. 127 With careful planning and appropriate medical care, women with CF of childbearing age may conceive and have successful pregnancies with good neonatal outcomes, especially if their nutritional state and lung function remain good. 67 Women with severe disease may be cautioned to avoid conception because there is a risk for significant deterioration during gestation. Women who are positive for Burkholderia cepacia in sputum also have a worse prognosis. 67 Pregnancy in women with CF is likely to be associated with increased health care utilization and more antibiotic use compared with that of non-pregnant women with CF; high rate of gestational diabetes (12%) compared with non-CF pregnancies; and aggressive interventions to ensure weight gain, including the use of total parenteral nutrition for some. 33,119,154 Women with CF may experience pulmonary infections, which should be treated promptly and vigorously with antibiotics, fluids, and respiratory therapy. Fetal risks related to CF include prematurity, IUGR, and perinatal death, caused primarily by maternal hypoxemia and infection. Because all infants born to mothers with CF will be heterozygous carriers for CF (at least), genetic counseling and carrier testing of the father are important components of preconceptual care and early prenatal care. 154

Maternal Behavior

Maternal health behavior is an important component of neonatal and childhood health and may even be the single most important factor for the overall health of a child. 120 Health behaviors evaluated here are smoking, substance abuse, and nutrition, but other maternal behaviors also influence pregnancy outcomes, such as sleep patterns and exercise. Appropriate preconceptual and prenatal counseling regarding maternal health behaviors can help optimize neonatal health. 71,128

SMOKING

From 16% to 25% of women in the United States smoke during pregnancy, 125,158 with approximately 60% of smokers continuing to smoke through pregnancy. Of those who quit during pregnancy, half resume smoking by 6 months postpartum, 101 putting children at risk for second-hand smoke. It is well established that maternal smoking is a risk factor for stillbirths, IUGR, placental abruption, placental previa, PROM, and preterm labor. 158 Long-term effects include childhood obstructive airway disease, sudden infant death syndrome (SIDS), neurodevelopmental abnormalities, and childhood cancer, 158 and concerns about exposure to second-hand smoke continue to escalate. The exact mechanism by which fetal growth is restricted or fetal health is compromised is not entirely clear; reduced uterine artery blood flow, reduced placental blood flow resulting from vasoconstriction or smaller fetal capillaries in the placental capillary bed, elevated nicotine and carbon monoxide levels, and chronic fetal hypoxia all may play a role. 71,94 Fetal risk increases with the number of cigarettes smoked, maternal anemia, and poor nutrition. 69The babies of smokers may undergo withdrawal-like symptoms manifested by jittery movements and may be more difficult to soothe.95
Eliminating or reducing smoking, especially by the end of the first trimester, can improve fetal growth and health. Smoking cessation programs consistently implemented during prenatal visits have been shown to significantly improve smoking cessation rates. 109 The use of nicotine patches to facilitate smoking cessation during pregnancy is controversial. 125 Smoking cessation during pregnancy must be a major priority in counseling women preconceptually and prenatally because these are times when women may be most receptive to quitting because of a strong desire for a healthy pregnancy and baby. 109

SUBSTANCE ABUSE

Prenatal substance abuse rates vary greatly; however, it is estimated that about 11% of childbearing women have used illegal substances. 17 Use of drugs and alcohol by the mother places the fetus and newborn at risk for a plethora of structural, functional, and developmental problems. Perinatal morbidity is related to the direct effects of the abused substance on the developing fetus, its sudden withdrawal, the interactions of multiple abused substances, the nutritional effects of addiction on the mother, and the social and health care implications of substance abuse. 13,44,159
Alcohol is one of the most commonly abused substances during pregnancy. Although known to be a teratogen since the 1970s, about 40% of women in the United States drink some alcohol during pregnancy and about 3% to 5% drink heavily throughout pregnancy. 62 Alcohol in the maternal circulation crosses the placenta, resulting in direct fetal exposure to alcohol and its metabolites. 22There may be a wide range of effects on the exposed fetus; these include developmental and behavioral abnormalities, spontaneous abortion, stillbirth, craniofacial malformations, growth restriction, preterm birth, CNS dysfunction, and organ or joint abnormalities.13,22,55 The mechanism of fetal injury is not entirely clear but is likely related to three main factors: a teratogenic effect, hypoxia as a result of increased oxygen consumption, and a diminished ability to use amino acids in protein synthesis. 22 The expression of fetal alcohol effects ranges from subtle to extreme and depends on the timing of exposure, the dose, and the genetic response of the mother and fetus to the effects of alcohol. Secondary factors such as maternal age, nutritional status, general health, and the effects of other abused substances also may influence outcome. 141,166 When the more severe effects are exhibited, the condition is known as fetal alcohol syndrome (FAS). FAS is characterized by growth restriction, physical dysmorphic features including facial anomalies (small palpebral fissures, low nasal bridge, indistinct philtrum, thin upper lip, shortened lower jaw), and neurologic dysfunction, including mental retardation and neurodevelopmental deficits.134Other physical abnormalities involve the heart, skeletal system, and ears. “Fetal alcohol spectrum disorders (FASD)” is an umbrella term for FAS and other less physically noticeable yet long-term effects of alcohol exposure on the fetus.22Infants with FASD also may exhibit problems with suck, tremors, irritability, and hypertonus related to alcohol withdrawal. Continued abnormalities in motor, behavioral, and intellectual development often persist into childhood. Safe levels of alcohol intake have not been established; therefore women should be advised to avoid alcohol intake during pregnancy.
Chemical dependency in pregnancy is a complex problem and creates a high-risk patient. The mother’s reporting of drug use often is unreliable; frequently, more than one substance is involved, and there may be a cycle of drug use and periodic abstinence during pregnancy. In addition, a host of medical and social problems are associated with maternal drug abuse. Substance abusers generally have poor health; infectious diseases such as pneumonia, sexually transmitted disease (including human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS]), urinary tract infections, and hepatitis are common. 13,34 Nutrition and prenatal care often are inadequate; anemia frequently is seen. These factors contribute to a poor pregnancy outcome and make it difficult to isolate the effects of any one drug on the fetus. However, several generalizations can be made. The majority of drugs used by the mother, including opiates (e.g., methadone, heroin), barbiturates, and sedative-hypnotic drugs, cross the placenta and affect the fetus. Fetal risks include growth restriction, malformations, intrauterine demise, prematurity, asphyxia, CNS dysfunction, and neurobehavioral abnormalities. Fetal drug dependence does occur and is associated with neonatal abstinence syndrome (NAS), which is manifested by CNS irritability and gastrointestinal dysfunction17,34 (see Chapter 11).
Cocaine use by the mother merits special attention. Cocaine is a CNS stimulant that produces vasoconstriction, tachycardia, and hypertension in both the mother and the fetus. Its use during pregnancy has been linked to growth restriction, smaller head circumference, genitourinary tract anomalies, placental abruption, stillbirths, RDS, congenital infection, NAS, and cerebral infarcts, as well as impaired performance as measured with the Brazelton behavioral assessment tool.13,121
All prenatal care providers should thoroughly assess pregnant women for alcohol and substance abuse at each prenatal visit, and treatment interventions should be initiated when abuse is identified. Toxicology screening of maternal blood or urine can verify suspicions of abuse; however, universal screening is not currently recommended. Neonatal urine or meconium screening can provide an accurate indication of exposure when there are clinical indications of drug effect. Laws in some states consider prenatal drug exposure to be a form of child abuse; thus the practitioner may be required to report positive drug tests in pregnant women or their newborns. (See Chapter 11 for a more complete discussion of complications in drug-exposed neonates.)

MATERNAL NUTRITION, MALNUTRITION, AND OBESITY

Maternal nutritional status and placental function during pregnancy can significantly influence the growth, development, and health of the fetus and newborn. Nutritional problems that interfere with fetal cell division (increases in cell number) can have permanent consequences. If the fetus is at a stage in which cells are only enlarging (increases in cell size), then nutritional deficits may be reversed if a healthy maternal dietary intake is resumed soon enough in the pregnancy. All women presenting for prenatal care should be questioned about their usual dietary intake and should have their weight and height assessed so that body mass index (BMI) can be determined and appropriate nutrition counseling initiated. BMI can be calculated by dividing a woman’s prepregnancy weight in kilograms by her height in meters squared; it is the most frequently used single tool in determining obesity. If a woman’s prepregnancy weight is unknown, the value obtained at the first prenatal visit should be used. Although the BMI values for classification vary, the Institute of Medicine (IOM) employs the relative weight classification and prepregnancy BMI values as follows117:
• Underweight: less than 19.8
• Healthy weight: 19.8 to 26
• Overweight: 26.1 to 29
• Obese: greater than 29
Optimal ranges for weight gain in singleton pregnancies are also based on the IOM recommendations. As a general rule, weight gain should be as follows: underweight women should gain 28 to 40 lb; normal-weight women, 25 to 35 lb; overweight women, 15 to 25 lb; obese women, up to 15 lb. The optimal weight gain for women carrying twins is 35 to 45 lb. 117 The IOM guidelines are continually being evaluated, but at least one study confirms that following these guidelines can improve pregnancy outcomes. 78 However, fewer than half of women gain the recommended weight during pregnancy, 165 with 43.3% of women gaining above the IOM guidelines. 149
Prenatal nutrition involves more than appropriate weight gain; a variety of healthy foods should be consumed, providing essential nutrients. The dietary reference intakes (DRIs) increase for most nutrients during pregnancy. Protein, iron, vitamin A, and iodine requirements nearly double, yet some nutrient requirements do not change much. 156 Other maternal factors that should be considered when counseling women on nutrition include age, parity, preconceptual nutritional status, preexisting medical conditions, current medical conditions complicating the pregnancy, food likes and dislikes, and cultural influences. Each woman’s counseling should be individualized, and referral to a nutrition specialist and other medical specialists may be indicated. 39
Malnourished and underweight mothers have more perinatal losses and preterm births, and their newborns have lower Apgar scores and more frequently are of low birth weight (less than 2500 g). This is especially true of significantly underweight women (low BMI) and women with eating disorders, such as anorexia and bulimia, who fail to gain adequate weight during pregnancy.165 Small-for-gestational-age (SGA) newborns, defined as below the tenth percentile birth weight for gestational age, have higher mortality rates in the perinatal period and are at risk for later problems such as insulin resistance and poor school performance. 165 However, it may be difficult to draw direct correlations between inadequate maternal diet and fetal growth unless the nutritional disturbances are severe. Many fetuses grow well despite suboptimal maternal nutrition, in part because of the complexities of placental transport and the ability of the fetus to be preferentially supplied with some nutrients.
Although reduced birth weight is associated with inadequate carbohydrate, protein, and total caloric intake, inappropriate amounts of other nutrients may also affect the fetus. Vitamin and mineral deficiencies have been linked to miscarriage and stillbirth, congestive heart failure (thiamine), megaloblastic anemia (folic acid, B 12), congenital anomalies including neural tube defects (folic acid, zinc, copper), and skeletal abnormalities (vitamin D, calcium). 90,161 Vitamin overdosage, especially of the fat-soluble vitamins, also has been implicated in fetal abnormalities. Vitamin A overdose has been associated with kidney malformations, neural or cranial defects, and hydrocephalus; vitamin D overdose has been linked with cardiac, neurologic, and renal defects. 39
Obesity

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