Enviromental pregnancy risk.

The purpose of obstetrics is to maintain the health of the pregnant woman and to ensure optimal health of the fetus. Preconception and postconception risks exist for both mother and child. Certain fetal and maternal conditions have been shown to have environmental and genetic components. Two determinations must be made when a physician responds to a patient's concerns about a specific exposure: (1) whether any quantity of the toxicant has known adverse effects on reproduction in humans and (2) whether the substance is present in sufficient quantity to affect the patient or population exposed. This issue is complicated in humans by the high natural spontaneous abortion rate of 15-30%, which makes determining the specific reproductive effects in humans difficult without studying large groups. Thus, reviewing the following criteria is useful for establishing a possible cause and effect: Reproductive risk of toxicant exposure includes fetal effects, especially congenital anomalies. The rate of congenital anomalies in the general population is 3% for defects that are detectable at birth in live-born infants and 6% for defects detected by the end of the first year of life. Because the baseline risk is small, if an exposure conveys a modestly increased risk, a large population of infants is required to detect an increase in anomalies. In addition, the gestational window is critical because exposures outside certain gestational periods may be nontoxic, while the same doses can cause devastating results within the window. 1 This lecture provides a summary of many environmental risks during pregnancy. .

Radiation Exposure
Diagnostic Imaging in Pregnancy The use of radiation for diagnostic imaging in the pregnant woman. is usually associated with a high level of anxiety for the woman, her family, and, often, the physician. A number of modalities may be required for diagnosis and treatment of exposures in pregnancy. It is necessary to balance the benefits of such procedures with an accurate assessment of the risk.2 In a broad sense, any energy-carrying waveform must be considered a kind of radiation. Ionizing Rays Documented effects include intrauterine lethality, organ malformation, mental impairment, and later-onset leukemia and solid tumors. X-rays are measured in several types of units, the most important of which are the radiation-absorbed dose (rad), which is a US measurement, and the gray (Gy), which is an international measurement. X-rays have both deterministic effects and stochastic effects. Deterministic effects are usually intrauterine, often postconceptual effects involving damage to growing and pattern-forming cell populations. If the exposure occurs when cell numbers are few, such as during the blastocyst or preimplantation stage, very early abortion or implantation failure results. These effects typically demonstrate both a dose-response curve and a threshold below which no effects are observed. As with other teratogens, the embryonic stage, defined as 10 weeks from the last menstrual period, is crucial because windows exist for the appearance of effects. The actual fetal dose is critical, and a simple application of a maternal calculated dose should not be substituted. The damage threshold begins at 0.1-0.15 Gy, which causes abortion at preimplantation, and extends to 1 Gy, which is associated with fetal death in utero at term.

Organogenesis represents a window of sensitivity for the fetus during gestational weeks 3-7. The threshold is thought to be 0.05-0.5 Gy. Skeletal defects have been reported in humans, most particularly reduced head circumference. Animal data suggest an increased risk of defects of the genitourinary system and eye in addition to skeletal effects. Severe mental retardation is another human effect noted at this threshold (0.05-0.5 Gy). The window for these effects is thought to be gestational weeks 8-25. Mental retardation has been noted at maternal doses of 1.5 Gy. Reported effects include mental retardation, a downward shift in intelligence quotient (IQ) of 30 IQ units/Gy, lower school performance, and unprovoked seizure. Importantly, while infants of normal intelligence remain within 1 standard deviation of normal following exposure, borderline infants are rendered mentally retarded at relatively low exposures. Stochastic effects do not show a threshold, and they occur in the later years of the exposed individual's life. Fetal x-ray exposure has been associated with later-onset childhood leukemias and solid tumors. The demonstrated relative risk in multiple case-control studies is 1.39 (95% confidence interval [CI], 1.3-1.49). This increased risk was documented by the Oxford Survey of Childhood Cancers and confirmed by multiple US and European studies. The increased risk is thought to occur following an exposure of 0.05 Gy. Thyroid cancer in childhood is a special concern. Multiple studies have shown that direct external exposure of the thyroid gland in children results in an increased frequency of cancer. Such exposures occurred following the Chernobyl accident and during medical procedures. The lag time until detection of cancer is 5 years after exposure. Similarly, in utero exposure during the second and third trimester of pregnancy (eg, Chernobyl, maternal thyroid ablation) is associated with an onset of childhood thyroid cancer, but with a less than 5-year lag time; these cancers are also associated with increased morbidity and aggressiveness.

Chemical Exposure
Lead Lead is common in the environment and continues to be a risk today. At high levels of exposure, it is associated with stillbirth and abortion. Epidemiologic studies have demonstrated adverse birth outcomes from either maternal or paternal lead exposure, including spontaneous abortion, low birth weight, preterm birth, and minor malformations. Even today, up to 52% of all homes in the United States may have unacceptable lead levels due to lead-based paint. Safety regulations have limited high levels of lead, but there are effects for even low levels of lead in the blood. Lead may also possibly be mobilized from a pregnant woman's bone stores. Mercury Mercury18,19 is a ubiquitous heavy metal with both natural and anthropogenic sources. The neurotoxic effects of exposure to high-dose mercury are well documented. Although mercury can affect the central nervous system at any developmental stage, unfortunate episodes of community-wide poisoning in Japan and Iraq revealed the particular sensitivity of the fetus to toxic effects from mercury exposure.20 The 3 types of possible mercury exposure for pregnant women are organic, inorganic, and elemental. Organic mercury compounds, such as methylmercury, are used as fungicides and in some paints. Uses of inorganic mercury include antiseptics, fungicides, electrical equipment, and some illicit skin-lightening creams. Elemental mercury is found in thermometers, dental amalgam, gold mines, and batteries. It is also used as a catalyst for the formation of some chlorine compounds. Organic mercury accumulates in the food chain, especially in fish. Importantly, it causes neurologic damage in human infants exposed in utero. An elevated incidence of cerebral palsy and microcephaly was noted in women who ate fish from Japan's Minamata Bay in the 1960s following industrial contamination of the bay.

Prescription Drugs
Prescriptions and Pregnancy Drugs are intentionally ingested chemicals that achieve measurable levels in the body and are usually used for therapeutic effects. Drugs are far more likely to be measurable in the fetal circulation compared to other chemicals. Recent studies indicate that more than 90% of pregnant women take medication during pregnancy, and many women take more than 4 different drugs during the course of pregnancy. The US Food and Drug Administration (FDA) requires animal testing before the approval of new medications. The FDA also uses a classification system to define fetal risks for all FDA-approved drugs. The pharmaceutical pregnancy risk classification by the FDA is as follows:

Category A: No fetal risk is observed in human studies. Category B: No fetal risk is observed in animal studies. No human risk is observed, although there is some risk in animals. Category C: No studies are available. Adverse effects are observed in animals, but no human studies are available. Category D: Evidence exists of increased risk to human fetus. The benefits of the drug may outweigh its risks. Category X: The drug has a proven risk to humans that outweighs any potential benefit.

Importantly, keep in mind that the same parameters used when considering the teratogenicity of chemicals also apply to drugs. An important developmental window may exist during which an effect can occur. Organogenesis, which occurs during postconception weeks 2-8, is typically the most important window. To be considered causative, the drug must be able to access the fetus through the placenta or be able to interact with maternal systems to create the effect. Medications can alter the fetal environment and pose a risk to fetal development. This risk must always be weighed against the benefit to the mother in the treatment of serious medical and mental conditions. Exposures to some kinds of medications are followed in national registries. These registries follow patients for very long-term effects. Examples include DES, anticonvulsants, and psychotropic medications. Anticonvulsants Epilepsy is a common disorder that affects women of reproductive age. It is has a prevalence of 5.25 per 1000 women. One third of people with epilepsy are women of reproductive age and 1 in 200 women attending antenatal clinics are receiving antiepileptic drugs.32,33 Both seizures during pregnancy and antiepileptic drug exposure in utero may contribute to adverse outcomes seen in children born to mothers with epilepsy. The risk for malformation doubles with use of anticonvulsants, and a few distinct syndromes are observed. The decision to cease an anticonvulsant is complicated by the fact that seizure itself may predispose the fetus to an anomaly. In late pregnancy, placental hypoxia can occur during prolonged seizure. In addition, many common anticonvulsants can contribute to folate deficiency. Heritable epilepsy also may be associated with other genetic abnormalities.

Valproic acid: Valproic acid is associated with a 1-2% increased risk of neural tubal defects, particularly at doses above 1000 mg/d. Phenytoin: Phenytoin is known to decrease the absorption of folate and is associated with characteristic fetal hydantoin syndrome, with effects including growth deficiency, microcephaly, dysmorphic facies, and mental deficiency; noted in 11% of fetuses exposed to phenytoin in utero. Trimethadione: Fetal trimethadione syndrome is associated with simian creases in the hands, cardiac anomalies, irregular teeth, and mental retardation with 50% incidence.

Phenobarbital: This is not associated with an increase in any anomaly, but it was associated with decreased intellectual performance at age 22 years in a Danish registry. Carbamazepine: This is associated with craniofacial defects, fingernail hypoplasia, developmental delay, and spina bifida.

Anticoagulants Pregnancy confers a fivefold risk of thrombosis. This predisposition results from the hypercoagulable state of pregnancy. The goal of anticoagulation is not only to prevent and treat maternal thromboses, but also to improve the outcome of pregnancy.34,35 Following is a brief summary of anticoagulants used in pregnancy. Although these medications, including heparin and aspirin, have not been approved for use in pregnancy by the US FDA, they are nevertheless widely used for appropriate indications in pregnancy.

Warfarin (Coumadin)

o o o o o o

Vitamin K antagonist Generally contraindicated during pregnancy If taken during the period of organogenesis in the first trimester, it carries up to a 30% risk of congenital anomalies The reported risk of miscarriage ranges from 14.6-56%. Placental transfer of warfarin later in pregnancy can result in fetal bleeding or stillbirth. Longterm neurologic damage has also been reported among children exposed in utero. The exceptional case for prescription of warfarin during pregnancy is the patient at high risk of mortality from thrombosis who may not be sufficiently anticoagulated with heparin or low molecular weight heparin (LMWH). Candidates for warfarin in pregnancy include women with mechanical heart valves or history of heparin failure with significant risk of rethrombosis.

Heparin and LMWH

o o o

Both unfractionated heparin and low molecular weight heparin exert their effect by activating thrombin. Heparins are the preferred agents for anticoagulation in pregnancy. Risks are as follows:

2% risk of major bleeding 17-36% reduction in bone density 2% risk of vertebral fracture Risk of heparin-induced thrombocytopenia. o No trials have been published comparing unfractionated heparin to LMWH in pregnant women, but in nonpregnant patients, LMWH has been associated with fewer side effects. o Heparins do not cross the placental barrier. Danaparoid o Low molecular weight heparinoid o Low placental permeability; drug of choice for cases of heparin allergy or heparin-induced thrombocytopenia in pregnancy o In published cases, no adverse fetal outcomes have been reported. Unfortunately, it is no longer available in the United States. o In vitro models show no placental transfer, but 10% of maternal levels have been detected in umbilical cord blood. Aspirin o Antiplatelet drug o Large randomized trials have demonstrated no increased risk of miscarriage, congenital anomalies, placental abruption, fetal hemorrhage, or neonatal bleeding.

Antihypertensives Certain well-studied older drugs are preferred for use during pregnancy in women who are chronically hypertensive and those with pregnancy-induced hypertension.36,37,38,39 Diuretics can lead to oligohydramnios.

Methyldopa: Methyldopa was, historically, the first-line agent for patients with hypertension in pregnancy. It is suggested to be safe in pregnancy. It is an alpha-adrenergic blocker. Beta blockers: Oral beta-blockers for mild-to-moderate hypertension during pregnancy have been specifically evaluated in the Cochrane Database. Beta-blockers seem to be associated with an increase in small for gestational age infants (RR 1.36; 95% CI, 1.02-1.82; 12 trials; n=1346). Maternal hospital admissions may be decreased, frequency of neonatal bradycardia increased, and respiratory distress syndrome decreased. Treatment with beta-blockers compared with the traditional methyldopa treatment appear to be no more effective and probably equally safe.

Hydralazine: Parenteral hydralazine may be associated with a higher incidence of maternal hypotension and other agents may be preferable, although a consensus has not been reached. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs): These should not be used at any point during pregnancy. Effects include oligohydramnios, renal anomalies, neonatal renal failure, pulmonary hypoplasia, hypocalvaria, intrauterine growth restriction (IUGR), and death.40

Nutrition
Nutritional Risks The overall nutritional status of the mother contributes to the environment of the fetus, but few deficits or surpluses are fetal risk factors. Folate Folate is essential in many metabolic pathways, especially synthesis of nucleic acids and amino acids. Strong evidence from prospective studies demonstrates that folate deficiency is associated with neural tube defects and spina bifida. An association is also observed with cleft lip and cleft palate. Aminopterine, a folate antagonist, is a known teratogen. Supplementation with folic acid and vitamins is problematic, since up to 50% of pregnancies are unplanned and a womens health status may not be optimal at conception. Iron Pregnancy carries a risk of iron deficiency anemia to the mother because of increased hematopoiesis and stores for the baby. The mother's need totals at least 7 mg/d of iron. Severe iron deficiency anemia (and other anemias) confers a risk of low birth weight, preterm birth, and increased perinatal mortality to the infant if the maternal hemoglobin level falls below 10.4 ng/mL. Some controversy exists regarding supplementation during pregnancy because a hemoglobin level of higher than 13.2 g/dL has also been associated with progressively higher incidences of pregnancy-induced hypertension, neonatal mortality, low birth weight, and preterm delivery. Iron supplementation is unlikely to be causative; rather, severe maternal conditions that contract the plasma volume (eg, severe early preeclampsia) are suggested. Maternal smoking is also associated with relatively high hemoglobin levels and could be a factor in low birth weight or preterm birth. Eating disorders In 2005, Koubaa et al published a prospective observational study of 49 nulliparous women with various eating disorders, compared with 68 controls. Twenty-two percent of women had a verified relapse in their eating disorders during pregnancy. Compared with control groups, women with past or current eating disorders were at increased risk of hyperemesis and delivery of an infant with lower birth weight and smaller head circumference.55 Although maternal mean weight gain among the patients was not significantly different from

that of controls, the patient group did not reach the recommended weight gain of 25-35 lb during pregnancy. Lower birth weight, prematurity, and higher miscarriage rates are also reported in women with eating disorders.56 Maternal eating disorders can improve during pregnancy but often worsen postpartum.57 Maternal obesity About one third of all pregnant women in the United States are obese. Neural tubal defects and other developmental anomalies are more common in infants born to obese women, especially in those with diabetes mellitus and poor glycemic control. Studies of women with impaired glucose tolerance show that replacing refined carbohydrates and saturated fats with complex, low-glycemic carbohydrates and polyunsaturated fatty acids improved metabolic homeostasis and pregnancy outcomes. Obesity causes significant complications for the mother and fetus. Interventions directed toward weight loss and prevention of excessive weight gain must begin preconception.58 Maternal obesity is a well-established risk factor for the development of preeclampsia. Obesity is also associated with tissue insulin resistance, decreased glucose uptake in skeletal muscle, and adipose tissue and enhancement of hepatic glucose production. This trend to increasing obesity has led to substantial increases in the number of women entering pregnancy with type 2 diabetes mellitus.59

Drugs of Abuse
Alcohol Alcohol is the most potent teratogen among the substances of abuse.61,62 Fetal alcohol syndrome (FAS) now surpasses all other known etiologies for mental retardation. A dose-dependent range of effects exists, and a threshold for effects is theorized, but not proven. In animal studies, even a single dose (comparable to a single binge of at least 4.5 drinks) causes pregnancy failure, craniofacial abnormalities, and CNS dysfunction. To make the diagnosis of FAS, components from each of the following categories must be present:

Growth: Intrauterine growth restriction; postnatal growth retardation CNS alteration: Tremor, poor sucking ability, hypertonia or hypotonia, attention deficit, mental impairment, developmental delay Dysmorphism and anomalies (at least 2): Narrow eye width, ptosis, short upper vermilion, broad upper lip, short upturned nose, absent philtrum, mid face hypoplasia, micrognathia, microphthalmia, microcephaly NonFAS-defining anomalies associated with FAS: Cardiac defects, spinal defects, limb defects, urogenital defects

FAS occurs at a consumption level typically at or above 21 drinks per week, which is approximately 3 drinks per day for heavy drinkers. The partial syndromes and effects are seen at lower levels of alcohol consumption (eg, 2 drinks per day). Drinking during the first trimester is associated with physical defects; growth restrictions and neurological effects are associated with second- and third-trimester alcohol consumption. Studies have demonstrated reduced incidence of ARND if heavy drinkers stop drinking for the second and third trimesters.

Tobacco Cigarette smoking is also very prevalent in society.63 Recently, Wollman coined the phrase "fetal tobacco syndrome" in exact parallel to FAS. The major effects of smoking during pregnancy are growth restriction, increased miscarriage rate, perinatal mortality, and childhood effects. Cigarette smoking is the most important cause of IUGR in developed nations, accounting for an astonishing 40% of cases. A well-documented dose-response curve is observed, ie, fetal weight decreases as the number of cigarettes smoked by mother increases. Fetal weight is reduced 5 percentile points per pack per day. The morbidity and health dollar expense is probably equal that of pregnancy-induced hypertension. The incidence of premature birth and pregnancy loss is also increased. The mean birth weight of infants of women who smoked during pregnancy has been found to be 170-200 g less than that of nonsmokers. Smoking alters the overall success rate of assisted reproductive technologies by 40%. In addition, women who smoke have a 50% reduced implantation rate and a 50% reduced ongoing pregnancy rate. Women who quit smoking prior to attempting assisted reproduction fare better. Women who smoke have increased levels of follicle-stimulating hormone (FSH), more abnormal oocytes in the ovary (diploid after meiosis), and early menopause. Daughters of women who smoked during pregnancy have a fourfold increased risk of taking up smoking in adolescence. This effect persisted after controlling for postnatal smoking, and the effect did not seem to occur in sons of mothers who smoked. Perinatal mortality rates are increased due to the association of both prenatal and postnatal smoking with sudden infant death syndrome (SIDS). SIDS has a prevalence of approximately 0.63 cases per 1000 births, and it is the most common single cause of postnatal death. The pervasive influence of smoking on birthweight is a contributing factor. In multiple studies, SIDS was twice as common in infants of women who smoked. Increases occurred when other members of the household smoked, and the effects seemed multiplicative, ie, the more individuals in the household who smoke and the higher the estimated exposure and number of cigarettes per day, the higher the rate of SIDS. Separating prenatal effects from postnatal effects is very difficult, but evidence indicates independent increases in risk for both. The adverse effects of prenatal smoking and passive smoking continue into the child's life. In the immediate neonatal period, withdrawal from nicotine is seen in a "jittery baby" constellation of symptoms. Also, asthma is linked to both prenatal and postnatal smoking. Overall lifetime lung function capability is decreased, regardless of whether full-blown asthma develops. Narcotics Cocaine Without question, cocaine use, especially crack use, has severe effects on the user. Effects include vasoconstriction, hypertension, seizure, respiratory collapse, crack lung, cardiac arrhythmia, and fatal myocardial infarction. The lethal dose is 1.2 g, but death has occurred with as little as 20 mg. During pregnancy, cocaine use is associated with hypertension, seizure, preterm labor, placental abruption, IUGR, and preterm delivery. Pregnant women may show an exaggerated response to cocaine toxicity, perhaps due to progesterone-induced alterations in the enzyme systems that metabolize cocaine.71 Cocaine is not a teratogen. Early concerns that its use might be associated with limb reductions and other vascular anomalies have not been substantiated. The catastrophes that were predicted because of increased cocaine use, such as large numbers of children with attention deficit and other permanent behavioral problems, have not occurred.

Caffeine Caffeine is widely considered a very benign substance, and it is ubiquitous in coffee, tea, and soft drinks. The estimated average daily intake is 99 mg. A cup of coffee can contain 127 mg of caffeine, tea up to 107 mg, and soft drinks up to 65 mg. In one study, approximately 28% of women consumed more than 150 mg/d throughout their pregnancy. At levels equivalent to 12-24 cups of coffee a day, rats experience skeletal malformations and ectrodactyly; however, teratogenic effects have not been noted in humans. Recent studies do indicate a slightly increased chance of experiencing preterm delivery, having an infant that is small for gestational age, and, perhaps, miscarrying in the late first or second trimester. Two studies were published in 2008. The first study by Savitz et al determined caffeine intake in early gestation in detail and stratified results by timing of the pregnancy loss to determine the probability of having a miscarriage at a specific week of pregnancy. Among all women, caffeine consumption any of the time points was unrelated to the risk of miscarriage (OR, 0.7 and 1.3).75 The second study by Weng et al sought to examine the risk of miscarriage as well but used a population-based prospective cohort study design. The researchers found a dose-response relationship, with the most risk found at 200 mg/day.76 Intervention Pregnant women should keep caffeine intake below 150 mg/d, especially early in pregnancy; small amounts (less than 2 cups) of caffeine daily do not increase the odds of miscarriage.