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:
The exposure must precede the outcome (eg, eliminate temporal ambiguity).
A dose-response effect is observed (ie, more severe effect with increasing dose). Thresholds may occur.
Plausible physiologic and biologic mechanisms: For example, positing that a major change in organ formation was due to late-trimester pesticide exposure would not be plausible because organogenesis would have been completed before the exposures.
Findings should be replicated in more than one study or population.
Cause is more strongly suggested if the effect is an independent variable after all possible confounders are eliminated.
Some researchers have recently suggested that any hypothesized toxicant should be compatible with current existing models of development and should include cumulative risk.
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. 
This article provides a summary of many psychosocial and environmental risks during pregnancy. The complex interplay of (1) genetic, (2) environmental, and (3) social factors requires sophisticated and thoughtful interventions on the part of health care providers.
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. 2014 study also showed that there is a deficiency in both emergency department (ED) and obstetric/gynecologic physicians' knowledge when counseling women about the risks of diagnostic imaging in pregnancy.  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.  In a broad sense, any energy-carrying waveform must be considered a kind of radiation.
The primary exposures include diagnostic radiographs, radiopharmaceuticals, workplace exposures, and environmental exposures such as those that occurred after the Three Mile Island and Chernobyl nuclear reactor accidents. [4, 5, 6, 7] 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. Both rads and grays typically refer to single-time exposures (eg, diagnostic procedures). The roentgen equivalent man (rem) unit of measure and sievert (Sv) unit are used to quantify radiation exposure over time (eg, environmental releases). Conversion factors for these measurements are 1 Gy equals 100 rad and 1 Sv equals 100 rem. When calculating the dose of ionizing radiation, several factors must be considered, including type of study, type and age of equipment, distance of organ from the radiation source, thickness of the body part penetrated, and method used for the study.
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 3-8. 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 to radiation 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 increased risk of onset of childhood thyroid cancer, but with a less than 5-year lag time; these cancers are also associated with increased morbidity and aggressiveness.
Clearly, preventing exposure during the first trimester is advisable. Informed counseling is needed for patients with conditions that require diagnostic imaging, and it is even more necessary for patients who must undergo radionuclide uptake scans or therapy. Patients should be advised that no known safe dose exists related to later-onset childhood cancers. The counseling must weigh the potential risk to both patients (fetus and mother) and the value that any given diagnostic test will have for decision-making. For occupational exposures, the limit is 1 mSv after pregnancy notification. According to the American College of Radiology, no single diagnostic procedure results in a radiation dose significant enough to threaten the well-being of the developing embryo or fetus. Radiation exposure in diagnostic ranges (< 50 mGy), has not shown to be associated with an increased incidence of any congenital malformations of significance in humans or animals.
Medical procedures and associated fetus and uterus radiation exposure are discussed below.
The most commonly used is the chest radiograph. Fetal exposure is exceptionally small for 2 views (approximately 0.07 mrad).
A single abdominal film has a higher dose because the fetus is in direct line with the x-ray beam, but the average exposure is still only 100 mrad.
Trauma series radiographs of the extremities, skull, and ribs deliver low doses because of fetal distance to the target area, except for the hip or pelvic radiograph, which delivers about 200 mrad
Computed tomography (CT) scanning
This important imaging modality is used commonly to evaluate for multiple disorders. Newer generation tomography equipment is more sensitive and there is less scatter, although higher resolution may be associated with higher radiation exposure.
Cranial CT is the most commonly requested study in pregnant women; it is the preferred technique to detect acute hemorrhage, exposing the fetus to 0.05 rad.
Spiral CT scanning of the chest exposes the fetus to 0.05-0.10 rad; this is the diagnostic modality often used for evaluation of pulmonary embolism in pregnancy.
Abdominal and pelvic CT for both trauma or for pelvimetry exposes the fetus to anywhere from 0.17-0.35 rad.
Fluoroscopy and angiography
Cerebral angiography exposure is about 10 mrad, whereas it is 0.05 rad for upper gastrointestinal series and up to 2 rad for small bowel series with upper gastrointestinal series.
Nuclear medicine studies
The fetal absorbed dose represents the combined effect of both the external irradiation from the maternal tissues and the placental transfer and fetal uptake of the injected or inhaled radiopharmaceuticals.
Ventilation/perfusion scans are typically measured with injected technectium-99 macroaggregated albumin for perfusion and with inhaled xenon 127 or xenon 133 for ventilation; fetal exposure for both is negligible at approximately 20-50 mrad. This is the preferred imaging study for diagnosis of pulmonary embolism in pregnancy. Recent studies have confirmed that ventilation/perfusion scans result in lower radiation to the fetus when compared with spiral CT scans of the chest for diagnosis of PE in pregnancy. [8, 9]
Radioiodine crosses the placenta readily and the fetal thyroid can concentrate iodine as early in the first trimester. If Iodine-125 treatment of hyperthyroid goiter is performed in the first trimester, there are significant risks to the fetal thyroid ablation. If pregnancy was undiagnosed at the time of treatment, then maternal hydration, frequent voiding, and potassium iodide may be attempted to minimize the fetal dose. But, the total fetal absorbed dose can be as high as 10 rad.
Magnetic resonance imaging (MRI)
Current guidelines from the US Food and Drug Administration require labeling MRI devices to indicate that the safety of MRI with respect to the fetus has not been established. In general, most studies evaluating MRI safety during pregnancy show no ill effects. Injury to the fetus is not a significant risk during prenatal MRI.
Intravenous gadolinium is teratogenic at high and repeated doses in animal studies.
Gadolinium does cross the placenta, where it is excreted by fetal kidneys.
The 2007 American College of Radiology Guidance Document for Safe MR Practices recommends that IV gadolinium should be avoided during pregnancy and used only if absolutely necessary.
Table 1. Procedures and Exposures (Open Table in a new window)
|Procedure||Mean mGy||Maximum mGy|
|Chest radiograph||< 0.01||< 0.01|
|Skull||< 0.01||< 0.01|
|Thoracic spine||< 0.01||< 0.01|
|Abdominal CT scan||8.0||49|
|Chest CT scan||0.06||0.96|
|Pelvic CT scan||25||79|
|Head CT scan||< 0.005||< 0.005|
Management of patients who are irradiated
The fetus is not at risk of teratogenesis if the dose of irradiation does not exceed the threshold dose. The exact threshold radiation dose below which no teratogenic effects occurs is not known, but it is estimated to range from 0.05–0.15 Gy (5-15 rads). A medical physicist can be consulted to provide the exact dose estimations after inadvertent radiation exposure, but practitioners should be familiar with the above general exposure guidelines. Providing patients with this accurate risk assessment is vital, as some women may terminate a desired pregnancy due to misperception about the effects of radiation exposure.  The American College of Obstetricians and Gynecologists states that exposure to x-rays during pregnancy is not an indication for therapeutic abortion. [4, 11]
Relatively few studies have been performed on human exposure to cosmic radiation. Cosmic radiation is ionizing radiation by heavy particles, such as protons and helium nuclei, that originate outside the Earth. This form of ionizing radiation is most evident at very high altitudes. Primary exposure requires many in-air hours; therefore, airplane crew members and pilots, rather than passengers, may be at risk.
Two organizations, the US National Council on Radiation Protection and Measurement (NCRP) and the International Commission on Radiologic Protection (ICRP), provide the following recommendations on permissible doses:
General public - 1 mSv (100 mrem) maximum per year
Aircrews - 20 mSv/y averaged over 5 years (maximum 50 mSv/y)
Fetuses - 2 mSv (not to exceed 0.5 mSv/mo)
The risks of all other forms of transportation outweigh those of flight, although an association exists between frequent flying and certain specific cancers, most notably brain, colon, and hematopoietic cancers. Also, ionizing radiation has the previously noted fetal effects of decreased head circumference, mental retardation, and childhood cancer.
Aviation workers can easily exceed the NCRP and ICRP limit recommendations. For example, working the London-to-Chicago route for 100 hours exceeds the fetal recommendation. Charter jet crews and passengers fly at higher altitudes with more consequent exposure. Changes in intensity occur with changes in solar flare activity on the sun, and the intensity may exceed 10 mSv/h at 42,000 ft. The US Federal Aviation Administration (FAA) and the US Occupational Safety and Health Administration recognize flight crews as individuals exposed to radiation.
A 2014 study confirmed that, during solar particle events such as solar flares, a flight attendant's radiation exposure may exceed the equivalent dose limit to the conceptus of 0.5 mSv/month (recommended by the National Council on Radiation Protection and Measurements. 
Computer systems are available to calculate exposures, but these systems are not mandatory. Presently, a major difference exists between the United States and Europe. Countries of the European Union, by law, limit fetal exposure of cosmic radiation to 1 mSv. In the United States, the FAA's documents on this subject are only advisory, not regulatory.
Health care providers should obtain complete occupational histories and discuss risk of exposure with pregnant patients. Given the variability of exposure and lack of effective monitoring, a mandatory cut-off or exclusion of pregnant workers from certain jobs could be potentially discriminatory. Physicians can assure pregnant women who are concerned about their radiation risks with air travel that under normal solar conditions, the risk of direct harm from cosmic radiation is negligible. However, during some solar energetic-particle events, the dose rates at airliner altitudes may be significantly greater than usual. During these rare events, a pregnant women should be advised to check the Website of the Space Weather Center of the National Oceanic and Atmospheric Administration to see if she should postpone her trip. [13, 14]
Ultrasonography [15, 16] involves the creation of high-frequency sound. Ultrasonographic imaging involves analysis of how the ultrasonographic wave alters upon encountering objects of different densities when reflected back to the emitter. Physical effects, such as well-contained thermal effects, occur when the vibration at these high speeds is used (eg, between the paddles of a harmonic scalpel). The energy of ultrasonography is carried by the physical particles of the media and objects affected. Higher energy is of particular concern for pulsed Doppler, color flow, first trimester ultrasonography with a long transvesical path (>5 cm), second or third trimester exams when bone is in the focal zone, when scanning tissue with minimal perfusion (ie, embryonic), or in patients who are febrile.
Operators can minimize risk by limiting dwell time, limiting exposure to critical structures, and following equipment-generated exposure information. Current equipment approved for use typically includes monitoring for application-specific intensity limits. The risk of inducing thermal effects is greater in the second and third trimesters when fetal bone is intercepted by the ultrasonographic beam and significant temperature increase can occur in the fetal brain. Nonthermal bioeffects may be more significant in early gestation. To ensure the continued safe use of ultrasonography in obstetrics, it is important that international ultrasonographic organizations, such as the International Perinatal Doppler Society, issue advice to members to allow sensible assessment of risk to benefit and on the practical implementation of the use of ultrasonography as low as reasonably achievable principle in pregnancy. To date, the available research does not support any DNA-specific effects being observed.
Despite multiple studies, including some very large studies, the low-energy electromagnetic fields generated by power lines, video displays, and other electric and electronic devices have no demonstrable effects. Some of these studies have been conducted in response to clusters of events such as increased spontaneous abortion rates in a specific area. 
Microwaves are a form of electromagnetic radiation with particularly long wavelengths. In contrast to ionizing radiation, which travels in extremely short, high-energy waves, energy in microwave radiation affects objects and cells by thermal action only. Microwaves raise the temperature within cells and are cytotoxic to individual cells only at high exposures. No specific DNA-damaging mechanism exists, and no stochastic effects are observed in exposed populations. 
However, a 2014 meta-analysis that examined pregnancy outcomes in the high-risk populations of physiotherapists who regularly use short-wave diathermy and microwave therapy reported significantly higher rates of infertility, spontaneous abortion, altered gender ratio, congenital malformations, and low birth weight.  These findings suggest that some groups frequently and regularly exposed to short-wave or long-wave electromagnetic fields may have worsened pregnancy outcomes when compared to control subjects. 
Another concern to the general public is the potentially harmful effect of various chemical exposures during pregnancy.  Typically, the presumed threat is in an obvious location, ie, industry and environmental pollution. In reality, environmental toxins pervade the ecosystem, and people wittingly and unwittingly expose themselves to myriad compounds. Unlike the traceable residue of radiation from relatively few sources, chemicals are insidious.
Chemicals thought to have adverse effects on reproduction and pregnancy include heavy metals, endocrine disruptors, organic solvents, and pesticides. Approximately 17% of working mothers are exposed to known teratogens in the workplace. At least 51 synthetic compounds are ubiquitous in the environment and are also known teratogens. Although some researchers consider tobacco smoke an environmental agent, in this article it is included with other substances of abuse.
Heavy metals are well-established toxicants, and some can be direct industrial contaminants that enter the food chain, for example in fish (methylmercury contamination) or grain. Other metals, such as lead, are more pervasive. Lead was widely used in paint and leaded gasoline, which has been banned; however, lead contaminates the soil long after the use of its primary source, leaded gasoline, has stopped.
Lead is common in the environment and continues to be a risk today, despite attempts to lower environmental lead levels by removing it from most paint and gasoline. 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.
In a study by Chen et al, patients with a maternal blood lead concentration of 20 mcg/dL or greater had a higher risk of mothering a small for gestational age child (risk ratio, 2.15; 95% CI, 1.15-3.83).  Although the current threshold for the toxic range of lead is 20-25 mcg/mL, levels as low as 10 mcg/mL in maternal or cord blood are associated with transient cognitive defects in children. One article assessed the neurocognitive status of 6-month-old infants whose mothers were exposed to low but varying amounts of lead during pregnancy. Lead levels in cord blood were then compared to performance on infant intelligence and visual recognition tests. Infants scored lower if the lead concentration in blood was higher.  Studies have also reported on the association of lead exposure and adult criminal behavior. 
More recent studies have also examined the effect of elevated blood lead levels on hypertensive disease in pregnancy. One cross-sectional study found that, in New Orleans neighborhoods with higher soil lead levels after Hurricane Katrina, pregnant women had a 1.48-fold increased risk of developing eclampsia, compared with pregnant women living in neighborhoods with lower lead levels. 
Some studies have shown lead exposure in avoidable routes such as beverage consumption; in a 2013 study in the Journal of Toxicology, it was found that 73% of commercial teas brewed for 3 minutes had lead levels considered unsafe for pregnant and lactating women. 
The US Occupational Safety and Health Administration (OSHA) requires that workers with blood lead concentration levels of 40 mcg/dL be removed from the workplace and recommends that blood lead concentration levels in a women of childbearing age be less than 20 mcg/dL. A study published in the Journal of Perinatology suggested that these current recommendations may need modification based on a significant relationship between maximum lead blood concentration levels of 10 mcg/dL or greater and problematic birth outcomes. 
A 2014 study by Nishioka et al showed that, even at levels less than 5 mcg/mL in maternal blood in the midtrimester, there is a higher incidence of small-for-gestational-age infants, suggesting that even low-level exposure to lead in early pregnancy may be harmful.  Maternal blood concentrations that were once considered acceptable may place some mother-infant pairs at risk. Along these lines, the CDC recommends a blood lead level of less than 5 mcg/dLfor pregnant and lactating women. 
Checking maternal serum lead values is currently performed in some public-assistance programs. Chelation with agents such as ethylenediaminetetraacetic acid (EDTA) should be considered for anyone with a lead level that is 25 mcg/mL or greater. Chelation therapy itself may pose a hazard to the pregnancy; data from experiments in rats showed an increased frequency of malformations. In addition, chelation could create deficiencies in other metals such as zinc.  Therefore, the current mainstay of treatment remains prevention—remove the source of exposure to lead or disrupt that route of exposure, if at all possible.
Mercury [29, 30] 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. 
The 3 types of possible mercury exposure for pregnant women are organic, inorganic, and elemental. Organic mercury compounds, such as methylmercury (MeHg), 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. It is converted to the damaging methylmercurgy (MeHg) by biotic sources. Importantly, MeHg 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. Maintenance of international standards of toxic waste management and reduction in the use of MeHg are necessary to limit wide-scale exposure.
Mercury amalgams may represent an occupational hazard for dental workers at all levels. Mercury vapor (inorganic mercury) is released as these amalgams are created. Once inside the lungs, mercury is oxidized. Between passage of elemental mercury through the alveolar membrane and complete oxidation, mercury accumulates in the central nervous system. During this process, mercury can irreversibly damage the central nervous system. At exposures of moderate duration, the kidneys are also affected. Occupational exposure to mercury vapor has caused psychiatric symptoms, hallucinations, erethism, insomnia, and muscular tremors. Some evidence exists for an increased risk of spontaneous abortion with more than 50 amalgam-creation exposures per week, but other research has not replicated this finding.
The fetal nervous system is currently considered to be the organ system most vulnerable to the effects of methylmercury. Two large prospective studies showed conflicting data; in a study in the Faroe Islands, elevated mercury was associated with poor cognitive outcomes at ages 7 and 14 years, whereas in a study in the Seychelles Islands, few adverse outcomes were noted for either cohort. [32, 33]
Currently, adverse effects are thought to be identified in the child when the pregnant woman's exposures result in maternal hair concentrations between approximately 5 ppm for subtle developmental changes to a range of 10-20 ppm for clinically obvious changes such as delayed walking. A study in Quebec showed that elevated levels of MeHg in umbilical cord blood were associated with cognitive deficits in the A-not-B test in 11 month olds; this indicates a decreased working memory and reflects poorly on early development of executive function. 
Organic mercury should be avoided completely by pregnant women. Using the data from several studies and the discovery of Minamata disease in the 1950s, the National Academy of Science-National Research Council investigated the matter and published a congressional mandated report of the developmental risks of methylmercury. The committee's consensus supported the Environmental Protection Agency's reference dose of 0.1 mcg/kg of body weight per day as a scientifically justifiable level for the protection of public health. The committee also supported the use of the benchmark dose level to estimate the reference dose, with the preferred benchmark dose level at 58 parts per billion of mercury in cord blood or 12 parts per million of mercury in hair. Working environments should have a mercury vapor level below 0.01 mg/m3.
No safe level of mercury in any form has been documented. Women should consider limiting fish intake to no more than 350 g/wk (about two 6-ounce servings) preconceptually and during pregnancy. The FDA provides a comprehensive list of MeHg levels in fish that are available in the United States. Pregnant women are advised routinely to avoid the 4 most heavily contaminated species: tilefish, swordfish, king mackerel, and shark. These fish contain MeHg at concentrations that are 10-20 times higher than fish such as herring, cod, pollack, shrimp, or scallops.
Specifically, the women should limit consumption to 12 ounces per week of fish species with lower mercury concentrations and to 6 ounces per week (1 fish meal) if species types are unknown. In addition, the Hawaii State Department of Health published its own advisory that more strictly limits fish intake than the EPA due to the increased consumption of fish in this population.
Cadmium is found in graphic arts material, paint, ceramics, welding material, solder, fish, and cigarette smoke. Animal research indicates that high cadmium levels can lead to cleft palate, anencephaly, lung problems, and neurologic damage. A 2014 study in North Carolina showed that women with high serum cadmium levels in pregnancy (>50 mcg/L) had increased odds of delivering a small-for-gestational-age infant.  Research in humans is under way. 
Manganese is found in tea, cloves, and some grains. Some gasoline contains manganese additives. A low level of manganese is required in the diet. High levels of manganese during pregnancy have been associated with an increased incidence of spontaneous miscarriage and stillbirth, as well as increased rates of pregnancy-induced hypertension and low birth weight. [37, 38]
Inorganic arsenic [39, 40, 41] is a naturally occurring element found at different concentrations in drinking water supplies in various areas of the world; areas with high rates of arsenic contamination of drinking water include the US South West, India, Bangladesh, and Argentina.
High exposures have been associated with a number of problems including hypertension; vascular disease; skin, lung, and bladder cancer; and diabetes. Parenterally administered arsenic induces neural tubal defects in several animal models; however, oral and inhalational exposures to arsenic are not teratogenic in rats. Reproductive outcomes have also been reported in human populations, including higher risk of low birth weight, spontaneous abortions, preeclampsia, congenital malformations, and infant mortality.
Endocrine disruptors [42, 43] are chemicals that mimic hormones, occupy hormonal receptors, or trigger inappropriate hormone responses in the body. Naturally estrogenic and androgenic molecules are abundant in soy and other plants. Many classes of synthetic chemicals also have estrogenic effects.
Xenohormones mimic or antagonize the activity of steroid hormones. Perhaps the most well-known xenohormone is dichlorodiphenyltrichloroethane (DDT), an organochloride. DDT is a proven reproductive toxin in birds and other wildlife. It remains an important chemical in the environment because it accumulates within the food chain, and unhealthy levels persist even today. DDT exposure usually occurs through consumption of game or food with high levels of DDT. Exposure during pregnancy is linked to low birth weight and small head circumference.
Methoxychlor, an organochloride, is an estrogenic pesticide that has largely replaced DDT. It is thought to be safer for humans. Methoxychlor reduces rat fertility and interferes with estrus. It also accelerates progression of pregnancy in mice, which results in early vaginal opening. Whether any significant estrogenic effects occur in women is unknown.
Dioxins are released into the environment during paper-pulp bleaching, pesticide production, and the management of chlorine compound waste. Like DDT and methylmercury, dioxins accumulate in the food chain and are harbored in adipose tissue. They can be measured in human breast milk. In rats and monkeys, 2,3,7,8-tetrachlorodibenzo-p -dioxin causes reproductive changes (eg, decreased fertility) and it may cause endometrial hyperplasia. In female rat offspring, in utero dioxin exposure results in a reduced ovarian weight and fecundity and induces malformations like cleft phallus and persistent tissue across the vaginal orifice.
Diethylstilbestrol (DES) was used in pregnant women until 1971 as a treatment to prevent miscarriage. It is a synthetic estrogen infamous for causing uterine anomalies, infertility, and adenosis in female fetuses exposed in utero. In utero exposure is also known to cause clear cell adenocarcinoma of the vagina with a young age of onset. Women with fetal exposure to DES have an increased risk of developing vaginal cancer at 20-30 years of age.
Lindane is a drug used to kill lice. It has antiestrogenic and weak estrogenic effects, but it does not occupy estrogen receptors. Heptachlor and hexachlorobenzene are also possible endocrine disruptors.
Phthalates are chemicals used in industry, plastic production, and metal can linings. Some preliminary evidence suggests that in utero exposure to phthalates in female fetuses can induce early sexual maturation. 
In recent years, bisphenol A (BPA) has been highlighted as an endocrine disruptor which alters metabolism of estrogens, androgens, and thyroid hormones. There has been a movement to remove BPA from the plastic in water bottles and other food receptacles, but BPA remains ubiquitous in the lining in canned foods and many other plastic products, among other routes of exposure. Studies have shown associations between maternal BPA levels and pregnancy and pediatric outcomes such as miscarriage rates, infant reactive airway disease, low birth weight, liver dysfunction, and neurologic complaints (eg, hyperactivity). [45, 46, 47, 48] A recent study found increased rates of depression and behavioral problems in young boys who were exposed to BPA in utero; this included an increase in rates of oppositional defiance disorder (ODD). 
Plant estrogens from soy and legumes can adversely affect reproduction in rats and sheep. Premature thelarche and alterations in menstruation in humans are speculated to be associated with plant estrogens.
Apart from the avoidance of accumulated DDT and the use of endocrine modulators early in pregnancy, few recommendations can be made definitively about endocrine disrupters. It would be reasonable to suggest that pregnant women avoid the use of certain products in which endocrine disturbers are found to be very prevalent, such as avoiding the excessive consumption of canned goods.
Manufacturing requires solvents that are frequently used in dry cleaning chemicals, paint, graphics, glue, electronics, chemical research, and chemical production. Of the many solvents, xylene has been linked to caudal regression in humans. Perchloroethylene may be associated with infertility, and styrene may alter menstruation. Toluene, xylene, and perchloroethylene may be associated with increased risk of spontaneous abortion. Recent retrospective research demonstrated increased odds of infertility for women exposed to solvents (odds ratio, 1.74).
Glycol ethers are a class of organic colorless solvents that are miscible with water and many organic solvents. They are used for a wide variety of solvent applications in the manufacture of lacquers, paints, dyes, inks, cleaning agents, and liquid soaps. Specific ethers like phthalate ester, used in the manufacturing of plastics and inks produces testicular atrophy in experimental animals, but no known information of this effect in humans exists. Female manufacturers of semiconductors were studied in an epidemiologic study from 1980-1989, which suggested that when exposed to a mixture containing ethylene glycol ethers, the women had increased risks of spontaneous abortion and subfertility.
In the past, polychlorinated biphenyls (PCBs) were used heavily in electronics, plasticizers, and adhesives. They have been banned in the developed world since the 1970s. PCBs remain pervasive in the environment; they accumulate in fish and they persist in dairy products, pork, and beef. PCB exposure is linked to prenatal death, infertility, fetal growth retardation, and poor short-term memory.
Long-term follow-up of children with high prenatal exposure to PCBs showed significantly decreased full-scale and verbal IQ scores; the average decrease was 6.2 points. Prenatally, mothers of these children consumed fish from Lake Michigan; PCB levels were confirmed by cord blood levels. These children were 3 times as likely to have poor IQ performance, to have poor verbal comprehension, and to be more distractible. They were also twice as likely to be 2 years behind unexposed children in word comprehension.
At levels high enough to cause maternal toxicity, PCBs cause low birth weight; skin, gum, and nail discoloration; and desquamative skin changes. Acne and nail pigmentation are likely to persist. Some evidence suggests that some PCB actions may affect the thyroid hormone system. Recent innovative mechanistic studies in rat models have shown that PCBs can act directly on uterine muscle, increasing uterine sensitivity to oxytocin-induced contraction.
Many classes of compounds are used as pesticides. Examples include endocrine modulators, such as DDT and related compounds, and organic synthetic compounds, which are discussed in this section. 
Organophosphates, such as parathion, malathion, and diazinon, have not been well studied. Animal studies show alterations in ovarian function, decreased serum levels of progesterone and luteinizing hormone, fetotoxicity, and pseudopregnancy.
Carbamates, such as carbaryl (Sevin), are widely used insecticides that inhibit cholinesterases. In animal studies, even maternally toxic doses showed few increases in defects in offspring. At the very highest doses, noted effects included omphalocele in rabbits, ventricular septal defects in sheep, and varied anomalies in beagles.
Pyrethrums are chrysanthemum-derived insecticides found in antilice treatments. They do not appear to have significant toxicity, but they have not been well studied in humans.
Arbuckle and Sever reviewed epidemiological studies of numerous individual pesticides and pesticide combinations. Overall, their review involved hundreds of thousands of individuals. Their data suggest an increased risk of fetal death associated with pesticides in general and with maternal employment in agricultural industries.
PCBs and other pesticides are associated with adverse pregnancy outcome, including pregnancy loss and preterm delivery. 
Healthcare providers should inquire about the occupation of any pregnant patient, and patients who work in agricultural industries should be advised accordingly. Avocations such as gardening should not be forgotten in the initial prenatal workup and counseling.
Because the number and type of chemical exposures are continuously increasing, databases and information services are essential. [52, 53, 54, 55, 56] The following resources may be helpful for physicians:
REPROTOX computerized database
Teratogen Information System (TERIS) computerized database; phone (206) 543-2465
Clinical Teratology Web, sponsored by the University of Washington
REPRORISK System by Micromedex; phone: (800) 525-9083
MotherToBaby, a service of the Organization of Teratology Information Specialists (OTIS); phone: (866) 626-OTIS (6847)
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 psychiatric 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.
A complete review of medication use during pregnancy is beyond the scope of this article. An essential reference on the use of specific medications during pregnancy is Drugs in Pregnancy and Lactation by Briggs, Freeman, and Yaffe; this text is available from Williams & Wilkins. William's Obstetrics also has concise but fairly comprehensive information on this topic; this text is available from Appleton & Lange. In addition, some major tertiary care centers and university hospitals have hotlines analogous to poison center hotlines for questions about medications during pregnancy.
Vitamin A–related compounds are essential for normal development and pattern formation in the early embryo. For this reason, medications based on these molecules are among the most potent teratogens.
Vitamin A is teratogenic in quantities of more than 10,000 IU/d, and many types of vitamins and nutritional supplements include doses of vitamin A at this level or higher. At this level of exposure, the risk of structural anomalies is 25%, and an additional risk of mental retardation is 25%. Congenital heart disease, eye and ear malformation, cleft palate, and cortical blindness are frequent occurrences. Importantly, beta-carotene, which is a naturally occurring precursor to vitamin A found naturally in vegetables, does not have any teratogenic effect.
Isotretinoin (Accutane) is a common dermatological drug used in acne treatment. Use during early pregnancy is associated with a pathognomic group of anomalies. Microtia, anotia, micrognathia, cleft palate, conotruncal heart defects, thymic abnormality, and brain malformation have been observed. The half-life of isotretinoin is 12 hours, and cessation of the drug before conception prevents isotretinoin embryopathy. Unique consent forms and contracts for adequate contraception have been developed for the use of this medication in women of childbearing age.
It is important to note that many countries have regulations in place regarding the need for contraception while being prescribed isotretinoin, but pregnancies still occur, largely due to isotretinoin prescriptions outside of the defined regulations, prescribing through the internet,  medication noncompliance. 
Etretinate is an extremely long-lasting oral retinoid used in the treatment of psoriasis. The medication is detectable in serum for more than 2 years after use. Neural tube defects, CNS malformations, skeletal abnormalities, and craniofacial defects have been observed. The duration with which the drug may continue to cause abnormalities is unknown. Etretinate should not be used in women of childbearing age.
Topical tretinoin (Retin-A cream) is used as an acne treatment. It is metabolized by the skin and is not associated with congenital anomalies.
Thalidomide is the sole drug in a unique class of sedatives, originally marketed for its sedative or hypnotic characteristics. It was prescribed for people with anxiety, insomnia, and gastritis, and then later, for women with nausea and morning sickness in early pregnancy. Despite years of study and use, its exact mechanism of action is unknown. When first isolated and produced, thalidomide was a racemic mixture with an extraordinarily variable range of effects. Its primary adverse effects involved the nervous system, and it was marketed as a safe drug with no potential adverse outcome. Despite the fact that testing did not show an increase in congenital anomalies in animals, thalidomide proved to be a potent and specific teratogen in humans. Defects appear in a precise order, depending on the exact timing of the thalidomide use. The progression and teratogenic effects associated with the use of thalidomide are as follows:
- Used 12-27 days postconception - External ear defects
- Used 27-30 days postconception - Upper limb phocomelia
- Used 30-33 days postconception - Lower limb phocomelia
- Used 35-39 days postconception - Triphalangism of thumbs
Thalidomide was marketed an as over-the-counter drug in Germany and Europe. It initially failed to receive FDA approval and was not legally available in the United States for decades. When its adverse effects and teratogenicity were revealed, it became a prescription medication in Europe. Recently, thalidomide was approved in the United States in a very limited fashion with a unique informed consent partially based on retinoid consent forms. It is an effective medicine for leprosy, graft versus host disease, some rheumatologic diseases, and some forms of cancer (eg, multiple myeloma).
DES is a synthetic estrogen that was used during early pregnancy in women with a history of miscarriage and hyperemesis. Exposure of female fetuses before gestational week 9 resulted in a 70% incidence of vaginal adenosis among female offspring, known as "DES daughters." In these women, reproductive tract malformation is very common and distinctive. Findings include cervical hoods and combs, a T-shaped uterus, a shortened vagina, and cervical stenosis. Reproductive capability is markedly reduced in these women. The United States has approximately 250,000-1,000,000 DES daughters. An estimated 1 in 1000 DES-exposed daughters develops vaginal clear cell adenocarcinoma, a formerly rare cancer previously observed in women aged 70 years and older. DES sons have an increased rate of cryptorchidism, epididymal cysts, and hypoplastic testes, but they do not have decreased fertility. DES was removed from the market in 1971.
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. [54, 55] Both seizures during pregnancy and antiepileptic drug exposure in utero may contribute to adverse outcomes seen in children born to mothers with epilepsy. Furthermore, some women are on this medication for treatment of psychiatric disorders such as bipolar disorder.
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.
The term fetal anticonvulsant syndrome has been used to describe an embryopathy associated with antiepileptic drugs that is variably characterized by major malformations, microcephaly, growth retardation, hypoplasia of mid face and fingers, other somatic abnormalities, and developmental delay. More distinctive phenotypes have been claimed to be associated with specific antiepileptic drugs, especially phenytoin, carbamazepine, and valproate. Retrospective and prospective studies have documented a higher prevalence of early developmental delay in children born to women with epilepsy, but studies following up children to later years have been conflicting, especially concerning the role of drug therapy.
Antiepileptic drugs with the potential for fetal malformations include the following:
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; this is noted in 11% of fetuses exposed to phenytoin in utero.
Trimethadione: Fetal trimethadione syndrome is associated with single transverse palmar crease 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. Based on published literature from the EUROCAT Antiepileptic Study Database and review of the literature, the use of carbamazepine monotherapy in the first trimester of pregnancy has been associated with a statistically significant increase in the occurrence of spina bifida (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2-5.3) when compared with those patients with no exposure to antiepileptic medications. The incidence of any major congenital malformation was not significantly increased above the baseline population risk for congenital anomalies (prevalence with carbamazepine 3.3%, [95% CI, 2.7-4.2]).  Overall, the true occurrence of malformations remains rare.
Many manufacturers of antiepileptic medications maintain active birth registries that are available to the obstetric care provider. Any patient receiving an antiepileptic agent should be encouraged to participate in these registries.
Avoiding seizures in pregnancy, if at all possible, is important. If a women has been seizure-free for a satisfactory period, the obstetrician, in consultation with the patient's neurologist, might consider tapering the patient off medication for 6 months prior to conception. Monotherapy is recommended if possible, using the minimal dose required to control seizure activity. The following are suggested:
Avoid trimethadione and valproic acid.
Measure total and free concentrations of the drug at first visit.
Follow total drug levels monthly.
Check free drug levels if active seizure activity is present or if a greater than 50% decline in total drug levels occurs.
If dosage increase is required during pregnancy, monitoring levels postpartum to avoid toxicity is important.
The American College of Obstetricians and Gynecologists also recommends that women with epilepsy on carbamazepine or valproate who are planning pregnancy receive 4 mg/d of folate for 3 months preconception and during the first trimester to try to decrease the incidence of neural tubal defects.
Certain antiepileptics are known to cross the placenta and may increase the rate of oxidative degradation of vitamin K, placing the neonate at increased risk of bleeding. Whether treatment with vitamin K helps is unclear because it is uncertain whether vitamin K crosses the placenta. Some obstetricians initiate maternal vitamin K supplementation at 36 weeks at the dose of 10 mg/d.
Antiepileptic drugs are transmitted in breast milk at the following rate: valproate 5-10%, phenobarbital 40%, phenytoin 30%, carbamazepine 45%, primidone 60%, and ethosuximide 90%. Breastfeeding can be encouraged, but it should be discontinued if the neonate demonstrates signs of sedation.
Pregnancy confers a fivefold risk of thrombosis. This predisposition results from the hypercoagulable state of pregnancy. Some women are at even higher risk of blood clots during pregnancy (eg, women with factor V Leiden thrombophilia, antiphospholipid antibody syndrome, or antithrombin deficiency). The goal of anticoagulation is not only to prevent and treat maternal thromboses, but also to improve the outcome of pregnancy. [59, 60] 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 is a vitamin K antagonist that is 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. Long-term 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. In a 2014 meta-analysis, women using warfarin at doses at or below 5 mg/day for mechanical heart valves showed no increased rates of embryopathy, spontaneous abortion, or maternal morbidity.  Outcomes were better when a lower INR of 1.5-2.5 was targeted.
Heparin and LMWH
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.
In nonpregnant patients, LMWH has been associated with fewer side effects. Heparins do not cross the placental barrier.
In a 2005 study, women with recurrent pregnancy loss and antiphospholipid antibody syndrome were given either LMWH or unfractionated heparin during pregnancy, and both groups had similar maternal and fetal outcomes. 
Danaparoid is a low molecular weight heparinoid with low placental permeability; its mechanism of action is through inhibition of factor Xa. This is the drug of choice for cases of heparin allergy or heparin-induced thrombocytopenia in pregnancy, although cross-reactivity has been reported in 10%-20% of cases.
In published cases, no adverse fetal outcomes have been reported.(ref) Unfortunately, it is no longer available in the United States.
Hirudin is a naturally-occurring protein found in the saliva of medicinal leeches. Medically-available hirudin is a recombinant version of this protein. The mechanism of action is to inhibit the procoagulant properties of thrombin. Lepirudin is a hirudin derivative that is no longer commercially available in the United States.
Placental transfer is not documented in humans, but low transfer in dogs and rabbits is less than 2%.
Fondaparinux is a selective factor Xa inhibitor. In vitro models show no placental transfer, but 10% of maternal levels have been detected in umbilical cord blood.
This drug is contraindicated in patients with renal impairment, and there is a low risk of heparin-induced thrombocytopenia (HIT).
Aspirin is antiplatelet drug used for anticoagulation as well as prevention of hypertensive disorders in pregnancy. Large randomized trials have demonstrated no increased risk of miscarriage, congenital anomalies, placental abruption, fetal hemorrhage, or neonatal bleeding.
A Cochrane review of aspirin for primary prevention of hypertensive disorders in pregnancy showed a 17% decreased risk of preeclampsia in high-risk pregnant patients treated with aspirin therapy. 
Other antiplatelet agents
No data exist for placental transfer of dipyridamole; numerous cases of its use in pregnancy with no adverse fetal outcomes reported.
No data exist for placental transfer of clopidogrel and ticlopidine with no adverse fetal outcomes in 2 case reports
There has been a case report of 1 patient treated with abciximab with no adverse fetal outcome.
Diuretics can lead to oligohydramnios. Certain well-studied older drugs are preferred for use during pregnancy in women who are chronically hypertensive and those with pregnancy-induced hypertension, including the following [72, 73, 74, 75] :
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. 
Thirteen randomized controlled trials were reported as having inadequate power to rule in or out benefits concerning antihypertensive treatment on maternal and fetal well-being. Information is scarce on the frequency of adverse effects attributable to antihypertensive agents. Overall, antihypertensive treatment in pregnancy reduces the risk of severe hypertension. No proof exists that antihypertensive drugs reduce perinatal mortality or the development of preeclampsia, and such drugs have not been associated with improved fetal growth. According to the Cochrane Database System Review, the choice of antihypertensive drug for treatment of severe hypertension in pregnancy should depend on the experience and familiarity of an individual clinician with a particular drug and what is known about maternal and fetal side effects.
Many of the most effective psychotropic medications have fetal effects, but many conditions, such as severe depression, manic depression, and psychosis, can have equally severe effects on both mother and fetus if untreated.
Selective serotonin reuptake inhibitors (SSRIs) are common antidepressant drugs. [77, 78] Recently in the literature, conflicting evidence has been shown for and against the use of SSRIs in pregnancy. A trial published in Reproductive Toxicology, which evaluated pooled data from multiple clinical trials, showed no increased risk of major cardiovascular or minor malformation but potentially an increased risk of spontaneous abortion.  A larger trial, published in JAMA the previous year, suggested that the use of SSRIs in the late third trimester may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care. Neither of these trials were randomized or prospective data.
Concern has also been raised regarding the risk of congenital heart defects and the use of SSRIs in pregnancy. A large retrospective trial performed in 2007 evaluated the use of SSRIs in early pregnancy and did not find any significantly increased risk of congenital heart defects. 
A second trial in 2007 found associations between specific SSRIs. Namely, an association between the use of sertraline and omphalocele, and the use of paroxetine and right ventricular outflow tract obstruction defects, anencephaly, craniosynostosis, and omphalocele.  However, these numbers were extremely small. In regard to paroxetine, only 6 of close to 10,000 infants had this defect, and more than 40 statistical tests were performed before these risks were found.
Exposure to SSRIs late in pregnancy is also associated with transient neonatal complications including jitteriness, mild respiratory distress, transient tachypnea of the newborn, weak cry, poor tone, and neonatal intensive care unit admission.  The American College of Obstetrics and Gynecology note that the use of SSRIs should be individualized and paroxetine use amongst pregnant women should be avoided, if possible.  The risks and benefits of any psychiatric treatment during pregnancy should be carefully weighed for each individual patient and with the help of a psychiatrist.
Lithium use is suggested to increase the risk of Ebstein anomaly, a severe cardiac defect. To date, further studies have not demonstrated severe teratogenicity with lithium use. Maternal sodium balance and fluid balance must be maintained as maternal metabolism changes throughout pregnancy.
In 1992, researchers reported a potential benzodiazepine syndrome that included dysmorphism, growth restriction, and CNS dysfunction. In 2003, a French study attempted a systematic review of the existing literature. Unfortunately, the results were not homogeneous due to extreme difference in methodologic approaches. This study also searched the French Central East registry of congenital malformations for births from 1976-1999. Of the 13,703 cases, 6.8% of mothers took a benzodiazepine during the first trimester. When these cases were formally reviewed, no increased risk for any specific malformation was shown. When the registry was searched specifically for lorazepam, a potential association with anal atresia was found but was not statistically significant. More research needs to be performed in this area. [83, 84]
A similar study performed in 2004 reviewed the medical records of 28,565 infants. Of these infants, during a 32-month period, 52 infants had been exposed to clonazepam, 43 of whom were treated with clonazepam as monotherapy. A total of 76% of monotherapy infants had been exposed during the first trimester. This study did not observe an increase in major malformations.
The postpartum period is associated with a high risk for symptom relapse or intensification of psychiatric disease, which can be reduced with the use of medications. Abrupt discontinuation of these medications increases the probability of relapse, which is associated with high-risk behaviors.  Treatment planning for pregnant women with psychiatric disease requiring treatment with benzodiazepines should consider not only the relative risks of fetal exposure to mood stabilizers but also the high risk of recurrence and morbidity associated with stopping maintenance mood stabilizer treatment. 
The overall nutritional status of the mother contributes to the environment of the fetus, but few deficits or surpluses are fetal risk factors.
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 women’s health status may not be optimal at conception.
Results from the prospective observational Norwegian Mother and Child Cohort Study suggest folic acid supplementation taken from 4 weeks before until 8 weeks after conception was associated with reduced risk of severe language delay in children at age 3 years. 
The recommended daily supplement for pregnant women without risk factors is 0.4 mg of folate.  Patients who are at risk for a defect, especially women who previously have given birth to an affected infant, should take 4 mg/d. As with many other active molecules during pregnancy, effect timing is important. Because the neural tube closes at 26-28 days of gestation, preconception supplementation is best. Recent policies in many countries, including the United States, have provided supplementation in all grains and flours. On average, women who consume these supplemented products should reach the recommended daily value of 0.4 mg. Remember that folate supplementation can mask underlying B-12 deficiency.
Women of reproductive age should be advised about the benefits of folic acid in addition to a multivitamin supplement during wellness visits, especially if contemplating pregnancy. Foods containing excellent sources of folate should be added to the diet. These include fortified grains, spinach, lentils, chickpeas, asparagus, broccoli, Brussels sprouts, corn, and oranges.
Retinoids and Other Vitamins
Excessive intake of vitamins is most frequently encountered in patients using megadose vitamins. Excessive intake can have effects on both the mother and fetus, ranging from no effect (most water-soluble vitamins) to reversible neuropathy (at least 500 mg/d of vitamin B-6) to severe congenital defects (vitamin A precursors and derivatives).
Vitamin A is a fat-soluble retinoid that can be stored in body fat for long periods. High levels are associated with a dose-dependent increase in fetal malformations such as hydrocephalus, microcephalus, and cardiac defects. Beta-carotene, the natural precursor found in orange vegetables, is not associated with congenital defects. Retinoids are now recognized as important pattern-formation molecules during very early embryogenesis.
Various other effects occur from vitamin overdose. Extreme levels of vitamin D intake (>15 mg/d) are noted in patients with soft tissue calcification. Excess iodine is associated with goiter and hyperthyroidism. Taking more than 45 mg/d of zinc has been associated with preterm delivery. High fluoride intake (>2 mg/L) can cause dental fluorosis of the baby's primary teeth.
Please refer to the previous section, Prescription Drugs, specifically Retinoids, for further information regarding Accutane use in pregnancy and topical acne therapies.
Avoid doses of vitamin A that exceed 10,000 IU because doses higher than 25,000 IU/d clearly exceed baseline risk.
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.
Iron supplementation, at least after the fourth month of pregnancy, helps prevent severe anemia. Between-meal dosing is best. Although vitamin C aids absorption, simultaneous calcium or magnesium intake can inhibit iron absorption. Approximately 30 mg/d of elemental iron is recommended for most pregnant women. A higher risk of anemia is associated with multiple pregnancies. Importantly, keep potentially dangerous amounts of iron pills from young children in the household. Iron fumarate is the most easily absorbed form.
General Nutrition Risks
A logical assumption is that a total energy deficit would be associated with smaller babies or IUGR. However, the evidence does not support a simple relationship between these two variables. [89, 90, 91] Data from several well-studied groups of women who were subjected to food rationing and famine during war show that extreme restriction of energy (caloric) intake (range, 1883-3347 kJ/d [450-800 kcal/d]) was associated with an average decrease in final birth weight of 250-535 g. These studies were conducted through World War II in the Netherlands and in Leningrad (since renamed St. Petersburg). In the Netherlands, the population of newborns was assessed at maturity. Males of that generation were examined for mandatory military service; no long-term sequelae were noted except for overall smaller stature. No effects on intelligence or mental function were observed.
In the past, opinions have varied on the appropriate weight gain during pregnancy. Thin women (< 19 body mass index) who have poor weight gain during pregnancy are clearly at risk for having an infant that is small for gestation age or has IUGR. In addition, mothers who gain the most weight (>2 standard deviations above the norm) are at risk for larger infants and higher cesarean delivery rates. Approximately 22% of women who gain the most weight have cesarean deliveries, compared with 16% of those who gain the normal amount of weight. The latest publication of the Annual Review of Nutrition suggests that the current dietary guidelines regarding amount and type of carbohydrates and fat for nonpregnant women seem to be appropriate for pregnant women as well.
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.  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.  Maternal eating disorders can improve during pregnancy but often worsen postpartum. 
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.  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. 
Nutrition should be assessed throughout pregnancy to uncover important deficits and discover important risks such as overuse of vitamin A or extremes in weight gain. According to the American Board of Obstetricians and Gynecologists, women who are considered underweight prepregnancy should gain 28-40 lb, women who are considered normal weight prepregnancy should gain 25-35 lb, and women who are considered overweight prepregnancy should gain 15-25 lb. Weight management is important for every women of reproductive age. Women with a normal BMI should strive for maintenance of a healthy weight, whereas women who are overweight and obese should aim for weight reduction prior to pregnancy. 
Drugs of Abuse
Prevalence and Reporting
Substance abuse is the deliberate use of licit or illicit drugs and substances for recreation or self-medication.
While women are likely to self-report radiation exposure and seek help if they have concerns about an occupational or chemical hazard, those who use and abuse drugs are more likely to deny the seriousness of their condition. Individuals who abuse drugs are also more likely to be reluctant to seek help due to the stigma associated with their condition. As is the case with prescribed medicines, the use of multiple substances is more common than the use of a single substance. Depending on the study, random urine screening in pregnant women produced positive results in 15% (range 5-20%) of samples. Substance use is prevalent across socioeconomic, racial, geographic, and cultural lines. An estimated 500,000 infants are exposed in utero each year.
The most severe effects result from the use of multiple substances, which is the most common form of substance abuse. The high frequency of multiple-substance abuse creates difficulty in designing and completing studies of single agents. 
Alcohol is the most potent teratogen among the substances of abuse. [99, 100] 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
Non–FAS-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 dose-response curve means that partial syndromes occur, which has led to a new suggested categorization of FAS and partial FAS, as follows:
Category 1 - FAS as defined above with documented maternal alcohol abuse
Category 2 - FAS as defined above without documented maternal alcohol abuse
Category 3 - Partial FAS (multiple features but lacking the full diagnosis)
Category 4 - Alcohol-related birth defects, with single or few physical changes of FAS
Category 5 - Alcohol-related neurological deficit (ARND), with cognitive and/or behavioral components of FAS
The first 3 categories are considered equally severe. 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.
Given the high prevalence of drinking in the United States (70%) and the worldwide incidence of FAS (1 case per 1000 births), every effort should be made to identify pregnant persons with drinking problems. Because benefit can be derived from ceasing alcohol consumption later in pregnancy, tools to detect those with drinking problems should be implemented at multiple points, not just at entry into prenatal care.
Multiple-question inventories are available, but many are long and difficult to use in a busy setting. The standard in obstetric care is the TACE (ie, tolerance, annoyed, cut down, eye-opener) questionnaire, and consists of only 4 items, as follows:
Tolerance: How many drinks can you hold? (2 points, any answer indicating more than 2 drinks is considered positive)
Annoyed: Have people annoyed you by criticizing your drinking? (1 point)
Cut down: Have you felt you ought to cut down on your drinking? (1 point)
Eye-opener: Have you ever had a drink first thing in the morning to cure a hangover or steady your nerves? (1 point)
If the total score is 0, the likelihood that the respondent drinks heavily is 1.5%. A response to the tolerance question of more than 5 indicates an 8.5-fold increased probability of heavy drinking, which identifies 80% of persons with drinking problems. Positive answers to all questions indicate a 60% chance of heavy drinking. Positive TACE results identify 90% of persons with drinking problems. The incidence of FAS in women with drinking problems is 59 cases per 1000 births.
To place the risks of alcohol consumption during pregnancy in perspective, persons who drink heavily should be advised that up to 30-40% of infants born to mothers who consume more than 2 drinks a day in the first trimester will have the full-blown FAS syndrome. This is one of the highest known rates of malformation caused by substances. Only the most potent retinoids approach a malformation rate of 50%, and even the notorious thalidomide had overall rates of malformation far below those of alcohol. Also, when folate deficiency and subsequent neural tube defects are examined, the highest-risk population incidence approached 5%, which is much less that the rate of FAS in mothers who are heavy drinkers.
Those identified as problem drinkers should undergo withdrawal in a supportive and supervised setting, and they should avoid the use of benzodiazepines and, if possible, other sedatives.
Small doses of pentobarbital can be used in place of benzodiazepines. Disulfiram should be avoided because it is teratogenic. After withdrawal, long-term treatment and support are necessary. Importantly, view all dependencies and addictions as chronic, possibly life-long illnesses. Relapse is very frequent. Counseling can be supplemented with naltrexone (category C), an opiate antagonist, even in pregnancy. Use caution with naltrexone because it can precipitate acute withdrawal from narcotics and should be discontinued 72 hours before labor. A major benefit is its ability to reduce alcohol cravings.
Persons who abuse alcohol have a high frequency of cigarette smoking, and some of the growth restriction associated with FAS may be attributable to tobacco. The other most frequent illicit substance used by persons with alcoholism is marijuana.
Cigarette smoking is also very prevalent in society.  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.
Both smoking and use of nicotine replacement therapy during pregnancy are associated with an increased risk of infantile colic in offspring. 
Clearly, the potential to eliminate 40% of IUGR cases in the United States indicates that eradicating smoking in pregnancy is a worthy goal. As is the case with alcohol, warning labels on cigarette packages have increased public awareness of the dangers of smoking during pregnancy. Yet, despite public awareness, smoking in certain groups, such as young women and women in inner city areas, persists and even increases. Whether recent public efforts to terminate cigarette advertising directed at children, stricter vending laws, and direct antismoking advertising will succeed remains to be seen. Also, evidence exists that cigarettes are more addictive for women than men and that women have more difficultly quitting smoking compared to men.
Counseling and support groups are recommended. Bupropion (category B) is an antidepressant that could be considered for women during late pregnancy, especially if they have a combination of depression and smoking.
As with alcohol, a stigma is attached to smoking during pregnancy, and questioning about smoking must be frank but supportive and occur at multiple points, not just at entry to care.
Sedatives are both widely abused, especially in polysubstance abuse, and widely prescribed. While not known to be directly teratogenic, barbiturates cause tolerance and abstinence (withdrawal) syndromes in both the mother and fetus. Both severe intoxication and withdrawal can cause maternal death. Thus, barbiturate abuse is listed third in severity in this article.
Along with benzodiazepines, barbiturates are used to counteract the effects of use and withdrawal of alcohol, cocaine, and amphetamines. Those who abuse barbiturates are generally heavily inculcated in the drug subculture and are most at risk for poor nutrition, poor prenatal care, sexually transmitted diseases (STDs), prostitution, and violence.
Signs of barbiturate intoxication include drowsiness with progression to depressed consciousness and coma, shock, slow irregular respiration, pulmonary edema, and pinpoint pupils.
Signs of barbiturate withdrawal include restlessness, irritability, insomnia, autonomic activation, delirium, psychosis, and seizures.
Many of the features of maternal withdrawal are observed in fetal withdrawal. Premature labor can be precipitated by sudden withdrawal.
Identification of the problem, a multidisciplinary team approach, and intervention at multiple time points are essential. A 4-question CAGE (ie, cut down, annoyed, guilt, eye-opener) survey, which is similar to the TACE survey for alcohol, can be used, as follows:
Cut down: Have you felt the need to cut down on your drug use?
Annoyed: Have you been annoyed by criticism of your drug use?
Guilt: Have you felt guilty about your drug use?
Eye-opener: Have you felt the need for an eye-opener to avoid withdrawal or recover from use of drugs?
One point is given for an affirmative answer to each question. A score of 1 is concerning, and a score of 2 indicates a high likelihood of abuse.
Step-down withdrawal in increments using phenobarbital or pentobarbital is the treatment of choice. Treatment of intoxication includes supportive measures, gastric lavage during early intoxication, medication to support blood pressure, and hemodialysis.
Heroin has recently regained popularity as a drug of abuse. [103, 104] Currently, it is more frequently smoked or snorted than it was in the past. A large number of persons who use heroin still inject, and particular risks exist for pregnant women who inject. Recent work in North America addresses the different experience of women in the drug subculture and identifies some of the factors that diminish the effectiveness of treatment and outreach.
As many as 39% of females who abuse substances, specifically those who inject substances, have a history of current or past sexual or physical abuse. One large North American study finds that 65% of women in methadone programs have been sexually and/or physically abused within the preceding 12 months.
Women who abuse drugs may support their habit through prostitution. This constellation of issues results in high rates of infection with human immunodeficiency virus (HIV). Poor outcome is compounded by the fact that women who abuse substances and are HIV-positive are half as likely as men to receive appropriate antiviral therapy.
During pregnancy, treatment is further complicated by fear and mistrust of the medical system, including fear of incarceration and, justifiably, fear that their babies will be removed from their care. Cessation of narcotics produces withdrawal in both the mother and fetus. Typically, this is not as life-threatening for the mother compared to withdrawal from alcohol or barbiturates. Early in pregnancy, withdrawal from narcotics may kill the fetus by causing expulsion of a very premature fetus. In utero fetal withdrawal may result in hypoxia, hyperactivity, meconium passage, and, ultimately, intrauterine fetal demise. Causes of maternal death can include overdose in those who use less frequently and overdose from adulteration of street drugs in those who use frequently. Maternal narcotic use during development is not frankly teratogenic, but IUGR, premature delivery, and chorioamnionitis have been associated with maternal narcotic abuse.
Methadone use results in babies with low birth weight who may develop neonatal abstinence syndrome (NAS). The severity of this is scored using a scale of 0-10 as described by Rivers et al, and treatment with triclofos instituted for a score of greater than 2. If the score is greater than 6, morphine treatment is initiated. In a large retrospective trial in the United Kingdom, babies that had been exposed to methadone had shorter neonatal stays, used less morphine in maximum dose, and had lower mean maximum NAS scores.
Recently, methadone has been compared with buprenorphine in small randomized trials. One study published in the American Journal of Addiction found that an earlier onset of NAS occurred in neonates born to mothers taking methadone than to mothers taking buprenorphine.  This preliminary study had limited power to detect differences, but the trends observed suggest that this research should be explored further. A study published in 2008 in Sweden compared the effects of buprenorphine and methadone exposure during maintenance treatment of women who were pregnant and dependent on heroin. This small study found that birth weight in neonates was higher, incidence of neonatal abstinence syndrome that required treatment was lower, and length of stay was shorter. This suggests that buprenorphine therapy may offer advantages for treatment of opiate dependence during pregnancy. 
Treatment of maternal overdose should include resuscitation and support along with reversal of the narcotic effects with a fast-acting antagonist such as naloxone (Narcan). Pulmonary edema may occur. Chronic lung changes from repetitive injury by particulate matter in diluents may worsen the prognosis and limit resuscitation. Treatment should be performed in organized programs, under direct supervision, and in a sheltered setting. A team approach with high-risk obstetric involvement is best.
Amphetamines are abused by all routes, (ie, oral, intravenous, inhaled).  They affect the adrenergic systems and are sympathomimetic. Symptoms of use include euphoria, hyperactivity, paranoia, anorexia, insomnia, hallucinations, and decreased attention to pain. Chronic use generally leads to severe malnutrition. Amphetamines can cause significant arrhythmia, including ventricular tachycardia and asystole during obstetric anesthesia. Amphetamines cause a withdrawal syndrome in babies that mimics the lethargy and severe depression observed in persons who use regularly but are abstaining.
When inhaled, adverse effects are similar to crack cocaine and include placental abruption, IUGR, and preterm delivery. When injected, infectious sequelae include endocarditis. An amphetamine-specific vasculitis is also reported with renal, cerebral, and pulmonary compromise.
An increase in methamphetamine use has occurred in several regions of the United States and worldwide. It is the most widely abused amphetamine and has been categorized as a schedule II stimulant since 1971 because of its high potential for abuse. Admissions to treatment programs for primary methamphetamine problems have been increasing steadily since 1992. Animal studies have observed an increase in maternal and offspring mortality, retinal eye defects, cleft palate, rib malformations, decreased rate of physical growth, and delayed motor development amongst those with prenatal methamphetamine (MA) exposure.
The few published studies of the effects of human prenatal exposure have many methodologic problems, including small sample size, other confounders including other drug abuse, and problems with detection of MA status. Most of these studies still found an association with clefting, cardiac anomalies, fetal growth retardation, behavior problems, and cranial abnormalities. These children might be at risk for poor child outcome due to both drug exposure, concomitant alcohol and tobacco use, and factors related to the caregiving environment. The recently published early report of the IDEAL study reported 5% of pregnant women using methamphetamines at some point during their pregnancy, highlighting the need for educating primary care physicians and other practitioners to be aware of treatment options and community resources to enable access to treatment.
Those who abuse amphetamines frequently use other drugs, especially cocaine. Detoxification and restoration of nutrition before delivery lead to improved pregnancy outcomes.
Over the past 175 years, cocaine has waxed and waned in both popularity and the concern its use invokes. [107, 108, 109] Initially available over the counter and in Coca-cola syrup, it is now the primary target in the "War Against Drugs." The increased availability of the inexpensive freebase form crack cocaine, has led to rampant use across all socioeconomic groups since the late 1970s. According to the 2005 National Survey on Drug Use, in the United States, an estimated 2.4 million people frequently (at least twice weekly) used cocaine. This report estimated that illicit drug use among pregnant women has approximately a 4% prevalence.
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. 
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.
Many states passed laws that treated substance abuse in women as a criminal or child abuse offense that was sometimes considered a felony. While some cases have involved alcohol or refusal of medical advice, the vast majority of charges have been brought against economically disadvantaged minority women. The ultimate result of this focus on "crack babies" and criminalization has been reduced access to treatment for persons who abuse substances.
Research continues into the possible subtle effects of prenatal exposure to cocaine. The bulk of effects observed thus far involve affective disorders and language skills. All effects resolve within 1-2 years of birth. Children with prenatal cocaine exposure perform on average an estimated 15% of a SD lower on measures of global language ability with compared with non-cocaine exposed children. Cocaine abuse is an important marker for polysubstance abuse and a suboptimal home life. Importantly, remember that supportive measures, nutritional education and support, and provision of regular medical care ameliorate the effects of cocaine on the fetus. Treatment should be the goal.
Substances such as lysergic acid diethylamide (LSD) and phencyclidine (PCP) alter sensation and produce hallucinations. Self-induced and accidental trauma are common and are often secondary to the labile mood induced by these substances.
Some evidence indicates that LSD can produce chromosomal anomalies. A few cases point toward spastic muscle change and craniofacial abnormalities in infants of persons who use PCP. Importantly, note that these drugs are frequently adulterated with a multitude of different substances, including warfarin and other teratogenic substances.
Users of hallucinogens frequently abuse numerous substances. The individual may be at risk of harming herself or others, or she may be harmed during restraint. Designer drugs may not produce a positive test result on standard toxicological screening tests.
Adverse events for mother and baby may be increased when substances of abuse are inhaled, as in the case of cocaine and amphetamines. Others inhale substances such as glue, solvents, or paint thinner in order to achieve a high. This practice is especially frequent in children and young adolescents. Survey results consistently show that nearly 20% of children in middle school and high school have experimented with inhaled substances.  Also known as huffing, aerosol propellant from cans may be used. Maternal and fetal renal tubular acidosis, pulmonary injury, liver damage, bone marrow toxicity, neural damage, and cardiac arrhythmia may result. Preterm delivery, IUGR, and intrauterine fetal death have been reported.
No well-controlled prospective studies have been conducted in this area. Several cases in the literature report children born to solvent-abusing mothers. Animal studies provide more direct evidence that prenatal exposure to toluene can produce reduced birth weights, skeletal abnormalities, delayed neurobehavioral development, and preterm birth. [112, 113]
Importantly, consider this form of substance abuse when confronted with an adolescent in preterm labor. Beta-mimetics that are administered to treat preterm labor (eg, terbutaline) exacerbate arrhythmias and are contraindicated in these patients.
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).  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. 
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.
Other Psychosocial Conditions
Effects on Pregnancy
Just as substance abuse issues exist in all realms of society, so do psychosocial issues, including violence, depression, anxiety, and inequities of care. These psychosocial issues can greatly affect pregnant women and their children.
Estimates indicate that 1 in 4 women experiences physical abuse during their lifetime. Physical abuse during pregnancy occurs at an incidence of 5-17%. Data concerning variation in different ethnic and socioeconomic groups are conflicting. Some studies indicate a higher rate of violence against white and Hispanic women compared to African American women.
Recent studies show that pregnancy is not a time of protection from violence, and it can be a time of escalation of violence, especially during the postpartum period. Martin and colleagues found that 77% of abused women sustained physical injury when abused during the postpartum period. Other studies have shown that abuse that occurs before pregnancy and during pregnancy continues in the postpartum period in approximately 90% of cases. Pregnant teenagers are at greater risk of abuse, but abused adult women sustain more physical injuries.
Violence is often associated with other pregnancy risks such as tobacco, alcohol, and substance abuse; gynecological infection; unmarried or unpartnered status; unintended pregnancy; rapid repeat pregnancy (pregnant within 24 mo of prior pregnancy); psychiatric disease; and emotional problems.
In reported cases, 95% of perpetrators are male intimate partners of the abused women. Risk factors associated with abusing a partner are drug, alcohol, and tobacco abuse; witnessing abuse as a child; and beliefs supportive of patriarchy. The causes of domestic violence are unclear. Most research has indicated that issues of power and control are central to abuse. Researchers identified 4 themes:
Jealousy toward the fetus
Pregnancy-specific violence not directed toward the fetus (stress caused by pregnancy)
Anger toward the fetus (undesired pregnancy)
A "business as usual" mentality (continued violence to the partner)
A link exists between violence toward women and violence toward children. An estimated 50% of perpetrators also abuse their children. The malignant environment also spills over to the victims of abuse; in one study, 28% of battered women demonstrated violent behavior toward their children. In a completion of the cycle, juveniles who are incarcerated for aggression have an increased likelihood of having sustained perinatal trauma.
Symptoms and presentation
Injuries and effects occur to both mother and fetus and range from violent behavior, depression, and grief to crime, severe injury, and death. Domestic violence accounts for 20% of violent crimes to women, and at least 30% of female murder victims are killed by their partner.
The leading cause of maternal death in the United States is trauma. Approximately 36-63% of these deaths are caused by homicide. Repetitive blunt or weapon trauma may be seen. The face, head, and extremities are frequent sites. During pregnancy, the trauma inflicted may be directed toward the breasts, abdomen, or genitals. Violence should be classed as severe if it results in injuries due to choking, hitting, kicking, or weapons. Damage to the spleen, liver, diaphragm, and uterus may occur.
Severe injuries caused by violence can cause uterine contractions, preterm delivery, and placental abruption. Persistent abuse throughout pregnancy is associated with IUGR, preterm delivery, and an increased incidence of miscarriage; these effects may be due to severe environmental stress. More rarely, direct fetal injury occurs, and results include soft tissue injury, organ damage, skull fracture, and other fractures. Violence in relationships has recently been linked to rapid repeat pregnancy, especially in teenagers, which is associated with an increased risk of delivering prematurely, having an infant that is small for gestational age, and miscarrying. In fact, these women have a 22.6-fold increased chance of miscarriage.
More typically, injuries are multiple, in various stages of healing, and inconsistent with the patient's story. If a patient's explanation of injuries does not match clinical findings, the clinician must be alert to the possibility of abuse. Protective bruising from a defensive posture is often seen on the extremities.
Patients may present with complaints of overt abuse, or they may present with nonspecific symptoms. Overt presentations include chronic pelvic pain, STDs, or complications of pregnancy. Late registration to care, loss to obstetrical care, and poor weight gain are particularly frequent in pregnant women who are abused. The abused woman may present with vague somatic complaints including nausea, headaches, pelvic pain, fatigue, and depression. As many as one third of women presenting to emergency departments are victims of abuse, yet as few as 1 in 20 abused women is identified by physicians.
Multiple studies and summaries of experience have demonstrated a need for consistent screening to identify abused women. Optimal results are obtained when direct questions are addressed to the patient in a completely confidential manner, excluding children who can speak and family-member translators. Women should be screened multiple times during pregnancy. Violence occurs across all socioeconomic classes, and no woman should forgo screening for this or any other reason.
A simple inquiry based on the Abuse Assessment Screen should be used; this screen has been proven to match the effectiveness of longer questionnaires:
Have you ever been harmed by someone close to you?
Within the past year, has someone hit, slapped, kicked, choked, or otherwise hurt you? If the patient answers in the affirmative, inquire as to the perpetrator, the number of times the abuse occurred, and the body sites of injury.
During this pregnancy, has someone hit, slapped, kicked, choked, or otherwise hurt you? If the patient answers in the affirmative, inquire as to the perpetrator, the number of times the abuse occurred, and the body sites of injury.
Has anyone, including your partner, forced you to have sex? If the patient answers in the affirmative, inquire as to the perpetrator and the number of times the forced intercourse occurred.
Are you afraid of anyone listed above? If so, of whom are you afraid?
Physicians often express frustration in dealing with the issue of domestic violence; they may fear loss of control during the interview, and they may feel as though they are "opening a Pandora's box." Yet, when performed in a confidential manner by a physician, screening works best. Not all abuse victims are able or willing to take the next step (escape from the situation) after the first contact. All providers who care for pregnant women should be aware of and act to complete their responsibilities toward abused women. As defined by the American College of Obstetricians and Gynecologists, these responsibilities are as follows:
Implement universal screening procedures at intake, during each trimester, and during the postpartum period.
Acknowledge the trauma.
Assess immediate safety.
Help establish a safety plan.
Offer educational materials.
Offer a list of local community resources in a confidential location, such as the bathroom.
Provide ongoing support in subsequent visits.
As is the case with many psychosocial and environmental risks during pregnancy, the provider must work within a political and social milieu. The immediate safety and medical status of the patient should be paramount. Documentation should be thorough and complete, and the clinician should use the patient's own words when possible. A complete history of the patient's relationships, abuse, and living situation should be included in addition to her obstetrical and gynecological history. Body maps and photographs should be included, as appropriate, and forensic kits should be used in cases of sexual assault.
The physician should provide a complete report, even though insurance companies have previously used this information to discriminate against victims of abuse when providing coverage or benefits. This discrimination is now illegal by state law in more than 50% of states, and it is illegal according to a federal law concerning insurance discrimination.
Because suspicion of revelation may cause the abuser to escalate violence, confidentiality is of the utmost importance. Items covered by confidentiality should include all correspondence, telephone calls, bills, and contacts with the patient.
Violence is increasingly recognized as an epidemic within our country. Efforts to remove the stigma from victims of abuse are underway, but these efforts will not succeed without support at every point of entry to medical care.
If you are a victim of domestic violence or would like to seek help for someone else, please contact the National Domestic Violence Hotline at (800) 799-SAFE. The TDD number for persons with hearing impairment is (800) 787-3224. In addition, the following is a list of useful Web sites that cover issues related to violence against women:
Office on Violence Against Women: This site is from the US Department of Justice and provides information on the coalitions against domestic violence.
The National Center for Victims of Crime: This web site includes information on the 1999 amendment to the Insurance Discrimination Provision of the Financial Services Modernization Act S.900. This amendment was offered by Representative Diane Degette (Democrat from Colorado). The amendment prohibits insurance companies from denying coverage, terminating coverage, or raising premiums because a subscriber is a victim of domestic violence.
Stop Family Violence: This organization is involved in advocating legislature regarding changes in domestic violence laws and policies.
American Medical Association: This site provides the American Medical Association guidelines for treatment of patients who are victims of domestic violence.
Maternal Psychiatric Illnesses
Babies of mothers with psychotic disorders are known to have higher rates of poor obstetric outcome, including higher mortality rates. King-Hele et al described the observations from a Danish national cohort study that estimated the risk for stillbirth and neonatal death of mothers with histories of severe mental illness compared with the general public. Risks of stillbirth and neonatal death were raised for virtually all causes of death for all of the maternal psychiatric diagnostic categories. They concluded that the higher risk of perinatal loss may be linked to factors associated with maternal psychiatric illness in general, such as insufficient attendance for antenatal care and unhealthy lifestyles, rather than the maternal mental illness itself. 
Depression mood disorders
Depression mood disorders, the most prevalent of which is depression, are common in this country, and a proportion of every physician's patients are affected. Some recent reviews estimate that as many as 40% of women have an episode of clinical depression in their lifetime. One in every 8 people is clinically diagnosed with depression, and this rate is almost doubled for women.
Risk of depression increases with age. Although pregnancy is usually a time of joyful anticipation, it is also a stressor for many women. In the United States, depression is both overtreated and undertreated, and only 1 in 5 patients is treated appropriately. Depression is often underrecognized during pregnancy. The immediate postpartum period (the puerperium) is a particularly high-risk time for very severe depression and even psychosis.
In an effort to avoid risks from psychiatric medications, many women suspend their medication when attempting conception or they discontinue their medication when they discover they are pregnant. Yet their pregnancies may be at risk from their illness. In particular, bipolar disorder (manic depression) may be risky for both mother and child because mania severely impairs judgment and suicide rates are high in the depressive part of the cycle. Worse, suspension of effective medication, especially lithium, may render the medication ineffective when resumed.
Important risk factors for the development of depression include the following:
Loss during childhood, especially parental death
Low socioeconomic status
Stress surrounding the patient's role in life
Depression screening is reasonable. Long surveys have been simplified using questions that address the most frequent defining symptoms. A diagnosis of major depression can be made when 5 of the following 8 criteria are met:
Depressed mood the majority of the day
Loss of almost all or all pleasure from normally pleasant activities
Significant weight change
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue, loss of energy
Reduced concentration, diminished ability to think
Recurrent thoughts of death, suicidal thought with or without plan to act
Duration of symptoms must exceed 2 weeks, and the first or second symptom listed must be present. In addition, the diagnosis may be in question if the symptoms are within 2 months of significant personal loss or if the clinician believes the symptoms are due to medication use or other medical conditions.
Similar to domestic violence, somatic complaints are frequent in patients with depression. Some complaints are specific to obstetricians and gynecologists. These symptoms include chronic vulvar pain, itching, or burning without clinical cause; chronic pelvic or genitourinary pain; prolonged depressed mood after a procedure or event; severe premenstrual symptoms; and multiple somatic complaints that do not match known etiologies.
Important risk factors for suicide include the following:
Underlying, long-standing history of depression
History of a suicide attempt
Talking about attempting suicide
Lesbian, gay, bisexual, or transgender (LGBT) sexual orientation
Although women are more frequently clinically depressed and make more attempts at suicide, men complete more suicide attempts. Isolation or exclusion from society is an important factor that exacerbates depression; isolation is often seen in elderly, immigrant, and LGBT populations.
The postpartum period is a time of particular risk. The reasons for this are not fully understood. Recent studies point to the possibility that neurosteroid molecules, specifically brain progesterone, may be involved. Pregnancy is a time of very high estrogen and progesterone levels. At delivery, progesterone levels plummet. At least 10% of women have situational depression, which is also known as the postpartum blues. If the blues deepen into full depression within 6 months of delivery (as indicated by the aforementioned criteria), postpartum depression is the diagnosis.
Approximately 1-4 of every 1000 new mothers have the most extreme form, postpartum psychosis. Postpartum psychosis is a serious illness that is characterized by a disconnection from reality, severe disorientation, psychotic delusions, and/or paranoia. Postpartum psychosis has a high risk of recurrence in subsequent pregnancies, especially when the interval between pregnancies is short. The patient and the patient's offspring may be at risk of suicide or homicide.
Depression screening should be performed before conception or during the first trimester. Patients with risk factors should have the topic revisited periodically. Continuation of any therapeutic counseling is a given. However, medications may require adjustment or discontinuation, and the decision must be made on a case-by-case basis.
Just as substance abuse carries a significant stigma, so too does mental illness. Sensitivity and openness are keys to caring for this very large group of patients. Depression serves as a model for caring for patients with other mental disorders, such as anxiety, impulse control disorder, personality disorders, obsessive-compulsive disorder, and schizophrenia. 
While treatment or nontreatment of active schizophrenia is a risk to the pregnancy,  intriguing evidence exists that environmental factors during pregnancy may affect the risk of schizophrenia for the child. In fact, the concordance for development of schizophrenia in monozygotic twins is only 50%. The genes involved in the inheritance of schizophrenia are thought to confer a sensitivity to developing the disease. Exposure to environmental triggers also must occur.
Season of birth is one such factor. People born in the late winter have higher rates of schizophrenia, schizoaffective disorder, major depression, and manic depression (bipolar disorder). In the Northern Hemisphere, the increase is observed in births that occur from December to May, with peaks in January and February. This effect is observed worldwide; July, August, and September births in the Southern Hemisphere demonstrate the same effect. This may be because infectious illnesses in late winter alter the fetal environment or are directly involved in triggering the illness.
Children with CNS infections have higher rates of schizophrenia later in life. Influenza and coxsackieviruses may be the culprits because the increased risk is 5-fold for children of infected mothers. In one study, schizophrenia was associated with exposure to influenza at 20-24 weeks' gestation for female fetuses. In addition, neonatal meningitis due to coxsackievirus B was associated with a high rate of later schizophrenia in a small group studied in Japan. Some studies, but not all, have found increased rates of schizophrenia in cohorts born in epidemic years. Peak vulnerability appears to occur during the second trimester.
Birth in a crowded urban environment is also associated with schizophrenia. Whether this is attributable to facilitated transmission of disease in population-dense cities, family stress caused by the environment, or some other factor is unknown.
In summary, both genetic and environmental components must occur in order for an individual to develop schizophrenia.
Pregnant women with risk factors should be counseled about their status. Potential risk factors include a family history of schizophrenia, a personal history of schizophrenia, an increased risk for infection, and an increased risk for preeclampsia. Women who will be in their second or third trimester during influenza season should be vaccinated. Prenatal influenza is known to cause fetal death, preterm delivery, low birth weight, and brain damage.