Pregnancy -Chemical, Environmental, Psychosocial risk factors

Caffeine

Caffeine is widely considered a very benign substance, and it is ubiquitous in coffee, tea, and soft drinks. The estimated average daily intake is 99 mg. A cup of coffee can contain 127 mg of caffeine, tea up to 107 mg, and soft drinks up to 65 mg. In one study, approximately 28% of women consumed more than 150 mg/d throughout their pregnancy. At levels equivalent to 12-24 cups of coffee a day, rats experience skeletal malformations and ectrodactyly; however, teratogenic effects have not been noted in humans. Recent studies do indicate a slightly increased chance of experiencing preterm delivery, having an infant that is small for gestational age, and, perhaps, miscarrying in the late first or second trimester.

Intervention

Pregnant women should keep caffeine intake below 150 mg/d, especially early in pregnancy.

Metals

 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

Lead is very common in the environment and continues to be a risk today. At high levels of exposure, it is associated with stillbirth and abortion. Epidemiologic studies have demonstrated adverse birth outcomes from either maternal or paternal lead exposure, including spontaneous abortion, low birth weight, preterm birth, and minor malformations. Even today, up to 52% of all homes in the United States may have unacceptable lead levels due to lead-based paint. Safety regulations have limited high levels of lead, but there are effects for even low levels of lead in the blood. Lead may also possibly be mobilized from a pregnant woman's bone stores. In a recent 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). 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. 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 that blood lead concentration levels in a women of childbearing age be less than 20 mcg/dL. A recent study published in the Journal of Perinatology (Jelliffe-Pawlowski, 2006) 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. Maternal blood concentrations that were once considered acceptable, may place some mother-infant pairs at risk.

Intervention

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.

Mercury

The 3 types of possible mercury exposure for pregnant women are organic, inorganic, and elemental. Organic mercury compounds, such as methylmercury, are used as fungicides and in some paints. Uses of inorganic mercury include antiseptics, fungicides, electrical equipment, and some illicit skin-lightening creams. Elemental mercury is found in thermometers, dental amalgam, gold mines, and batteries. It is also used as a catalyst for the formation of some chlorine compounds.

Organic mercury accumulates in the food chain, especially in fish. Importantly, it causes neurologic damage in human infants exposed in utero. An elevated incidence of cerebral palsy and microcephaly was noted in women who ate fish from Japan's Minamata Bay in the 1960s following industrial contamination of the bay. Maintenance of international standards of toxic waste management and reduction in the use of methylmercury 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. 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.

Intervention

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 0.1mcg/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 preconceptually and during pregnancy. The FDAprovides

a comprehensive list of methylmercury 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 methylmercury at concentrations that are 10-20 times higher than fish such as herring, cod, pollack, shrimp, or scallops. They should also 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

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. Research in humans is underway.

Manganese

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 clubfoot and stillbirth.

Arsenic

Inorganic arsenic is a naturally occurring element found at different concentrations in drinking water supplies in various areas of the world. 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.
 

Solvents

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.

Retinoids

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 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.

Etretinate is an extremely long-lasting oral retinoid used in the treatment of psoriasis.  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

Thalidomide is the sole drug in a unique class of sedatives. 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

Diethylstilbestrol

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. 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.

Anticonvulsants

Epilepsy is a common disorder that affects women of reproductive age. It is has a prevalence of 5.25 per 1000 women. One third of people with epilepsy are women of reproductive age and 1 in 200 women attending antenatal clinics are receiving antiepileptic drugs.
 

• Valproic acid: Valproic acid is associated with a 1-2% increased risk of neural tubal defects, particularly at doses above 1000 mg/d.
• Phenytoin: Phenytoin is known to decrease the absorption of folate and is associated with characteristic fetal hydantoin syndrome, with effects including growth deficiency, microcephaly, dysmorphic facies, and mental deficiency; noted in 11% of fetuses exposed to phenytoin in utero.
• Trimethadione: Fetal trimethadione syndrome is associated with simian creases in the hands, cardiac anomalies, irregular teeth, and mental retardation with 50% incidence.
• Phenobarbital: This is not associated with an increase in any anomaly, but it was associated with decreased intellectual performance at age 22 years in a Danish registry.
• Carbamazepine: This is associated with craniofacial defects, fingernail hypoplasia, developmental delay, and spina bifida.

Psychotropic medications

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.

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are common antidepressant drugs. Recently in the literature, conflicting evidence has been shown for and against the use of SSRIs in pregnancy. A trial published in Reproductive Toxicology, (Rahimi, 2006), 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. 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.

Benzodiazepines

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.

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

Alcohol

Alcohol is the most potent teratogen among the substances of abuse. 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

Tobacco

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.

Barbiturates

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.

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