Environmental Toxins Associated With Recurrent Pregnancy Loss

Jennifer R. Gardella, R.N.C., M.S.N. and Joseph A. Hill III, M.D.

Semin Reprod Med. 2000;18(4) 

Abstract and Introduction

Couples experiencing recurrent pregnancy loss are often concerned that toxins within the environment have contributed to their reproductive difficulty. Questions posed by these couples to their health care providers are difficult to answer because scientifically accurate information regarding the reproductive impact of potential environmental toxins and other teratogens is not readily available. Heavy metals such as lead and mercury, organic solvents, alcohol, and ionizing radiation are confirmed environmental teratogens, and exposure could contribute to pregnancy loss. Caffeine, cigarette smoking, and hyperthermia are suspected teratogens, and the teratogenic impact of pesticides remains unknown. The teratogenic potential of multiple other environmental factors has been studied and is reviewed. Before definitive conclusions can be drawn regarding the teratogenicity of environmental exposures, several clinical factors need to be addressed, including gestational age at the time of exposure, the amount of toxin reaching the conceptus, the duration of exposure, the impact of other factors or agents to which the mother or her conceptus is simultaneously exposed, and the physiological status of the mother and conceptus. In addition, in a given population, the interrelationship between frequency of exposures, frequency of effects, and recognizability of adverse outcomes, such as spontaneous abortion, should be considered.

Since the publication of Rachel Carson's Silent Spring in 1962,[1] society has become more aware of and concerned about environmental toxins. Many couples who have experienced recurrent pregnancy loss are concerned that toxins within the environment may have contributed to their reproductive difficulty. Scientifically accurate information concerning the reproductive impact of potential environmental toxins is not readily available to the public. In addition, popular media coverage often leads to exaggerated or inappropriate conclusions from research findings. Thus, it is important that health care providers, counseling patients about exposures to substances in the environment, have current and accurate information in order to respond to these concerns.

This article is designed to assist physicians and other health care providers in counseling patients who have concerns about possible effects of environmental agents on reproduction, specifically early pregnancy loss. Counseling should be tailored to each patient's individual intellectual, educational, psychosocial, and cultural background. Difficult or complex cases should be referred to appropriate specialists. The interested practitioner is encouraged to read additional texts and reviews, which provide more comprehensive information.[2-6]

Teratogen: Definition and Characteristics

A teratogen is defined is as a substance, organism, or physical agent to which an embryo or fetus is exposed that produces a permanent abnormality in structure or function, causes growth retardation, or causes death. Types of teratogens that have been identified include radiation, infections, maternal metabolic imbalance, drugs, environmental chemicals (including solvents and heavy metals), hypoxia, hyperthermia, trauma, and operative procedures.2 The spectrum of potential phenotypic effects of teratogens continues to be debated and redefined. Traditionally, identification of a teratogen was based on its ability to produce structural defects. More recently, studies have included effects such as spontaneous abortion, growth retardation, microcephaly, patterns of major and minor malformations, metabolic dysfunction (e.g., diabetes mellitus in congenital rubella), cognitive dysfunction or disability (e.g., decreased IQ and maternal hypothyroidism), altered social behavior (e.g., in males exposed to diethylstilbestrol), malignancy, decreased fertility, increased perinatal morbidity, and altered offspring sex ratios.[7]

Women are exposed to a myriad of substances during pregnancy but relatively few are considered teratogens. Although experts in the field of teratology have debated the criteria by which an environmental factor is considered to be a human teratogen, there is general consensus that certain basic principles apply.[8-10] These include the following: (1) an increase in the frequency of the phenotypic effect in the exposed group should be seen over its frequency in the general population; (2) an animal model should exist such that when the same route of exposure is applied, it duplicates the effect observed in humans (i.e., there should be a plausible biologic explanation for the mechanism of action of the teratogen); (3) a dose-response relationship should be observed (i.e., the greater the dose of the exposure during pregnancy, the more severe the phenotypic effect); (4) a genetically more susceptible group of exposed individuals should exist (i.e., genetic variability will determine the differences in placental transport, absorption, metabolism, and distribution of an agent accounting for the variation in teratogenic effect observed between species and individuals); (5) a threshold effect should be observed, implying that there is a level of exposure or dose below which the incidence of a phenotypic effect is not statistically greater than that of controls; and (6) the teratogenic insult is stage sensitive, meaning that the effect varies depending on the stage of embryonic development at which the exposure occurs. For example, if the period of exposure is from fertilization through early implantation (postfertilization days 0 to 15), the effect of an insult is often all-or-nothing, where "either the agent affects enough cells to result in embryolethality or so few cells are affected that the embryo is able to effectively repair itself."[10] Implantation failure or spontaneous abortion would be the likely outcome when teratogenic exposure occurs during the first 15 days of development. During the second stage of development, the period of organogenesis (day 18 through day 60), anatomical malformations may be induced. During the third stage, the period of fetal development during the second and third trimesters of pregnancy, exposures may lead to growth restriction, stillbirth, or impaired cognitive development.

In 1995, Shepard[2] proposed a more streamlined set of criteria for determining the teratogenic potential of a substance, which include the following: (1) the agent must be present during critical periods of development; (2) the agent should produce defects in an experimental animal, and the defect rate should be statistically higher in the treated group than in control animals; and (3) proof should be obtained that the agent acts on the fetus either directly or indirectly through the placenta. Despite the preceding tenets, Karnofsky's law still applies, that any substance "administered at the proper dosage, at the proper stage of development to embryos of the proper species will be effective in causing disturbances in embryonic development."[11]

Epidemiology

Human teratogens are identified by interpreting data from multiple sources, including clinical case reports, epidemiologic studies in humans, and studies in experimental animals. Clinical case reports often provide the first evidence that a substance is teratogenic in humans. Case reports are most useful if they reveal a recurrent pattern of anomalies in infants whose mothers were exposed during similar, well-defined points during embryonic or fetal development. For example, the association between maternal rubella and blindness was identified when Gregg[12] diagnosed several cases of an unusual form of congenital cataract temporarily related to a rubella epidemic in Australia. On closer questioning, Gregg noted an excess history of rubella among the mothers during their pregnancies. Although case reports are important in raising hypotheses for causation, most are unsubstantiated and purely coincidental, especially if the exposure or the congenital defect or both occur relatively frequently. If, however, relatively few women are exposed to the agent in question or the agent causes a rare malformation, then a small number of cases can establish a strong association. Warfarin, diethylstilbestrol, and isotretinoin were originally identified as human teratogens on the basis of case reports.[13]

Pregnant women are generally excluded from randomized, placebo-controlled clinical trials of new drugs brought to the market. Thus, epidemiologic studies provide the only means of obtaining quantitative estimates of the strength and statistical significance of associations between exposures in pregnant women and abnormalities in their children. Epidemiologic studies comprise either cohort studies or case-control studies. In cohort studies, the frequency of anomalies in the children of women exposed to the agent and the frequency in those who are unexposed are compared. Prospective cohort studies have more power than retrospective studies. In case-control studies, the frequency of prenatal exposure is compared in children with and without a given anomaly. If a teratogenic agent increases the risk of anomalies only slightly, very large studies are necessary to demonstrate this relationship with statistical significance. On the other hand, investigations involving large numbers of comparisons between exposed and unexposed or affected and unaffected subjects can result in spurious associations. In addition, caution must be exercised in drawing conclusions from epidemiologic studies, in that the maternal disease or the situation that led to the exposure may itself be responsible for the observed association.

The number of known human teratogens is approximately 56 (Table 1). To date, only two are known to have caused human maldevelopment as a result of environmental contamination: high-dose ionizing radiation and mercury poisoning. Agents suspected of being teratogens on the basis of animal studies are more numerous, and when these agents are found to pollute the environment, there is justifiable concern about potential prenatal exposure and adverse reproductive effects.

In order to demonstrate a teratogenic effect in humans, human investigation is necessary, but it is not generally initiated until an agent has already affected many children. Not until the early 1960s, when the thalidomide tragedy was forced upon international consciousness, did we become aware that improved testing for potential teratogens was needed. Although the U.S. Food and Drug Administration (FDA) performed tests for reproductive effects at that time, the only mandatory testing was for toxicity to the adult animal (lethal dose at 50%). The FDA currently bases decisions regarding the safety of substances in the food supply by extrapolating human health risk from animal data. Unfortunately, findings in animals are not necessarily applicable to clinical situations involving pregnant women. In addition, animal studies often employ doses of an agent that are many times greater than those likely to occur in humans. In general, an effect seen in animals is considered to be more relevant if the exposure is similar in dosage by weight and route to that encountered clinically and if the species tested is closely related phylogenetically to humans. Most important, the observed association should make biological sense.6 It is even more difficult to assess the clinical relevance of in vitro teratology assays.

Selected Environmental Teratogens

During the 1920s and 1930s, ionizing radiation (Table 2) was used to treat women with pelvic disease; soon afterward, it was identified as the first known environmental human teratogen.5 Systematic studies of atomic bomb survivors in Japan showed that in utero exposure to high-dose radiation increased the risk of microcephaly and mental and growth retardation in their offspring. Spontaneous abortions, premature deliveries, and stillbirths were also increased after exposure to atomic fallout.[14-16] Using data from animals and outcomes from reported human exposures at various times during pregnancy, a timetable for extrapolating acute high-dose radiation (>250 rads) to various reproductive outcomes in humans was devised. Exposure between 0 and 3 weeks gestation is probably embryolethal or has no demonstrable effect on offspring.[17] The radiation dose below which no adverse effect occurs is not known.

Diagnostic x-rays in the first trimester delivering less than 5 rads are not teratogenic.5 A chest x-ray study delivers 8 millirads, an intravenous pyelogram 407 millirads, an upper gastrointestinal series 558 millirads, and a barium enema 805 millirads.[18] These procedures deliver relatively low doses to the female pelvis. Large doses (360 to 500 rads) used in therapeutic radiation, however, induce abortion in offspring exposed in uteroin the majority of cases.[18]

Adverse effects of chronic low-dose radiation on reproduction have not been identified in humans. No increased risk of adverse outcomes was detected among animals with continuous low-dose exposure (<5 rads) throughout pregnancy.5 Epidemiological studies in different geographic areas have looked for a relationship between human malformation and background radiation. Cosmic radiation was once thought to be a factor contributing to increased rates of anencephalus.[19] Additional studies of geologic estimates of natural radioactivity, cosmic radiation exposure, and congenital malformation rates have not supported an association.[20] Given that low-dose radiation could be one of a multitude of environmental exposures that affect the risk of fetal malformations, it is perhaps not surprising that a relationship was not identified.

Air Travel

Air travel involves exposure to reduced atmospheric pressure, very dry air, prolonged immobilization, and increased exposure to cosmic radiation. Continuous fetal heart rate monitoring was used during air transport of women with obstetric complications to assess whether reduced atmospheric pressure was associated with decreased oxygen delivery to the fetus.[21] Fetal hypoxia was not present on the basis of fetal heart rates without late decelerations. In another study of 10 healthy pregnant women in the third trimester, no abnormalities of fetal heart rate tracings were found during jet air travel in spite of slight decreases in maternal transcutaneous partial pressure of oxygen (Po2).[22] The low moisture content of cabin air could potentially induce dehydration in pregnant women, and prolonged immobilization may exacerbate the risk of a thrombotic event.[23] Therefore, increased fluid intake and frequent ambulation during air travel should be advised. Exposure to ionizing radiation at increased elevation does not involve doses great enough to pose a risk to the developing fetus.

Microwave Any damage to fetal structures from either microwave or shortwave radiation in animal studies was related to hyperthermia, which may be teratogenic under certain conditions.[24,25] Most microwave ovens and diathermy treatment generate approximately 2450 MHz, but even at the maximum permissible level of 1 to 10 mW, no hazard to the human embryo would be expected.[25] Any adverse fetal effects of radio frequency (300 MHz to 3000 GHz) are also associated with hyperthermia.[26]

Rubin and Erdman[27] reported four case histories of pregnant women inadvertently treated with microwave for chronic pelvic infection. One miscarried after 10 days of treatment and the others delivered normal infants. The woman who miscarried became pregnant again, continued the diathermy treatment, and subsequently gave birth to a normal infant. More recently, a study of female physical therapists with occupational exposure to diathermy found an association between miscarriage and exposure to microwave but not shortwave diathermy. Ouellet-Hellstrom and Stewart[28] mailed questionnaires to 42,403 physical therapists comparing 1753 pregnancies that resulted in miscarriage with 1753 matched control pregnancies. A pregnancy was considered exposed if the mother reported using microwave or shortwave diathermy any time during the 6 months prior to the first trimester or during the first trimester. Miscarriage was associated with microwave diathermy exposure (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.02-1.59), and the overall odds ratio was lower when the authors controlled for prior fetal loss (OR 1.26, 95% CI 1.00-1.59). The weak association found in this study may be at least partly accounted for by recall bias.

Mannor et al[29] used various levels of microwave radiation for up to 60 minutes in the mouse at varying periods of gestation. Higher intensity microwave produced tissue defects identical to those expected from overheating. Up to 490 mW did not cause critical temperature rises; no defects were produced in this group, and postnatal fertility and chromosomal findings in the offspring were normal. Lary et al[30] exposed pregnant rats to microwave radiation at varying intensity and found malformations of the central nervous system (CNS), skeleton, and palate when treatment was on day 9, 11, 13, or 15. The defects were related to measured maternal hyperthermia to 43.0°C. In addition, Brown-Woodman et al [31] found a close association between the amount of heating and defects produced in rats.

Ultrasound The biological effects of ultrasound have been studied with no clear consensus regarding safety.[32-36] There remain, however, no human data that support an increased risk of congenital malformations or pregnancy loss following in uteroexposure to ultrasound.[37] The FDA maintains that ultrasound energy delivered to a fetus cannot be regarded as innocuous and that such exposure is not justified when there is no anticipation of benefit to the mother or the fetus. This opinion was based on studies in laboratory animals in which high-dose ultrasound caused a variety of fetal effects, including neurologic, developmental, hematologic, genetic, and structural abnormalities. Some of these effects may be due to hyperthermia or to tissue destruction resulting from exposure to continuous or high-amplitude ultrasonic radiation. This is in contrast to diagnostic ultrasound used in medicine, which is generated in low-amplitude pulses. Carefully controlled studies in humans are difficult to perform because of the widespread use of ultrasound imaging. Analysis is further complicated by the increased use of ultrasound in more complicated pregnancies. No additional risks, however, have been documented in humans as a result of diagnostic ultrasound.

Electromagnetic Fields and Video Display Terminals Data concerning the adverse effects of electromagnetic fields have been difficult to interpret and not consistently reproduced.[38] There is no evidence to support an adverse effect of electromagnetic fields on reproduction, even at high-dose exposure.[39]

In a case-control study, no excess of specific malformations was found among the offspring of mothers residing in areas of high exposure to electromagnetic fields from overhead power lines.[40] Similarly, in an animal study using exposure to a 50-Hz magnetic field throughout gestation, no evidence of adverse fetal effects was found.[41] Another study using pregnant mice exposed to static or flux magnetic fields for 20 days found no increased rate of fetal malformation but did note an increase in the rate of fetal resorptions in the static field-treated group over that observed in the control group.[42]

The odds ratio for spontaneous abortion for 1583 women who used video display terminals (VDTs) for more than 20 hours weekly was 1.8, but no significant increase was found for women working with VDTs less than 20 hours weekly.[43] Six maternal variables (age, education, occupation, smoking, alcohol consumption, and other characteristics) could not explain the increased risk, but the authors question whether those with miscarriages might have overreported their VDT exposure times. A smaller study in 852 VDT users in California found no association with spontaneous abortion rates, low birth weight, or intrauterine growth restriction.[44] In another study, McDonald et al[45] interviewed women regarding their exposure to VDTs over 56,000 current pregnancies and 48,000 past pregnancies. A slight increase in spontaneous abortions (7.5 versus 6.8%) was found among those exposed to VDTs, but the authors stated that this result could reflect biased recall. Schnorr et al[46] measured electromagnetic fields at workstations in a cohort of 2430 female telephone operators, both using and not using VDTs. They found no increased risk of spontaneous abortion among women who used VDTs during the first trimester of pregnancy (OR 0.93, 95% CI 0.63-1.38) and a dose-response relationship was not apparent. There continued to be no risk associated with the use of VDTs when they accounted for multiple pregnancies; conducted separate analyses of early abortion, late losses, and all fetal losses; or limited the analysis to spontaneous abortions for which a physician was consulted. Therefore, VDT use is unlikely to affect pregnancy adversely.

Aspartame No significant relationship between the consumption of the chemical sweetener aspartame and fetal malformations or spontaneous abortion has been found in either laboratory animals or humans. Mice gavaged with up to 4000 mg/kg aspartame on days 15 through 18 of gestation compared with control mice gavaged with normal saline revealed no differences in development.[47] Aspartame fed as 1% of the diet to rats during gestation also caused no ill effects.[48] Stegnik et al[49] found no clinically significant effects of aspartame on phenylalanine levels in normal and phenylketonuric heterozygous adults even at doses as high as 49 to 58 mg/kg.

Saccharin There is no evidence for an increased incidence of spontaneous abortion or fetal malformations in either laboratory animals or humans exposed to moderate use of saccharin.[50] Fritz and Hess[51] reported no teratogenic effects in rats, and Kline et al[52] found no increase in spontaneous abortions among women using saccharin. In long-term studies with mice, Kroes et al[53] also reported that saccharin was not teratogenic. An increase in bladder neoplasms in the male offspring of rats maintained on a diet of 7.5% saccharin has been found but was not observed with a diet containing 5% saccharin.[54]

Caffeine There is no evidence that modest caffeine intake (up to 150 mg/day or 1.5 cups of coffee per day) is associated with an increased risk for first-trimester spontaneous abortion or fetal malformations. Several studies have shown, however, that caffeine in excess of 300 mg/day (3 cups of coffee per day) is associated with a modest increase in risk for spontaneous abortion, but it is not clear whether this relationship is causal. Animal and human data on the toxicity of caffeine have been reviewed,[55] concluding that congenital defects are unlikely to be associated with coffee consumption and that the data on spontaneous abortion and prematurity are inconsistent at best.

Animal data have demonstrated teratogenicity for caffeine only at doses that are clearly embryotoxic. Studies in rodents using acute dosing with caffeine by either gavage (oral-gastric intubation) or intraperitoneal injection with doses ranging from 6 to 250 mg/kg indicate that at a dose of 250 mg/kg, 50% of the mothers die, and at 200 mg/kg survivors frequently develop seizures within minutes of dosing. Evidence of teratogenesis was seen when dosing rose above 75-80 mg/kg. This dose also resulted in a doubling of the number of fetal deaths and resorptions. The incidence of congenital malformations was not statistically significantly different from that in controls until a dose of 125 mg/kg was exceeded.56 Extrapolated to humans, the caffeine ingested by drinking 1 liter of coffee daily would be approximately 20 to 25 mg/kg, an order of magnitude less than that shown to cause malformations. A potential association between caffeine exposure and congenital malformations has been investigated in thousands of women, yet no evidence has emerged to link caffeine exposure to an increased risk for congenital malformation in humans.[57,58]

A number of human studies have looked at the association between caffeine exposure and miscarriage. Although the notion of what constitutes a serving (i.e., cup of coffee) is variable, 6 oz of coffee typically contains approximately 100 mg of caffeine, 6 oz of decaffeinated coffee contains 2 to 3 mg of caffeine, tea 35 mg, 12 oz cola 50 mg, and a cup of cocoa 35 mg. In a prospective cohort study involving 3135 women, the relative risk for spontaneous abortion for women consuming over 150 mg of caffeine daily was 1.73 (P = .03).[59] In a case-control study, Kline et al[60] karyotyped 900 pregnancy losses prior to 28 weeks of gestation and employed 1423 controls. In women who consumed more than 225 mg of caffeine daily during pregnancy, the adjusted odds ratio for chromosomally normal losses versus controls was 1.9 (1.3-2.6), which was statistically significant. In a case-control study of 331 women interviewed at admission for treatment for first-trimester spontaneous abortion, a significantly increased risk for fetal loss among women consuming 163-321 mg and greater than 321 mg of caffeine per day was noted.[61] The odds ratios were 1.95 (1.29-2.93) and 2.62 (1.38-5.01), respectively. For women consuming less than 162 mg/day, the odds ratios were not significantly increased between women with losses and those with uneventful pregnancies. In a cohort study of women with uncomplicated delivery compared with those with spontaneous abortion, an increased mean daily caffeine intake in women with spontaneous abortions was reported.[62] Heavier caffeine consumers were also significantly older and more likely to smoke cigarettes, which could have confounded the results of this study.

Successful pregnancies may be more often associated with food aversion, nausea, and vomiting than pregnancies destined to result in miscarriage, and because coffee is one of the foods most commonly found unappealing under these circumstances, women with successful pregnancies may therefore decrease their coffee intake, whereas women destined to early pregnancy loss may not.[63] Therefore, even though several studies have reported an association between higher caffeine intake and spontaneous abortion, the relationship may not necessarily be causal.

Chocolate Chocolate consumption is not associated with adverse pregnancy outcome. Pregnant rats fed 2.5, 5.0, or 7.5 mg/kg cocoa powder in their diet daily had no adverse fetal effects. In the human, this is the equivalent of up to 10 pounds of milk chocolate per day.[64]

Municipal Drinking Water Disinfection by-products in municipal tap water have been evaluated as a possible health hazard. Water utilities in the United States use chlorination to disinfect water, which gives rise to chlorination by-products, termed trihalomethanes. Several reports associated tap water in Santa Clara County, California with an increased risk of early pregnancy loss.[65-69] An analysis of pregnancies from 1989 to 1991 indicated that the miscarriage rate was increased in this county among women drinking six or more glasses of cold tap water daily (OR 2.17, 95% CI 1.22-3.87) compared with women who used bottled water.[70] There was no such relationship in two other regions of California. In another study, an association between spontaneous abortion and high levels of trihalomethanes in tap water in some regions of California was identified but not for Santa Clara County.[71] Because the association of early pregnancy loss with trihalomethanes in this study was not evident in Santa Clara, the only region in which spontaneous abortion had been shown to be related to high tap water intake, it was concluded that trihalomethanes were not responsible for pregnancy loss. Perhaps the effect may be explained by socioeconomic factors associated with drinking tap versus bottled water. In North Carolina, spontaneous abortion was not associated with drinking tap water, although there was a significant increase in the estimated risk for pregnancy loss in the highest sectile of estimated trihalomethane intake (OR 2.8, 95% CI 1.2-6.1).[72]

Two studies in pregnant rats fed tap water from Santa Clara County homes identified a small but statistically significant increase in fetal resorptions compared with animals given bottled or deionized water.[73] Previous studies comparing municipal drinking water with purified water in relation to fetal development in mice failed to observe any significant differences in pregnancy outcome.[74,75] A study of the potential teratogenic effect of trihalomethanes in rats found no increase in congenital anomalies of offspring or fetal resorptions, except at doses that induced maternal and fetal toxicity (five orders of magnitude greater than levels present in tap water in the California study).[76]

Bovine Growth Hormone Bovine growth hormone (somidobove) has been used to increase milk yield in dairy cattle.[77] In response to treatment with growth hormone, milk fat increases and protein levels decrease. Animal studies using pituitary extracts of purified growth hormone showed an increase in pup size and prolongation of gestation in rats.2 Studies in rodents also indicated that growth hormone prolongs the estrous cycle, increases litter size and pup weight, and increases placenta and brain size.[78] Milk produced under the influence of bovine growth hormone contains insulin-like growth factor (IGF)-1.[79] The small amounts of IGF-1 present in bovine milk, however, are thought unlikely to produce adverse health effects in humans.[80]

The evidence for human teratogenicity from elevated maternal body temperature, whether from fever or hot tub use, continues to accumulate.[81,82] Retrospective clinical studies in women suggested that maternal hyperthermia is teratogenic.[83-86] In a review of 43 pregnancy histories of women who gave birth to infants with meningomyeloceles, three had fevers of over 102°F (38.9°C) between the 25th and 28th days of gestation.[83] None of the 63 control subjects had fever during this period of gestation. A significant increase in fever among mothers who delivered infants with spina bifida has also been found.[85] In a study of 23 retrospectively selected children who had been prenatally exposed to temperatures of 38.9°C or more between 4 and 14 weeks of gestation, similar patterns of malformations were found including growth deficiency, CNS defects, and variable facial malformations. In 6 of 23 cases, heat exposure was attributable to sauna bathing or hot tub use, suggesting that hyperthermia rather than an infectious agent was the teratogenic insult.[87]

In a prospective follow-up study of 23,491 women who were screened by serum a-fetoprotein or a-fetoprotein in amniotic fluid following amniocentesis, Milunsky et al[88] identified 5566 women exposed to either hot tub, sauna, fever, or regular electric blanket use during the first trimester of pregnancy. Exposure to heat in the form of hot tub, sauna, or fever was associated in all cases with an increased risk for neural tube closure defects. Of the three, the adjusted relative risk for hot tub use was the highest at 2.8 (95% CI , range 1.2-6.5). Electric blanket exposure was not associated with a risk for neural tube defects. In another study of karyotyped spontaneous abortuses, 18% of women who had euploid spontaneous abortions had experienced a fever of 100°F or more, compared with women with aneuploid abortuses, of whom only 7.1% had febrile episodes.[89]

Hyperthermia experimentally produces spontaneous abortion and congenital defects in animals.[90] Immersion of one uterine horn in water of 40 to 41°C for 40 to 60 minutes on the 8th to 16th day of pregnancy in rats produced neural tube closure defects, other CNS anomalies, and a high rate of fetal resorption.[91] In pregnant guinea pigs, exposure to 43°C external temperature for 1 hour daily was associated with multiple fetal anomalies when the exposure occurred from the 18th to the 25th day of gestation in 86% of fetuses. When this treatment was performed before the 18th day of gestation, there was an equally dramatic rate of fetal death and resorptions.[92]

Phytoestrogens The precursors of biologically active phytoestrogens originate in soybean products (mainly isoflavonoids), whole grain cereals, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria into hormone-like compounds with weak estrogenic and antioxidative activity. Phytoestrogens have been shown to influence sex hormone metabolism and biological activity.[93]

Coumestrol, a phytoestrogen found in many fruits, grains, and coffee, when fed to mice in amounts of 100 or more parts per billion was associated with decreased ovulation and increased embryo degeneration.[94] In rats, high phytoestrogen exposure was associated with persistent estrus and a variety of other reproductive alterations, and in sheep, phytoestrogens have been linked to abnormalities in cyclicity and infertility.[95,96]

In women, the effects of phytoestrogens on the reproductive system are controversial. Some studies suggest that phytoestrogens are beneficial to women, whereas other studies suggest that phytoestrogens are linked with harmful reproductive outcomes. For example, phytoestrogens have been associated with reduced risk of uterine cancer, breast cancer, and menopausal hot flashes.[93,97] Potential adverse effects include alteration in menstrual cyclicity, premature thelarche, and association with the development of endometriosis.[98] The significance of these conflicting reports is unclear, largely because most studies to date have not been of adequate sample size or have not included enough information concerning exposure to allow definitive conclusions to be drawn regarding phytoestrogens and reproductive outcome.

Phthalates Phthalates are chemicals used in the manufacturing of automotive parts, medical supplies, plastic wraps, beverage containers, and the lining of metal cans. Phthalates are weakly estrogenic and have been associated with adverse reproductive effects in laboratory animals.[99] The dietary contribution of estrogenic industrial compounds is estimated to be approximately 0.0000025% of the daily intake of estrogenic flavonoids.[100] The effect of phthalates on reproduction in women has not been reported.

Herbicides Dioxin (2,3,7,8-tetrachlordibenzodioxin) was a contaminant of production of the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and is also released into the environment as a by-product of bleaching of paper pulp and incineration of chorine-containing waste. The herbicide 2,4,5-T is no longer marketed in the United States because of concerns about teratogenic and fetotoxic effects. These effects were described when high doses of the pesticide were administered to animals during critical periods of organogenesis.[101] The effects of dioxin on human reproduction are unclear. Dioxin is an aryl hydrocarbon receptor (AhR) agonist, is weakly estrogenic, and is also antiestrogenic at some concentrations.[100] Dioxin may be a complex endocrine disruptor in humans.[102] To date, however, data are inadequate to support allegations of adverse reproductive outcomes following human exposure to dioxin.

Agent Orange was a mixture of herbicides and was regularly contaminated with trace amounts of dioxin. Agent Orange was used extensively in agriculture and forestry in the United States before the Vietnam War and was used as a defoliant in Vietnam. Public opinion fueled debate about the potential teratogenicity of Agent Orange because the long-term human effects were unknown. The U.S. Public Health Service, therefore, began to follow Vietnam veterans exposed to Agent Orange and found that there was no greater risk of fathering babies with birth defects or of early pregnancy loss.[103] A study of reproductive outcomes in Italian women exposed to high levels of dioxin following a factory explosion found no increased risk of spontaneous abortion, cytogenetic abnormalities, or birth defects.[104]

Organic solvent is a broad term that applies to many classes of chemicals. Perchloroethylene, toluene, xylene, and styrene have all been linked to adverse reproductive outcomes in laboratory animals and in humans. Solvent intoxication is an established occupational hazard in painters and workers in the rubber, semiconductor, and dry-cleaning industries. Exposure routes include inhalation, transdermal application, and ingestion. Toxic symptoms include headache, nausea, dizziness, and confusion, progressing to CNS depression and loss of consciousness. Chronic exposure to low levels of organic solvents may lead to neuropsychiatric impairment and to peripheral neuropathy. Typical incidental exposures may include vapors from gasoline, lighter fluid, aerosol sprays, and paints. Often these exposures are short term and low level. Exposures that occur in industrial or laboratory settings as well as through intentional gasoline or glue inhalation are more serious.

Maternal solvent abuse by inhalation is reported to cause an embryopathy similar to fetal alcohol syndrome.[105] A syndrome of effects including developmental and intellectual impairment, facial dysmorphism, and intrauterine growth restriction has been described in women who chronically abused toluene or other unnamed solvents during pregnancy.[106,107] Perchloroethylene, toluene, and xylene exposures have been associated with an increased risk of spontaneous abortion in women.[108-112]

Various organic solvents have been shown to be embryotoxic in animals.[113] Perchloroethylene decreases pup survival, reduces fetal body weight, and increases the number of resorbed fetuses in rodents. Toluene exposure reduces fetal weight and delays skeletal development in animals. Xylene increases the number of fetal resorptions, delays fetal development, reduces birth weight, blocks cyclicity, and prevents ovulation in rodents. Styrene has been shown to be embryotoxic in rats.

In a survey of Danish women in selected occupations, comparing female painters and unexposed women, a slightly higher risk for spontaneous abortion was observed in painters (OR 2.9, 95% CI 1.0-8.8).[114] In a study of pregnancy outcomes among women employed at a semiconductor factory, an increased risk of spontaneous abortion for women working in the diffusion area was found (risk ratio [RR] 2.18, 95% CI 1.11-3.6) compared with nonexposed women.[115] These studies included only a small number of women in the exposed and nonexposed groups, and exposures were not quantified. In a meta-analysis of published studies from 1966 to 1994, describing the outcomes from five papers (three retrospective and two prospective), an overall odds ratio of 1.25 indicated that maternal occupational exposure to organic solvents by inhalation was associated with a small increased risk for spontaneous abortion.[116]

Overall, organic solvents as a class, and toluene in particular, are teratogenic at high exposure levels. The risk for "fetal solvent syndrome," however, is unknown, and no exposure threshold for this effect has been identified at this time. There is no conclusive evidence that low-level exposure increases the risk of congenital malformations or other adverse reproductive outcomes.

Cigarette smoking reduces fertility, increases the rate of spontaneous abortion, and increases the incidence of abruptio placentae, placenta previa, bleeding during pregnancy, and premature rupture of placental membranes.[117] Smoking is also related to poor outcomes for exposed infants, who are more likely to be of low birth weight (<2500 g) and have twice the risk of infant mortality from all causes, specifically from sudden infant death syndrome. The effects of maternal smoking are thought to result in many thousands of preventable fetal and neonatal deaths.[118] None of the studies examining the relationship between spontaneous abortion and smoking has validated the accuracy of reporting with biochemical measures of tobacco exposure. Studies in the aggregate, however, suggest a clinically significant detrimental effect of cigarette smoking that is dose dependent, with the relative risk for miscarriage among moderate smokers (10 to 20 cigarettes a day) being 1.1 to 1.3.

A progressive decline in fecundity and increase in spontaneous abortion rate are consistently demonstrable in smokers.[119] In a study of 1500 karyotyped spontaneous abortions, a significantly increased number of chromosomally normal losses was found in women who smoked (50%) versus women who did not smoke (62%).[120] In a prospective study[121] of 32,019 women at the beginning of pregnancy, 24% of women reported smoking and 48% also consumed alcohol during pregnancy. After adjustment for alcohol use, the only subgroup in which smoking had a significant adverse effect was in those smoking more than two packs of cigarettes per day. In this group, the odds ratio for second-trimester pregnancy loss was 2.02 (95% CI, 1.01-4.01). In a large retrospective study analyzing data from 47,146 women using logistic regression analysis, assessing age, pregnancy history, ethnicity, education, employment status, and caffeine and alcohol use, a dose-response effect was noted for smokers that reached significance at more than 10 cigarettes a day.[122] Another retrospective study found an unadjusted odds ratio for spontaneous abortion among smokers versus nonsmokers of 1.2 (95% CI, 1.09-1.33).[123] A similar study in 2714 Finnish women produced an adjusted odds ratio of 1.37 (0.94-2.0).[124]

In three case-control studies comparing smoking histories from women with spontaneous abortions and viable pregnancies, odds ratios ranged from 0.83 to 1.8.[125-127] In one such study, the smoking habits among 574 women who aborted spontaneously and 320 women who delivered after the 28th week of gestation were assessed. Of those aborting, 41% smoked, compared with 28% of those reaching 28 weeks of pregnancy. This association did not vary with age or previous obstetrical history. Because of important differences between cases and controls and because of the potential for recall bias, these results should be interpreted with caution.

In summary, the data evaluating smoking and miscarriage are extensive (approximately 100,000 subjects). Although the studies are clinically heterogeneous, they nevertheless suggest an increased risk for early pregnancy loss and other reproductive difficulties that is dose dependent.

Alcohol is a teratogen resulting in the fetal alcohol syndrome (FAS). A dose-response relationship exists between the amount of alcohol consumed during pregnancy and the effects on the fetus (Table 3). Because no clear threshold has been established, no amount of alcohol in pregnancy is considered to be safe. Using hospital discharge data, the Birth Defects Monitoring Program of the Centers for Disease Control (CDC) in 1992 reported the incidence of FAS to be 3.7 per 10,000 births.[128] The incidence of children born with lesser effects or partial features has been estimated to be three to five times that in the general population. Correlates with heavy drinking in pregnancy[129] include women who are more than 35 years old, nonwhite, unmarried, have limited or no prenatal care, low annual income, multiparity, and history of previous alcohol problems.

The phenotypic effects of FAS are well described.[130] A spectrum of effects probably exists that ranges from FAS to lesser effects with partial features of the syndrome to neurocognitive effects without other physical features. The distinguishing features of children with FAS include growth restriction (low birth weight, microcephaly, and failure to thrive), a pattern of craniofacial anomalies (small palpebral fissures, a smooth, flat philtrum, thin upper lip), neurological effects (fine and gross motor delays, decreased IQ, learning disabilities, impaired cognition), and behavioral effects (impulsivity, difficulties in peer relationships, lack of judgment, aggressiveness, and impaired adaptive behavior).[131]

Although exposures are difficult to quantify because of underreporting and variability in drinking patterns, a dose-response relationship between the effects and amount of alcohol has been delineated.[132-134] FAS is induced at greater than or equal to 4 oz AA (absolute alcohol)/day, birth weight reduction at greater than or equal to 2-3 oz AA/day, I.Q. effects (decrease of 5 to 7 points) at greater than or equal to 1.5 oz AA/day, spelling and reading difficulties at greater than or equal to 0.5 oz AA/day, and functional deficits at greater than or equal to five drinks per occasion at least once a week. Notably, daily alcohol consumption is not necessary to induce effects; binge drinking (greater than or equal to five drinks at a sitting) before the recognition of pregnancy or in midpregnancy has been associated with decrements in academic skills, memory, and attention.[135]

Even moderate drinking may be associated with an increased risk for spontaneous abortion in the first or second trimester.[136-138] In a Russian population, spontaneous abortion occurred in 29% of women who drank alcohol during pregnancy; perinatal deaths occurred in 12-25%, premature births in 22%, and offspring with signs of FAS in 0.1-0.4%.[139] An increased spontaneous abortion rate has also been documented in monkeys gavaged weekly with alcohol (2.5 or 1.8 g/kg) after the first 30 days of pregnancy.[140,141] Intravenous alcohol administration (1.0 and 2.0 g/kg ethanol) in pregnant rats at 6 and 7 days of gestation caused embryolethality but no defects in surviving fetuses.[142]

The combined effect of other substances of abuse may be additive with those related to alcohol consumption. Studies describing the potentially additive effects of cigarette smoking and alcohol are conflicting. The effects of smoking on birth weight are not as dramatic as those of alcohol. The adverse effects of cocaine on birth size and head circumference (independent of prematurity) are likely to be additive with those of alcohol. Any association between opiates and decreased birth size may be secondary to alcohol and cigarette use.[143]

Mercury Mercury is the most extensively documented environmental pollutant associated with adverse reproductive events.[144,145] At Minamata Bay, Japan between 1953 and 1965, the offspring of some women who ate shellfish contaminated with methyl mercury waste products released from large chemicals plants on the bay developed symptoms of a generalized disorder of the CNS.[146] In 1972, similar fetal effects were observed in Iraq after an epidemic of methyl mercury poisoning.[147]

In the United States, exposure to organic mercury compounds such as methyl mercury or ethyl mercury is uncommon but may occur through the consumption of contaminated fish or through releases from batteries, thermometers, and dental amalgams containing mercury. Encapsulated amalgams have been employed that reduce mercury exposure, and mercury thermometers and manometers are now less widely used. The persistence of organic mercury in the body and its accumulation in hair make it possible to reconstruct prenatal exposure.[148] Methyl mercury crosses the placenta easily and accumulates in embryonic and fetal tissues, particularly in brain tissue, at concentrations exceeding those in the mother. Methyl mercury does not cause obvious structural malformations in humans, so the devastating effects, which may not be obvious at birth, become evident only as abnormal neurologic development proceeds.

Little is known of the human effects of methyl mercury at low levels of exposure. In nonhuman primates chronically treated with low-dose methyl mercury, reproductive failure (nonconception, spontaneous abortion) was more likely to occur than in nontreated controls.[149] In other laboratory animal studies, methyl mercury was found to be embryolethal and caused various structural malformations when high doses were given during critical periods in development. There appears to be no association between similar birth defects and human environmental exposure.

Considering that large numbers of women of childbearing age may have been occupationally exposed to mercury vapor, there is a surprising lack of animal and human epidemiologic studies concerning the potential reproductive effects of this exposure. The few epidemiologic studies that have been conducted concerning the potential reproductive effects of mercury exposure have been conducted in women working in the field of dentistry. As a whole, the limited data presently available provide no conclusive evidence that occupational exposure to mercury vapor is teratogenic or results in other adverse reproductive outcomes. In a case-control study of female dentists and dental assistants in Poland, an association between increased hair mercury content and self-reports of spontaneous abortion, congenital malformations, and stillbirths was reported.[150] There was little difference in mean hair mercury values between the two groups, the rates of these outcomes were not much greater than those expected in the general population, and no adjustment was made for maternal age or dietary fish consumption.

In a large survey of Danish women in several occupations, dental assistants and dentists were not found to have an increased risk of either self-reported or hospital-recorded spontaneous abortions.[151] In another survey of female dentists and dental assistants in the United States, no association was found between mercury exposure and self-reported spontaneous abortions or congenital malformations in offspring.[152]

Methyl mercury exposure, as assessed by hair mercury levels, from a maternal diet high in oceanic fish in the Republic of Seychelles, where fish is the major dietary protein source, was not found to be associated with adverse neurodevelopment in offspring.[153] The lowest dose of methyl mercury that impairs neurodevelopment in the human fetus is not known, nor has an embryolethal dose been identified.

Lead Exposures to high levels of lead are known to cause embryotoxicity, growth and mental retardation, increased perinatal mortality, and developmental disability.[154] Adverse reproductive effects were seen in the 19th century, when women in occupational settings were exposed to concentrations of lead in the air that far exceeded levels allowable today. Although lead toxicity has been recognized for years, the usefulness of various forms of lead has kept it widely available in many societies. In the recent past, the burning of lead alkyl additives in gasoline constituted the largest and most widespread exposure to lead. Now, federal guidelines are eliminating this use of lead, significantly lowering atmospheric exposures. Lead exposure resulting from residual soil contamination from a variety of sources including lead solders, pipes, storage batteries, lead-based paints, dyes, and wood preservatives is still a source of concern. Lead is also one of the most common groundwater contaminants from hazardous waste sites.[155]

The toxic effects of lead on human pregnancy were suspected over 100 years ago in women who worked with lead salts in pottery glazes. Stillbirths and miscarriages were commonly recognized in this population.[156] Lead pills were sold as an abortifacient in the late 1800s and early 1900s.[157] In 1930, the spontaneous abortion rate in the general population of Milan, Italy was 4 to 4.5%; wives of male printers exposed to lead in inks had a spontaneous abortion rate of 14%; and in female printers, the spontaneous abortion rate was 25%.[158] In Germany, spontaneous abortions were three times more common in female lead-exposed printers than in nonexposed workers.[158]

Maternal serum and cord blood lead concentrations are directly correlated. Thus, lead concentrations in maternal blood should not exceed 25 mg/dL.[159] In occupational settings, federal standards mandate that women should not work in areas where air lead concentrations reach 50 mg/cm3 because this may result in blood concentrations above 25 to 30 mg/dL. The nervous system is most susceptible to the toxic effects of lead during the embryonic and fetal periods of development. Studies suggest that in children, subtle but permanent neurologic impairment may occur at blood levels of 10 mg/dL.[160] Thus, although it is controversial, the federally mandated occupational standards for lead exposure may inadequately protect the fetus.

At present, no conclusive studies have been performed evaluating the potential teratogenic effect of pesticides. The four major chemical groups of insecticides are organophosphates, carbamates, chlorinated hydrocarbons, and pyrethrins. At peak usage, nearly 300 million pounds of chlorinated hydrocarbon insecticides were produced each year in the United States.[161] The organophosphates and the carbamates are the most commonly used pesticides, and studies are needed to assess their impact on human reproduction. Associations between maternal exposure to pesticides and adverse reproductive outcomes are speculative and remain inconclusive.[162]

Most insecticides are neurotoxins. Symptoms of acute organophosphate poisoning include increased salivation, tearing, rhinorrhea, coughing, wheezing, nausea, and vomiting. In severe cases, bradycardia and hypotension have led to stupor, convulsions, and coma.[163] No increase in spontaneous abortion, stillbirths, or birth defects has been described in families of agricultural pilots who spray insecticides.[164] In a study of workers in flower-growing companies in Bogotá, Columbia, in which all subjects had been engaged in work in the industry for 6 months or longer and multiple pesticides were used, there appeared to be an increased risk for spontaneous abortion (OR 1.79) in female workers. Recall bias however, was suspected, as risk decreased over time.[166] In another study, a high incidence of spontaneous abortions was seen in Spanish greenhouse workers who were exposed to a variety of pesticides.[167]

Mixtures of pesticides and fertilizers did not affect fertility and were not teratogenic in mice or rats given doses up to 100 times those found in groundwater.[164] Following contamination of the milk supply on the island of Oahu, Hawaii, between 1980 and 1982 by heptachlor, an organochlorine pesticide, a comparison of the rates of major malformations on Oahu, the other Hawaiian islands, and the continental United States suggested that heptachlor is probably not a human teratogen.[168] This negative study is particularly significant because organochlorine insecticides remain in the environment for a long time, and because they are lipid soluble, they also remain in body tissues for an extended period of time.

Reports of increased risks of pregnancy loss or of parenting a child with birth defects were abundant in the press after men and women who served in Desert Storm (the Gulf War) returned from duty. The reports are reminiscent of press coverage of Agent Orange exposure after service in Vietnam. There have also been concerns that occupational exposures to toxins in janitors, wood workers, firemen, electric workers, and printers have led to adverse reproductive outcomes. The theoretical mechanisms by which a paternal exposure could have a harmful fetal effect would have to involve either the presence of a drug or toxicant in seminal fluid or the induction of a genetic mutation or chromosomal abnormality in sperm. Because most teratogens induce adverse fetal effects in a dose-dependent fashion, the drug would have to be highly concentrated in seminal fluid in order to expose the unfertilized ovum or early conceptus directly. Concentrations of this magnitude would probably cause paternal toxicity or death. In addition, testicular germ cells have inherently high mitotic activity (100 million new cells are produced each day) and germ cells continue to proliferate throughout life, from puberty to death. Following proliferation, germ cells enter meiotic prophase and subsequently undergo two meiotic divisions to become haploid spermatids. Because of the nature of the male reproductive system and the constant turnover of new cells, exposure to a toxin might decrease the number of cells available for fertilization in the short term but would not change the transmission of genetic material over time. Because of similarities in spermatogenesis in man and rodents, animal studies of male-mediated effects are relevant to humans.[169]

There is no evidence that the pregnancies of veterans of the Gulf War (men and women) are at increased risk for birth defects or early loss. The most extensive study published to date was a review of the discharge diagnoses of 33,998 infants born to Gulf War veterans and 41,463 to nondeployed veterans at military hospitals. This review showed no evidence of an increased risk of adverse fetal effects.[170]

Occupational exposures in men are also a concern in terms of reproductive failure. In 18 battery workers with lead intoxication, azoospermia and oligospermia have been reported.[171] Sperm concentration, total sperm count, and total motile sperm count were inversely related to blood lead concentrations in 119 lead smelter workers.[172] An epidemiological study reported a significant increase in the risk of spontaneous abortion when the father was exposed to lead.[173] It was not clear whether the pregnant spouses were exposed indirectly through laundering of lead-contaminated work clothes.

Alcohol exposure can adversely effect male fertility but is not known to be teratogenic through the father.[174] Men occupationally exposed to ethanol at airborne concentrations within the recommended occupational exposure limits had normal sperm counts.[175] Studies concerning preconceptual drinking by fathers found no associations with abnormal birth weights.[176] In another large study, involving 10,232 pregnancies, no association between gestational age or birth weight and paternal alcohol use was found.[177]

Hair Dye The use of hair dyes during pregnancy in women has not been well studied. No increase in fetal defects in the offspring of 118 women, 18 of whom used hair dyes in the first trimester, has been reported.[178] Hair dyes have been more extensively studied in laboratory animals. Rats fed a composite of a series of commercially available hair colorings from days 6 to 18 of gestation with doses of up to 97.5 mg/kg/day exhibited no teratogenicity.[179] Five oxidative hair dyes were administered by gavage to rats with up to 500 mg/kg daily on days 6-15 and again no adverse fetal effects were observed.[180] Mice injected with up to 1024 mg/kg hair dye on days 6-15 had an increase in maternal mortality at 64 mg/kg but no increase in fetal malformations. At doses that were toxic to the mother (160 and 256 mg/kg/day), defects were produced with two types of dye (4-nitro-p-phenylenediamine and 4-nitro-o-phenlyenediamine). Cleft palate was the most common defect observed, but staining of fetal myocardium was also noted.[181] The outcomes of 714 pregnancies among hairdressers revealed no increased risk for either early pregnancy loss or other adverse fetal outcome (OR 0.94).[182]

Nail Polish Nail polish application involves the use of pigments, lacquer, surfactants, flocculants, colloids, plasticizers, and thinners. Many of the agents involved are organic solvents such as toluene, isopropyl alcohol, and acetone. The extent of exposure depends on ventilation and length of use. The occasional use of nail polish seems unlikely to constitute great risk to fetal well-being as long as exposure time is limited and ventilation is adequate. A study of licensed cosmetologists, however, suggested a 60% increased risk of early pregnancy loss in the women exposed to nail polish compared with other unexposed employees.[183]

Summary

The Occupational Safety and Health Administration (OSHA) has issued standards for lead, mercury, ethylene oxide, ionizing radiation, and dibromochloropropane on the basis that these substances adversely affect reproduction,[184] including spontaneous abortion.[185] Additional reproductive concerns include occupational exposure to anesthetic gases and organic solvents.[184] Adequately controlled prospective studies demonstrated that exposure to electromagnetic fields was not associated with an increased risk of pregnancy loss.[46]

Other agents implicated in spontaneous abortion include ethanol, caffeine, nicotine, and other metabolic products of cigarette smoking. Alcohol consumption of more than two drinks per day is associated with a risk of spontaneous abortion of twice that in non-alcohol-consuming controls.[186] Low-level alcohol consumption, however, does not appear to be a significant risk factor for spontaneous fetal loss.[187] The minimum threshold dose for increasing the risk of spontaneous abortion is 2 ounces of alcohol per week.[188]

Smoking also has a dose-response relationship with spontaneous abortion.[189] Women who smoked half a pack of cigarettes per day had a higher risk of having chromosomally normal spontaneous abortions than women who did not smoke.[188] There is also a dose-response effect with caffeine consumption but only at doses higher than 300 mg/day.[190]

Before definitive conclusions can be reached regarding the teratogenicity of environmental factors, the following need to be considered:

  1. Gestational age at the time of exposure.

  2. Amount of toxin reaching the conceptus.

  3. Duration of exposure.

  4. Impact of other factors or agents to which the mother or the conceptus is simultaneously exposed.

  5. Physiologic status of mother and conceptus: genetic differences.

  6. Interrelationship between frequency of exposures, frequency of effect, and recognizability of adverse outcome, such as spontaneous abortion.[191]

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