Adverse Environment And Prevention Of Early Pregnancy Disorders

Orna Diav-Citrin, MD and Asher Ornoy, MD

Correspondence: Prof. Asher Ornoy , The Israeli Teratogen Information Service, Laboratory of Teratology, The Hebrew University - Hadassah Medical School and Israel Ministry of Health,
PO Box 12272, Jerusalem, 91120, Israel, Tel./fax. 972-2-6758430

Introduction

Major congenital defects are found in 1-3% of the newborn infants (Heinonen, 1977). Careful follow up increases the number detected later in life to up to 5%. Major birth defects cause 20% of infant mortality and are responsible for a substantial number of childhood hospitalizations. Of those defects, about 20-25% are of genetic origin (autosomal genetic diseases account for 15-20% and 5% are cytogenetic in origin) and 65% are of unknown etiology (multifactorial, polygenic, spontaneous errors of development and synergistic interactions of teratogens). Less than 1% of the anomalies are thought to arise in association with drug treatment. The remaining defects are associated with other environmental exposures during pregnancy including infectious agents (3%), maternal disease states (4%), mechanical problems (1-2%), irradiation and unknown environmental causes (Schardein, 1993).

Teratology is the study of environmentally induced congenital anomalies. A teratogen is an agent, which by acting on the developing embryo or fetus can cause a structural or functional anomaly. To date, very few drugs are proven human teratogens. However, malformations induced by drugs are important because they are potentially preventable.

The timing of embryonic and fetal exposure to a teratogen is crucial in the risk it carries.

Timing of embryonic and fetal development

The effect produced by a teratogenic agent depends upon the fetal developmental stage at time of exposure. Several important phases in human development are recognized:

The pre-organogenetic phase, from conception until somite formation known as the "all or none" period, when insults to the embryo are likely to result in death of the conceptus and miscarriage (or resorption) or in intact survival (Fabro, 1986). At this stage, the embryo is undifferentiated and repair and recovery are possible through multiplication of the still totipotential cells to replace those, which have been lost. Exposure of embryos to teratogens during the pre-somitic stage usually does not cause congenital malformations (Moore, 1998), unless the agent persists in the body beyond this period.

The embryonic period, from 18 to 60 days after conception is the period when the basic steps in organogenesis occur. This is the period of maximum sensitivity to teratogenicity since not only are tissues differentiating rapidly but also damage to them becomes irreparable. Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. Since teratogens are capable of affecting many organ systems, the pattern of anomalies produced depends upon which systems are differentiating at the time of teratogenic exposure.

The fetal phase, from the end of the embryonic stage to term, is the period when growth and functional maturation of organs and systems already formed occur. Exposure to teratogens in this period will mainly affect fetal growth causing intrauterine growth retardation or macrosomia, the size of a specific organ, or the function of the organ. They will rarely cause gross structural anomalies, except for the brain which may be affected almost throughout the entire pregnancy. The term fetal toxicity is commonly used to describe such an effect. Of particular interest is the potential effect of psychoactive agents (e.g. antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system, which has lead to a new field of "behavioral teratology". Many organ systems continue their structural and functional maturation long after birth. Most of the adenocarcinomas associated with first trimester exposure to the synthetic estrogen, diethylstilbestrol, occurred many years after the exposure. Intrauterine infections may induce fetal damage that occurs years after birth (i.e. diabetes mellitus associated with congenital rubella syndrome).

This review focuses on adverse effects of the environment during early pregnancy (until the end of the embryonic period) and on prevention strategies of such effects.

Proven teratogenic drugs in humans (in alphabetical order).
The drugs that will be discussed in this review are those with sufficient evidence for their embryotoxic and teratogenic effects. These drugs are relatively few and should be replaced prior to pregnancy with less teratogenic drugs. Sometimes they must still be used during pregnancy in spite of their teratogenicity as their benefit outweighs the risk they impose on the fetus. There are many other drugs, not discussed here, that may also adversely affect the embryo or fetus but the scientific data for their action is incomplete. Although it is generally advisable to refrain from drug intake during pregnancy, drugs should be given if they are needed to treat chronic or acute maternal diseases, as often maternal uncontrolled diseases may be more harmful to the developing fetus than the administered drug (Ornoy and Arnon,1993).

Alcohol
The Fetal Alcohol Syndrome (FAS) (Jones, 1973) is a clinical pattern of anomalies characterized (Lemoine, 1968) by intrauterine growth retardation which commonly continues postnatally, microcephaly, developmental delay, and dysmorphic facies consisting of low nasal bridge, midface hypoplasia, long featureless philtrum, small palpebral fissures and thin upper lip. Cleft palate and cardiac anomalies may also occur. Full expression of this syndrome occurs with chronic daily ingestion of at least 2 grams alcohol per kilogram (8 drinks per day). The full syndrome is present in about one third of these mothers (Council on Scientific Affairs, 1983). The complete fetal alcohol syndrome consists of abnormalities in at least three areas: prenatal and postnatal growth deficiency, central nervous system dysfunction (often including mental retardation) and craniofacial dysmorphology. Various other abnormalities are often involved. The data on women drinking less heavily are more difficult to interpret. At drinking levels greater than two drinks per day, a partial fetal alcohol syndrome not meeting the minimum criteria, termed fetal alcohol effects has been described. Partial effects occur in approximately three-quarters of offspring born to exposed mothers.

Carbamazepine
Exposure to carbamazepine in-utero carries a 1% risk of neural tube defects (Rosa, 1991) (10 times their baseline risk). A pattern of malformations similar to those described with the fetal hydantoin syndrome has also been associated with carbamazepine exposure in pregnancy (Jones et al, 1989; Ornoy and Cohen,1996). Of particular interest is the fact that developmental retardation was observed among offspring of epileptic mothers receiving carbamazepine during pregnancy (Jones
et al.1989, Ornoy and Cohen 1996). These findings are in debate as several investigators (Scolnik et al, 1994) did not observe developmental delay in similarly exposed children (Ornoy and Arnon, 1998).

Chemotherapeutic agents
Cytotoxic drugs given during the first trimester of pregnancy have been associated with a significant increase in the incidence of fetal malformations (Zemlickis, 1992; Buekers, 1998; Sorosky, 1997) as well as with an increased risk of early miscarriages (Barber, 1981).

Cocaine
Cocaine use during pregnancy has been associated with abruptio placenta, prematurity, fetal loss, decreased birth weight, microcephaly, limb defects, urinary tract anomalies, and poor neurodevelopmental performance. The contribution of cocaine to the incidence of congenital malformations is difficult to assess because of methodological problems, which make the results difficult to interpret. Cocaine abuse is often associated with polydrug abuse, alcohol consumption, smoking, malnutrition, and poor prenatal care. Experimental animal studies and human epidemiology indicate that the risk of major malformation from cocaine is probably low, but the anomalies may be severe (Miller et al, 1995, Ornoy and Arnon,1993).

Coumarin anticoagulants
First trimester exposure to coumarin derivatives is associated with a characteristic pattern of malformations termed the fetal warfarin syndrome (DiSaia, 1966; Hall 1980). Clinical features consist of nasal hypoplasia and calcific stippling of the epiphyses. Intrauterine growth retardation and developmental delay due to central nervous system damage, eye defects, and hearing loss have also been described. The critical period of exposure for the fetal warfarin syndrome appears to be between 6 and 9 weeks of gestation. A prospective study found evidence of warfarin embryopathy in about one third of the cases where a coumarin derivative was given throughout pregnancy. Oral anticoagulants are also associated with a high rate of miscarriage. Exposure to oral anticoagulants in the second and third trimesters presents a risk of central nervous system damage due to hemorrhage. Unlike heparin, oral anticoagulants readily cross the placental barrier.

Diethylstilbestrol
Diethylstilbestrol was used in the 1950’s and 1960’s for the diagnosis of recurrent miscarriage. Clear cell adenocarcinoma of the vagina was found to be associated with diethylstilbestrol treatment of the patient’s mother during the first trimester of pregnancy (Herbst, 1971). Over 90% of the cancers occurred after 14 years of age. Clear cell carcinoma has not occurred in women exposed in utero after the 18^th week of gestation. A high incidence of benign adenosis of the vagina was found in women prenatally exposed to this non-steroidal estrogen analogue. In a prospective study, exposure starting at 4 weeks was associated with adenosis in 56% of the offspring, decreasing later to 30% at 16 weeks and 10% at 20 weeks (O’Brien, 1979). It is estimated that the risk of clear cell adenocarcinoma of the vagina and cervix in diethylstilbestrol exposed women younger than 24 years is between 0.14 and 1.4 per 1,000 (Herbst, 1981). The Diethylstilbestrol Adenosis (DESAD) Project reported an incidence of female genital structural changes in approximately 25% of 1,655 women exposed in utero (Jefferies,1984). Miscarriage rate and preterm delivery were significantly more common in women exposed in utero to diethylstilbestrol compared to matched controls (Barnes, 1980). In 134 males exposed in utero to the agent no signs of malignancy were found but 27% had genital lesions (epididymal cysts, hypotrophic testes, or capsular induration of the testes) (Gill, 1976). In 29%, pathologic changes were found in spermatozoa.

Folic acid antagonists: Aminopterin and methotrexate
Aminopterin has been known since 1950 to result in fetal death, which led to its use as a human abortifacient. The fetal aminopterin syndrome was described based on anomalies observed in aborted fetuses and in infants born following unsuccessful attempted pregnancy terminations (Thiersch, 1950). Malformations include central nervous system defects (hydrocephalus, meningomyelocele), facial anomalies (cleft palate, high arched palate, micrognathia, ocular hypertelorism, external ear anomalies), abnormal cranial ossification, abnormalities of first branchial arch derivatives, intrauterine growth retardation and mental retardation. Infants have been born with features of the aminopterin syndrome after pregnancy exposure to methotrexate (methylaminopterin) (Warkany, 1981). It was suggested that the maternal dose necessary to induce defects is above 10 mg per week with a critical period of 6 to 8 weeks post conception being postulated.

Hydantoins (diphenylhydantoin, mephenytoin)
Hydantoins have been associated with a recognizable pattern of malformations termed the fetal hydantoin syndrome (Hanson, 1975). The clinical features include craniofacial dysmorphology (wide anterior fontanelle, ocular hypertelorism, meitopic ridge, broad depressed nasal bridge, short anteverted nose, bowed upper lip, cleft lip, cleft palate), as well as variable degrees of hypoplasia of the distal phalanges, nail hypoplasia and low arch dermal ridge patterning. Growth retardation, mental deficiency and cardiac defects are additional features of the syndrome.

Isotretinoin (13-cis-retinoic acid)
Isotretinoin is a synthetic vitamin A derivative, prescribed for severe cystic acne. It has been proven to be a potent human teratogen as well as a behavioral teratogen when given systemically. A pattern of anomalies termed retinoic acid embryopathy has been associated with isotretinoin (and other retinoic acid derivatives such as etretinate and probably megadoses of vitamin A) exposure in pregnancy (Lammer, 1985). The clinical features include craniofacial anomalies (microtia or anotia, accessory parietal sutures, narrow sloping forehead, micrognathia, flat nasal bridge, cleft lip and palate, and ocular hypertelorism), cardiac defects (primarily conotruncal malformations), abnormalities in thymic development, and alterations in central nervous system development. The risk for associated miscarriage is 40%.

Lithium
By 1983, the International Registry of Lithium Babies had collected retrospective information on 225 babies exposed to lithium during the first trimester. Despite the lack of a control group and the likely over-reporting of abnormal outcome, the data suggested a higher risk for major anomalies than in the general population and a specific risk for cardiac teratogenesis in early gestation. The number of cases of Ebstein’s anomaly, a rare malformation of the tricuspid valve, by far exceeded its spontaneous rate of occurrence (Nora, 1974). In a prospective study (Jacobson, 1992). Of 148 women who took lithium during the first trimester of pregnancy 3 infants were born with major malformations, a rate comparable to that found in the control group. One pregnancy was terminated following prenatal diagnosis of Ebstein’s anomaly. In four case-controlled studies no cases of Ebstein’s anomaly were found among 207 lithium exposed pregnancies as compared with two cases of the defects among 398 nonexposed controls. Cohen et al (1994) concluded that the teratogenic risk of lithium exposure during the first trimester was lower than previously reported. Leonard (1995) suggests that lithium be avoided during the period of cardiac organogenesis i.e. weeks 5-9 of pregnancy. Fetal echocardiography is recommended in the management of pregnancies exposed to lithium in the first trimester.

Misoprostol
Based on a Brazilian case-series there seems to be an association between first trimester exposure to this prostaglandin E1 analogue and limb defects with or without Moebius sequence (Gonzalez, 1993). A recent case-controlled study supports an association between misoprostol use in the first trimester for attempted abortion and subsequent Moebius syndrome in the infants (Pastuszak, 1998). However, the absolute teratogenic risk of misoprostol is probably low (Schuler, 1997).

Thalidomide
More than any other event, the thalidomide tragedy alerted humanity to the teratogenic potential of drugs. Thalidomide was marketed in 1956 and was available for 4 years before its teratogenicity was recognized (McBride, 1961; Lenz, 1962). Thalidomide produced malformations limited to tissues of mesodermal origin, primarily limbs, ears, cardiovascular system, and gut musculature. The types of malformations could be related to the developmental stage of the embryo at the time of ingestion. Malformations resulted from repeated use as well as from a single ingestion during the critical period from the 27^th day to the 40^th after fertilization. In women, a single dose of less than 1 milligram per kilogram has produced the syndrome. Abnormal development of long bones produced a variety of limb reduction defects. Typically, the upper limbs were more severely involved than the lower limbs. However, any of the bones could be defective or, in severe cases, totally absent. Phocomelia, polydactyly, syndactyly, oligodactyly were all reported. Lower extremities could be similarly affected, although less frequently and less severely. Defects of the external ears ranging from agenesis to preauricular tags occurred in 20% of cases and were the earliest of the recognized thalidomide anomalies. Other anomalies associated with phocomelia are facial capillary hemangiomas and palsies of cranial nerves VI or VII. A wide variety of cardiovascular defects were seen, affecting about 10% of infants. Visceral anomalies included agenesis of kidneys, spleen, gallbladder and appendix and atresia or stenosis of the esophagus, duodenum and anus. Cleft palate was a rare complication. The central nervous system was not adversely affected as reflected by normal intelligence. It has been estimated that the embryopathy was found in about 20% of the pregnancies with exposure to thalidomide in the susceptible period. Thalidomide is effective in the treatment of erythema nodosum leprosum. Leprosy accounts for most of its current use worldwide, leading to ongoing occurrence of birth defects caused by thalidomide in South America (Castilla, 1996). In recent years its indications were extended to a wide variety of medical conditions (D’Amato, 1994; Powell 1996) including the wasting of AIDS.

Trimethadione, paramethadione
In utero exposure to trimethadione or paramethadione has been associated with a pattern of congenital malformations termed fetal trimethadione syndrome (German, 1970). Numerous subsequent cases were reported with similar findings, consisting of characteristic craniofacial anomalies, growth retardation and delayed psychomotor development, clefting and congenital heart defects. The incidence of fetal loss was also increased compared with that seen in the general epileptic population (Anderson 1976). Because trimethadione and paramethadione have demonstrated fetal risk greater than other anticonvulsants, their use in women of childbearing age should be abandoned.

Valproate
First trimester exposure to valproic acid or its sodium salt is associated with neural tube defects and carries a 1-2% risk of meningomyelocele, primarily lumbar or lumbosacral (Robert, 1982; Lammer, 1987). Recently, this risk assessment was challenged by Martinez-Frias (1999) suggesting a risk of 3-4% for spina bifida following exposure to valproic acid. A number of investigators have delineated an associated pattern of malformations which they termed the fetal valproate syndrome (DiLiberti, 1984). The clinical features include narrow bifrontal diameter, high forehead, epicanthal folds, infra-orbital creases, telecanthus, low nasal bridge, short nose with anteverted nares, midfacial hypoplasia, long philtrum, thin vermillion border, small mouth, cardiovascular defects, long fingers and toes, hyperconvex fingernails, and cleft lip.

Intrauterine infections

The incidence of intrauterine infections ranges between 3% and 15%. In the past, the most common intrauterine infection with a teratogenic agent was rubella. Today, because of effective immunization programs against rubella, the most common infection is that apparently caused by cytomegalovirus (CMV). In infants who are small for their gestational age, the incidence of intrauterine infections seems to be higher.

Intrauterine infections with long-term fetal sequellae may be viral, parasitic, and bacterial. The more common intrauterine infections have a viral cause. There are two modes of transmission of the infection to the embryo: hematogenous spread from the maternal circulation through the placental barrier and then to the fetal circulation, and ascending infection from the mother through the fetal membranes with direct contamination of the amniotic fluid (Ornoy and Arnon,1993). Villitis and deciduitis are common placental pathological manifestations in cases of hematogenous spread, whereas chorioamnionitis and funisitis are found in ascending infections. Cases of suspected intrauterine infections are initially evaluated on the basis of their clinical findings and by measuring the serum levels of maternal specific antibodies during pregnancy, but it is often difficult to evaluate the significance of antibody levels (Hagay et al,1996 ).

In intrauterine infections with CMV and toxoplasmosis, distinct clinical manifestations are seen only rarely in the mother. Moreover, a maternal rise in levels of specific antibodies is diagnostic for maternal and not necessarily for fetal infection. To diagnose fetal infection, the infective agent should be identified in the amniotic fluid by culture or by the presence of specific DNA or RNA demonstrated by polymerase chain reaction (PCR) on amniotic fluid cells, or by specific IgM found in fetal blood following percutaneous umbilical blood sampling. These tests should be done after 22 weeks gestation, to avoid false-negative results. At birth, specific cord blood IgM or typical clinical findings (or both) are the most relevant diagnostic tools (Ornoy and Arnon, 1996).

Cytomegalovirus
Cytomegalovirus produces a clinical syndrome (cytomegalic inclusion disease) consisting of intrauterine growth retardation and microcephaly. In addition, there may be chorioretinitis, seizures, blindness and optic atrophy. In the neonatal period, hepatosplenomegaly, jaundice and thrombocytopenia may develop.

It is accepted that 0.5%-2.5% of newborn infants are infected with CMV in utero and excrete cytomegalic virus in their secretions. Of those at least 10% will have clinical signs of intrauterine infection. Of the remaining 90% that are asymptomatic at birth 10%-15% will develop symptoms such as deafness, chorioretinitis and mental deficit later in life (Hagay et al. 1996).

Epstein-Barr virus
Most studies have not proved any association between Epstein-Barr virus infection in utero and an increased incidence of malformations. Cases of prenatal Epstein-Barr virus infection and infants born with malformations have been reported, however. These include infants with cataracts, several infants with congenital heart defects, and infants with diffuse myocarditis. In addition, another cohort study reported on a statistical increase in prematurity, growth retardation, and fetal death. The added risk of malformations in an infant after prenatal exposure to Epstein-Barr virus appears to be minimal, however (Ornoy et al. 1982 Ornoy and Arnon,1993).

Rubella
The congenital rubella syndrome, originally described by Gregg in 1941, consisted of heart disease, deafness, and cataracts. Rubella embryopathy includes intrauterine growth retardation, encephalitis, radiographic changes in the long bones, and continued infection in the infant for months after birth. After birth findings of hepatosplenomegaly, obstructive jaundice and thrombocytopenic purpura are common. Long-term sequellae include mental retardation, neurologic deficits, and behavioral abnormalities. Children unaffected at birth may later have deterioration of hearing or mental functions, as the infections tend to be chronic. In addition, older persons may have late sequellae such as diabetes mellitus or progressive rubella panencephalitis. Rubella during very early stages of pregnancy results in a high rate of early spontaneous abortion (Aboudy et al,1997, CDC, 1989).

Syphilis
In utero exposure to syphilis may result in congenital malformations, prematurity, or stilbirth. The characteristic clinical findings in infants with congenital syphilis include hepatosplenomegaly, osteochondritis or periostitis, jaundice, petechiae or purpuric skin lesions, lymphadenopathy, hydrops, edema, ascites, rhinitis, pneumonia, myocarditis, nephrosis, and bulbar pseudo paralysis. Maternal antibiotic treatment reduces the extent of fetal damage (Ray, 1995).

Toxoplasmosis
The clinical features of congenital toxoplasmosis in severely infected infants include encephalitis, hydrocephalus, intracranial calcifications, chorioretinitis, erythroblastosis, anemia, jaundice, hepatosplenomegaly, glomerulitis, myocarditis, and myositis, as well as increased neonatal mortality. Central nervous system damage is found in almost all affected cases. Manifestations of the disease, which may appear later in infancy, include seizures, mental retardation, cerebral palsy, deafness, and blindness.

The best way to diagnose intra-uterine toxoplasma infection seems to be by PCR in the 22^nd week of pregnancy (Hohfield et al. 1994). In proven intrauterine infection the risk for fetal anomalies is about 10% (from 6%-20%). Antibiotic treatment (spiramycine) of the infected mother will decrease the extent of fetal damage (Berrebi et al. 1994, Hohfield et al. 1994).

Varicella-zoster virus
An unusual array of abnormalities has been described in infants with in utero exposure to varicella. The features include skin lesions, fetal growth retardation, limb hyopoplasia brain and eye defects. Cerebral and cerebellar atrophy, seizures, developmental delay, and nerve palsies are common. Many of the affected newborns die in infancy. The highest risk to the fetus following transplacental exposure to varicella zoster virus is at weeks 13-20 of pregnancy. Primary varicella zoster infection to the pregnant mother at that time may result in 2-3% of fetal anomalies. Recurrent infection does not apparently cause fetal anomalies (Enders et al. 1994, Mouly et al. 1997).

Immunization
Immunization with attenuated live viruses during pregnancy does not seem to have any adverse effect on the fetus. This includes polio vaccine, measles, mumps, hepatitis yellow fever, and even rubella (CDC, 1989, Ornoy et al, 1989). Despite the fact that there is no report of increased congenital anomalies with these immunizations, it is advisable to use them during pregnancy only when there is a substantial risk of maternal infection

Diabetes mellitus
The most important maternal disease causing an increased incidence of fetal congenital anomalies is diabetes mellitus, especially insulin-dependent diabetes mellitus (type I). The rate of congenital anomalies among the offspring of women with diabetes increases in direct relation to the severity of the disease. In women with type I diabetes and nephropathy, retinopathy, or both, the incidence of malformations may be three to four times higher than in the general population. It is important for pregnant women with diabetes to achieve strict control of their blood glucose levels as early as possible, preferably before conception. Because most congenital anomalies occur during the first 3 months of gestation, the control of the disease after that period will not reduce the rate of anomalies. Even good control of diabetes during pregnancy will still result in a higher-than-normal incidence of congenital defects in the offspring.

We recently conducted developmental studies on 57 school age children born to diabetic women and found normal cognitive function when compared to pair-matched controls (Ornoy et al. 1996). However, fine and gross motor functions were slightly abnormal and there was a high rate of minor neurological dysfunction and inattention. Similar findings were observed among 37 school age children born to women with gestational diabetes (Ornoy et al. 1999).

Epilepsy
Epilepsy during pregnancy carries an increased risk of maternal seizures. Maternal seizures themselves can pose hazards to the woman and her offspring. Congenital malformations are seen in 4-6% of infants born to epileptic mothers (Yerby, 1996). There is evidence that epilepsy per se is associated with an increased risk for malformations even when anticonvulsants are not used. Schardein (1993) has reviewed studies in epileptic women and in most of them untreated epileptic women had a tendency for a higher rate of malformations up to two-fold that of controls.

Sickle Cell Disease (SCD)
SCD poses considerable risks for both the woman and her infant (Koshy, 1991). An extensive review comparing maternal and perinatal outcomes from before and after 1972, reported a decline of maternal mortality from 6% to 1% in these two periods (Powars, 1986). A recently published report on maternal and fetal outcomes of pregnancy in women with SCD provided data on 320 pregnancies to 155 women with SCD. Non-sickle cell related antepartum and intrapartum complication rates were comparable with those of African-American women who did not have SCD (Smith, 1996).

Malaria
Malaria during pregnancy is often associated with high fever. Therefore, in addition to the possible adverse effects of the parasites on the fetus, for which we have very little knowledge, there is the possibility of hyperthermia-induced fetal damage (Ornoy and Arnon,1993). It is therefore important to treat pregnant women with malaria by proper antiparasitic therapy and to carefully reduce the fever. 'As a rule, most antimalaria drugs are safe in pregnancy.'

Prevention
As a part of the regulatory process after the devastating effects of thalidomide, the teratogenic potential of drugs has to be tested in pregnant laboratory animals. The standard teratogenicity testing in animals prevented a post-marketing disaster in the case of isotretinoin but it also has severe limitations. Data from animal studies cannot be simply extrapolated to humans. Differences exist in pharmacokinetics, embryology, target organ sensitivity, as well as in other aspects. Pharmacologic prediction based on chemical structure, as a predictor of teratogenicity, is another potential mechanism for prevention of human teratogenicity. In vitro testing may also play a role in prevention. Human monitoring is another defense mechanism. It may be carried out at an early stage (embryonic or fetal loss, stillborn infants, newborn infants) or at a late phase, as in the case of diethylstilbestrol and vaginal adenosis. Amniocentesis and chorionic villous sampling are techniques for prenatal diagnosis of chromosomal and other disorders. Fetal ultrasonography is an important tool in the prenatal detection of defects. 'Biochemical and molecular biology screening methods are available for the diagnosis of many genetic disorders.'  There is evidence for the important role of periconceptional folic acid supplementation in prevention of both recurrence and first occurrence of neural tube defects. The Teratogen Information Services (TIS) also contribute to the prevention of environmentally induced birth defects.

Teratogen Information Services
Over the past few years, public awareness of the possible risk to the developing embryo and fetus following in utero exposures to environmental agents has been growing. This has led to a need for teratogen information services as a part of comprehensive prenatal care programs. Teratogen information regarding the effects of chemical, physical, or infectious agents on fetuses is given to pregnant women and physicians or other professionals in the medical and paramedical services. The risk evaluation following each exposure takes into account the developmental stage of the embryo or fetus at exposure, the duration of exposure, the dosage, and the medical history of the mother and family. Most of the services are telephone services, with the caller being interviewed in person in a clinic only rarely. In most cases, the risk evaluation can be given directly to the caller during the first phone call. In other cases, a more thorough review of the literature is necessary, and the caller is requested to call back within a few days. Some services also send a written response summarizing the case, the risk evaluation, and any recommendations for prenatal testing. In cases with high risk for fetal adverse effects, pregnancy termination may be advised. In our TIS, counseling is mostly performed over the telephone. A letter with a risk estimate is sent, in most cases, to the caller. The experience in our TIS in Jerusalem, now starting its eleventh year, involves about 26,000 calls. Of them, 75% were due to exposure to drugs, 9% were following exposure to diagnostic irradiation, 6% were suspected to have intrauterine infection, 5% were due to vaccination and 2% were following exposure to environmental pollutants. We found that in about 76% of calls, the exposures did not increase the risk of malformations to the conceptus. In 17% there was a slight (less than 1%) increase in the risk of malformations. In 6% of the calls, there was a substantial increase in the risk of congenital anomalies, and the callers were informed of this increased risk and advised what to do. The main roles of a TIS are, alleviation of women's fears in regard to exposure during pregnancy, whenever appropriate, and prevention of unnecessary terminations of otherwise wanted pregnancies.  Hopefully, it also improves prenatal diagnosis of defects and reduces the number of infants born with congenital anomalies.

For personal use. Only reproduce with permission from SIEP.

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