Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.

Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n=2/89, 2.25%) was in keeping with the expected background rate (2-4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study.

BACKGROUND: Proton pump inhibitors are used to treat gastro-oesophageal reflux and peptic ulcers. Gastro-oesophageal reflux is a common condition in pregnancy. Human pregnancy experience with lansoprazole or pantoprazole is very limited. More data exist on the safety of omeprazole in pregnancy. AIM: To assess the safety of proton pump inhibitors in pregnancy. METHODS: The rate of major anomalies was compared between pregnant women exposed to omeprazole, lanzoprazole, or pantoprazole and a control group counselled for non-teratogens. The study design is a multicentre (n = 8), prospective, controlled study of the European Network of Teratology Information Services. RESULTS: We followed up 295 pregnancies exposed to omeprazole [233 in the first trimester (T1)], 62 to lansoprazole (55 in T1) and 53 to pantoprazole (47 in T1), and compared pregnancy outcome to that of 868 European Network of Teratology Information Services controls. The rate of major congenital anomalies did not differ between the exposed and control groups [omeprazole nine of 249 (3.6%), lansoprazole two of 51 (3.9%) and pantoprazole one of 48 (2.1%) vs. controls 30 of 792 = 3.8%]. No differences were found when exposure was limited to the first trimester after exclusion of genetic, cytogenetic or infectious anomalies. CONCLUSIONS: This study suggests that proton pump inhibitors do not represent a major teratogenic risk in humans.

Adverse effects of prenatal methimazole exposure.

BACKGROUND: A specific phenotype of methimazole (MMI) induced malformations has recently been postulated. MMI embryopathy is characterized by minor dysmorphic features, choanal atresia and/or esophageal atresia, growth retardation, and developmental delay. METHODS: We prospectively studied the outcome of pregnancy in 241 women counseled by 10 Teratology Information Services (TIS) of the European Network of Teratology Information Services (ENTIS) because of MMI exposure, and compared them with those of 1,089 pregnant women referred to TIS because of exposure to nonteratogenic drugs (control group). Information was obtained by mail or telephone interview. RESULTS: There was no increase in the general rate of major anomalies or of spontaneous or induced abortions in the MMI-exposed group in comparison with the control group. Two newborns were affected with one of the major malformations that are part of the postulated embryopathy. CONCLUSIONS: The results of this study indicate that choanal as well as esophageal atresia may have a higher incidence than expected in fetuses exposed to MMI between 3 and 7 gestational weeks. Until further data are available, thyrotoxicosis should be treated with propylthiouracil, as it is apparently safer for use during the fertile period.

Genetic and teratogenic effects of cancer treatments on gametes and embryos.

Male and female germ cells vary in their sensitivity to the mutagenic effects of chemotherapy and radiotherapy, depending on their stage of maturation and the agent used. Although sperm DNA damage exists following treatment, no increase in genetic defects or congenital malformations was detected among children conceived to parents who have previously undergone chemotherapy or radiotherapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk; hence caution should be exercised. In female cancer patients, miscarriage and congenital malformations are not increased following chemotherapy. However, when IVF and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence the babies should be screened. During pregnancy, the potential teratogenic effects of chemotherapy influence the choice and timing of therapy. Termination is usually recommended in the first trimester. Second- and third-trimester exposure does not usually increase the teratogenic risk and cognitive development, but it may increase the risk of poor obstetric outcome and fetal myelosuppression. During the first two weeks after fertilization of the embryo, radiation is lethal but not teratogenic. High doses of radiation during pregnancy induce anomalies, impaired growth and mental retardation, and there may be an increased risk of childhood leukaemia and other tumours in the offspring.

Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies.

The Israeli Teratogen Information Service prospectively followed up 210 pregnancies with first trimester carbamazepine exposure. Pregnancy outcome was compared with that of two overlapping controls, matched and general (n = 629), exposed to nonteratogenic agents. Our study suggests a twofold increase in the rate of major congenital anomalies (12/160 [carbamazepine] versus 18/560 [general control]; relative risk 2.24; 95% CI 1.1-4.56) and a birth weight reduction of approximately 250 g after in utero exposure to carbamazepine.

Pregnancy outcome after gestational exposure to metronidazole: a prospective controlled cohort study.

BACKGROUND: Metronidazole is an important antibacterial agent commonly used in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The objective was to examine the fetal safety of metronidazole. METHODS: The Israeli Teratogen Information Service prospectively collected and followed up 228 women exposed to metronidazole in pregnancy, 86.2% of whom with first-trimester exposure. Pregnancy outcome was compared with that of a control group, who were counseled during the same period for nonteratogenic exposure. RESULTS: There was no difference in the rate of major malformations between the groups (3/190; 1.6% [metronidazole] vs. 8/575; 1.4% [control], P = 0.739). The rate of major malformations did not differ between the groups even after including elective terminations of pregnancy due to prenatally diagnosed malformations (5/192; 2.6% [metronidazole] vs. 12/579; 2.1% [control], P = 0.777). A reduced neonatal birth weight was found in the metronidazole group compared with controls without significant differences in the rate of prematurity or in gestational age at delivery. The mean birth weight was lower in the metronidazole group when comparing the subgroup of term infants. CONCLUSIONS: This study confirms that metronidazole does not represent a major teratogenic risk in humans when used in the recommended doses.

The use of psychiatric drugs in pregnancy and lactation.

To help determine which drugs can be used with relative safety during pregnancy, we reviewed the literature on the possible teratogenic, perinatal, behavioral or developmental effects of the various groups of commonly used psychiatric drugs, and their effects on lactation. Tricyclic antidepressants, fluoxetine, phenothiazines, and most benzodiazepines are not considered to be teratogenic and may be used during pregnancy. All anti-epileptic drugs seem to have an embryotoxic and teratogenic potential and we recommend, if possible, avoiding these drugs. Lithium administration during the first trimester of pregnancy increases the risk of cardiac malformations, but the risk is not as high as originally reported. Therefore lithium may be continued whenever it seems to be the "drug of choice" if fetal echocardiography and ultrasonography are performed. There is a lack of information on the teratogenic effect of the newer drugs, and in spite of the fact that similar "older" drugs do not seem to adversely affect the fetus, they should be used with care. Although the data on the development of children following in-utero exposure to psychiatric drugs is limited, there seems to be no evidence of any long-term adverse effects on the development of children exposed to most psychotropic medications. However, children exposed in utero to anti-epileptic drugs may exhibit long-term developmental problems. Most of the drugs are detected in breast milk only at low concentrations. In nursing women taking these drugs, breastfeeding is possible. The infant should be carefully monitored for any clinical side effects and whenever observed, nursing should be discontinued. In light of our knowledge today, there seems to be only rarely an indication for pregnancy interruption following maternal exposure to psychiatric drugs during pregnancy.

First trimester exposure to cefuroxime: a prospective cohort study.

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.

Prospective, controlled, multicentre study of loperamide in pregnancy.

BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies. OBJECTIVES: To determine whether loperamide use in pregnancy is associated with an increased risk of major malformations. The secondary end points were rates of minor malformations, spontaneous and therapeutic abortions, and premature births, and mean birth weights. PATIENTS AND METHODS: Women counselled by five teratogen information centres on the safety and risk of loperamide in pregnancy were followed after delivery and compared with a similar group of women matched for age, smoking, alcohol and other exposures. RESULTS: One hundred and five follow-ups were completed; 89 of the women were exposed to loperamide in the first trimester of pregnancy. There were no statistically significant differences between the study group and the control group in any of the end points that were analyzed. However, of women who took loperamide throughout their pregnancy, 21 of 105 had babies who were 200 g smaller than babies in the control group. CONCLUSIONS: The results of this study suggest that the use of loperamide during pregnancy is not associated with an increased risk of major malformations.

Exposure to yellow fever vaccine in early pregnancy.

We report on a data collection concerning exposure to yellow fever vaccine (YFV) during early pregnancy, ascertained through the European Network of Teratology Information Services (TISs) and the Pharmacovigilance Department of Pasteur Merieux Connaught (PMC). Six TISs had had no inquiry about YFV. Five submitted prospectively collected cases. Seventy-four cases were analyzed, 58 with a completed follow-up. Pregnancies ended in 46 births, five voluntary abortions and seven spontaneous abortions. Three newborns had minor anomalies and two had major defects (ureteral stenosis and triphalangeal hallux). Although the sample is too small to rule out a moderate increased risk of adverse reproductive effect of YFV, it gives no argument for such an effect and should lead to reassure pregnant women who might be inadvertently vaccinated.

[The Israel Teratogen Information Service: a report of the last ten years with 20,613 calls].

The Israel Teratogen Information Service (TIS) was established 10 years ago with the help of the Ministry of Health and the Hebrew University-Hadassah Medical School. During these 10 years we have had 20,631 calls. We describe the results of our experience in counseling. There was a gradual increase in the number of calls, which in 1997 reached 4,447. Most calls (84.5%) were during pregnancy, while 12% were prior to pregnancy. In 75.7% the calls were due to drug exposure during pregnancy; 10.9% were due to exposure to X-rays; there was maternal infection in 6.6% and in 5% immunization during pregnancy. The callers were: physicians in 46.6%, nurses 18.9%, pregnant women 39.5%, and 4.8% others. In 76.6% there was no additional risk to the embryo or fetus and in 17.4% there was a small additional risk of less than 1%; a significant additional risk to the fetus was expected in only 6%. In 3625 pregnant women with known outcome there were 8.9% spontaneous and 9.2% induced abortions. Of the 2968 live-born children, 2.3% were malformed, a rate similar to that among controls. The information provided by the TIS alleviated the fears most pregnant women have, and reduced unnecessary terminations of pregnancy planned because of unjustified fear of the teratogenic effects of agents to which women were exposed. It reduced the number of children born with congenital anomalies, since pregnancies were interrupted whenever there was a high risk for congenital anomalies.

Is benzodiazepine use during pregnancy really teratogenic?

Benzodiazepines (BDs) have a widespread use among people suffering from anxiety. These drugs easily cross the placenta and may affect the developing embryo and fetus. The literature is divided as to whether BD may cause an increase in spontaneous abortions or congenital anomalies. From the years 1988 to 1996, 756 women called the Israeli TIS concerning exposures to BD prior to or during pregnancy. Of 599 women who called us during pregnancy, we have follow-up information on 460 pregnancies (76.6%). The incidence of congenital anomalies (3.1%) was not different from that found in 424 control pregnancies (2.6%). There was a significantly higher incidence of induced abortions (14.1% vs. 4.7%, P = 0.00) and of spontaneous abortions (8.7% vs. 5.2%, P = 0.01). From an examination of our results, it does not appear that BD during pregnancy caused an increase in the incidence of birth defects. There was no specific defect in the offspring. The increase in the rate of induced abortions is probably related to the counseling of the callers, and the increase in spontaneous abortions seems to be a result of the lower gestational age at the time of counseling in the women exposed to BD. It is unknown whether BD could be responsible for developmental or behavioral problems, which are observed only at a later stage.

The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS).

The European Network of the Teratology Information Services (ENTIS) has collected and evaluated data on 689 pregnancies in which exposure to tricyclic and nontricyclic antidepressants occurred. Data were collected prospectively from the time of in utero exposure and all the cases were followed up to the first few weeks of postnatal life using standardized procedures. In most cases, no longer term follow-up data were available. Approximately two-thirds of the mothers were on multidrug therapy, and of those, half took a benzodiazepine. About 95% of the patients were exposed during the first trimester. The most striking feature of the pregnancy outcomes is that 97% of live-born babies were morphologically normal. The incidence of spontaneous abortion and late fetal/neonatal deaths were within the normal range. Fourteen live-born babies and one fetus had either major or minor malformations, and six had minor anomalies. However, there was no increase in either a particular type of malformation or a specific pattern of defects. Another 31 infants without malformations had neonatal problems; these were usually associated with chronic multidrug therapy, especially near term. Elective termination of pregnancy occurred more frequently in the multidrug groups (86 out of 488) than in the monotherapy groups (20 out of 201), but data concerning the condition of the fetus are not available in the majority of the cases. Overall, no causal relationship could be established between in utero exposure to antidepressants and adverse pregnancy outcome.

Clinical teratology counseling and consultation case report: outcome of pregnancy after failure of early induced abortions.

PIP: In 1992 in Israel, a woman in whom a missed early abortion (blighted ovum) was diagnosed underwent a dilatation and curettage procedure during the seventh week of pregnancy. When it was determined that the pregnancy was not terminated, it was allowed to continue until week 24 when suspected severe intrauterine growth retardation (IUGR) led to induction of labor and delivery of a female fetus with severe asymmetric IUGR, no congenital abnormalities, and a normal skeleton. Four other cases of failed pregnancy interruption between 1991 and 1994 ended in the delivery of normal infants at weeks 37, 39, and 40, and fetal death complicated by the development of a hydatidiform mole. Most cases of failed induced abortion occur in early abortions, and most women will return for another procedure. In most cases of failed abortion, damage to the placenta will result in damage to the fetus. The most likely cause of IUGR in the case described above was vascular disruption of the placenta due to the curettage. These rare occurrences of failed induced abortion are associated with a high emotional, physical, and legal cost.^ieng

Clinical teratology.

The field of teratology has become increasingly important in preventive medicine programs. By avoiding specific teratogenic agents, many birth defects can be prevented. In this review we will summarize the currently documented teratogenic agents in humans.

Ultrastructure and function of the rat yolk sac: damage caused by teratogenic anti-VYS serum and recovery.

It was hypothesized that heterologous anti-rat visceral yolk sac serum (AVYS) exerts its teratogenic effect by reducing the endocytosis of serum proteins by the visceral yolk sac (VYS), thus reducing the supply of amino acids to the embryo and VYS. To evaluate this hypothesis, we studied the effect of teratogenic AVYS on the endocytic function of the VYS and the ultrastructure of the VYS and parietal yolk sac (PYS). Rat conceptuses were exposed to a teratogenic dose of AVYS on the 10th day of gestation in vivo or in vitro. Control and AVYS-exposed specimens were collected 24-192 hr later and prepared for scanning and transmission electron microscopy (SEM and TEM, respectively) utilizing standard procedures. The Endocytic Index was calculated for the VYS utilizing standard procedures. Approximately 97% of the in vivo exposed and 94% of the in vitro exposed embryos were morphologically abnormal. Ultrastructural observations showed that exposure to AVYS in vivo or in vitro caused severe damage to the VYS endodermal epithelial cells with loss of cellular borders, reduction in the number and length of microvilli, and increased cellular inclusions; and some damage to PYS endodermal cells with increased blebbling and decreased cell number. Recovery was evident at 72 hr and complete by 96 hr. The Endocytic Index was significantly reduced in the VYS 24 and 48 hr after injecting AVYS into the pregnant rat but was not significantly different at 96 and 192 hr. Our results show that the AVYS antiserum damaged visceral endodermal epithelium experienced ultrastructural recovery with parallel functional recovery. These studies suggest that transient yolk sac placental ultrastructural damage and dysfunction was probably sufficient to cause irreversible damage to the developing embryo during early organogenesis. We conclude that the proximate effect of the AVYS was on the plasma membrane of the visceral endoderm and that decreased pinocytosis is a consequence of this effect.

[Teratological counseling in Israel].

For the past 6 years this laboratory has offered counseling on external factors which may harm the fetus. The number of calls on the service doubles yearly. From 1987 through the first half of 1990 there were 1182 calls, about half from women and half from physicians, nurses, geneticists, etc., most during the first trimester. In 88% there was no increased risk for congenital malformations as a result of the exposure, or the increased risk was minimal. In only 6% of cases was there significant increased risk, well above the 3% found in pregnancies in general. In 6% we were not able to assess accurately fetal risk, although we could assume it was relatively small. Outcome of pregnancy was available in 27% of the cases. There was no increase in spontaneous abortions, prematurity, or congenital anomalies in pregnancies in which we had decided there was no increased risk for malformations. However, the number of cases is still too small for significant conclusions. Reliable information concerning factors which may influence the fetus is important in allaying fear and anxiety in families in which fetal risk is not increased. In cases in which fetal insult is suspected, appropriate means of prenatal diagnosis are suggested, and the option of terminating pregnancy is offered.

Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs.

A term amelic female infant was born to an apparently nonconsanguineous Arab Moslem couple. This was followed by the birth of 4 normal children. Afterwards, in 2 subsequent pregnancies, 2 amelic fetuses were diagnosed by transabdominal ultrasonography in the 18th and 12th week of gestation. Pregnancies were terminated and on autopsy both amelic fetuses had severe lung hypoplasia and aplasia of the peripheral pulmonary vessels. The first fetus also had apparently low-set ears and micrognathia, whereas the last had hydrocephaly and left cleft lip beside the lung hypoplasia and aberrant pulmonary artery. This appears to be a new autosomal recessive malformation syndrome.

An evaluation of the polymerase chain reaction in HIV-1 seronegative men.

The apparent detection of human immunodeficiency virus (HIV-1) DNA by the polymerase chain reaction (PCR) in seronegative individuals has been the subject of great concern. In this study, 324 seronegative participants in the San Francisco Men's Health Study were evaluated for evidence of infection using a PCR testing algorithm with multiple amplifications targeting different regions of the HIV-1 genome. While most PCR reactions were negative, 8.6% of the specimens showed weak reactivity with one or more primer sets. However, all were negative with at least one primer set and no definitively positive specimens were identified. This study addressed the possibility that some of these PCR reactions might represent latent infection or abortive exposure, leaving residual integrated DNA, rather than false-positive reactions. The frequency of such reactions was determined in homosexual men who have been at risk for HIV-1 infection and in exclusively heterosexual men who have little or no past exposure. The results demonstrate an identical frequency and distribution of equivocal PCR reactions in both populations. Assuming that there is minimal HIV-1 infection among seronegative heterosexual men in San Francisco, we conclude that PCR testing does not provide evidence for a reservoir of occult HIV-1 infection in seronegative homosexual men.