Better data needed from pregnancy registries

This article is a consensus position statement from the Research Committee of the Organization of Teratology Information Specialists (OTIS). The Committee believes that more specific information on the timing and dose of drug exposures from pregnancy birth defect registries sponsored by pharmaceutical companies (herein called pregnancy registries) would improve the estimation of risk for developmental toxicity (i.e., growth alteration, structural anomalies, functional/neurobehavioral deficits, or death). Specifically, the Committee believes that the exposure timing should be stated in gestational weeks and days rather than simply weeks. In addition, the Committee believes that the exposure dose should be stated in patient‐specific terms, such as body weight (mg/kg) or body surface area (mg/m²) rather than simply dose strength. Although the focus of this position is pregnancy registries, it also is applicable to any source of medication‐induced embryo‐fetal toxicity. Birth Defects Research (Part A), 2009. © 2008 Wiley‐Liss, Inc.     

Human teratogens update 2011: Can we ensure safety during pregnancy?

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer‐generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is “safe” for use during pregnancy. In the absence of adequate, well‐controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus. Birth Defects Research (Part A), 2012. © Published 2012 Wiley Periodicals, Inc.     

Human teratogens update 2011: can we ensure safety during pregnancy?

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is "safe" for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus.     

Arrhenius thermodynamics and birth defects: Chemical teratogen synergy. Untested,testable, and projected relevance

This article addresses the issue of hyperthermia‐induced birth defects with an accompanying additional teratogen, be it a chemical or a physical agent (i.e., a simultaneous “combinational” exposure to two teratogens, one of which is hyperthermia). Hyperthermia per se is a recognized human and animal teratogen. An excellent example of such combinational exposures is an epileptic woman who becomes pregnant while taking valproic acid (VPA) to control seizures. VPA is a recognized chemical teratogen, and fever (hyperthermia) is not an uncommon event during pregnancy. While VPA also may occasionally induce fever as a side effect, we are concerned here with fevers arising from other, unrelated causes. There is a small but internally consistent literature on these combinational‐teratogen exposures involving hyperthermia plus a chemical teratogen; in each instance, the effect level has been observed to be synergistically elevated above levels induced by the separate teratogenic components. The data were empirical. The observed synergy is, however, consistent with Arrhenius thermodynamics, a well‐known chemical rate equation. The need for information about combinational teratogen exposures is acute; fever is a common occurrence during pregnancy; and there are many instances whereby there is also the simultaneous presence of some other teratogen(s). Given that the rate of autism spectrum disorders in the United States was recently presented as 1 in 88 births, it seems reasonable to suspect that such combinational regimens are much more prevalent than previously thought. Our hypothesis is that synergistic birth defect levels from combinational regimens are consistent with Arrhenius thermodynamics. Birth Defects Research (Part C) 99:50–60, 2013. © 2013 Wiley Periodicals, Inc.     

Postmarketing surveillance for human teratogenicity: a model approach.

BACKGROUND: Most congenital defects associated with prenatal exposures are notable for a pattern of major and minor malformations, rather than for a single major malformation. Thus, traditional epidemiological methods are not universally effective in identifying new teratogens. The purpose of this report is to outline a complementary approach that can be used in addition to other more established methods to provide the most comprehensive evaluation of prenatal exposures with respect to teratogenicity. METHODS: We describe a multicenter prospective cohort study design involving dysmorphological assessment of liveborn infants. This design uses the Organization of Teratology Information Services, a North American network of information providers who also collaborate for research purposes. Procedures for subject selection, methods for data collection, standard criteria for outcome classification, and the approach to analysis are detailed. RESULTS: The focused cohort study design allows for evaluation of a spectrum of adverse pregnancy outcomes ranging from spontaneous abortion to functional deficit. While sample sizes are typically inadequate to identify increased risks for single major malformations, the use of dysmorphological examinations to classify structural anomalies provides the unique advantage of screening for a pattern of malformation among exposed infants. CONCLUSIONS: As the known human teratogens are generally associated with patterns of structural defects, it is only when studies of this type are used in combination with more traditional methods that we can achieve an acceptable level of confidence regarding the risk or safety of specific exposures during pregnancy.     

Measurements of birth defect prevalence: Which is most useful as a comparator group for pharmaceutical pregnancy registries?

Pharmaceutical pregnancy registries document birth defects and other complications reported in pregnancies exposed to specific medications or diseases. A baseline estimate of birth defect prevalence is necessary for comparison. To identify potential teratogenic signals, the pregnancy registry must have a comparator that most closely matches the exposed population and data collection methodology, which are characteristics that vary among the multiplicity of birth defect surveillance systems. The system that yields the most accurate prevalence data may be different from that most closely matching the pregnancy registry methods. State public health programs have highly accurate and precise statistics, but their populations are broader than those of a pharmaceutical pregnancy registry. Large collaborative databases may have a more useful covered population, but there are secondary problems related to data precision. Health care databases enroll large numbers of patients and have good information about exposures and health problems, but the data can be difficult to access and lack useful detail. Exposure‐related databases are closer in population definition and collection methods, though the presence of different diseases and exposures can be problematic. Internal comparators are likely to be most useful in formal statistical analysis, but added cost and management burden and may require significantly increased registry enrollment. There is no ideal comparator, and this must be taken into account when planning a single‐exposure or single‐disease pregnancy registry. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

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.     

Unintended pregnancies and exposure to potential human teratogens

BACKGROUND: We aimed to investigate the risk factors associated with unintended pregnancies as well as the association between unintended pregnancies and potential teratogenic exposures. METHODS: A cross-sectional survey was performed among women attending the Maternity School of the Samsung Cheil Hospital and Women's Health Care Center in Seoul, Korea. Demographic data, obstetric history, socioeconomic status, intention to become pregnant, and exposure to potential teratogens were obtained. RESULTS: A total of 1354 women with median age of 29 years and median gestational age of 29 weeks were included. Of these, an educational level above high school was 74.2%, primigravida was 77.3% and unintended pregnancy was 48%. In the logistic regression analysis, women younger than 24 years of age had a relative risk (RR) of 2.5 (95% confidence interval [CI], 1.3-4.7) of having an unintended pregnancy and women with lower household monthly income level had a RR of 1.3 (95% CI, 1.0-1.6). Women with unintended pregnancies had an RR of 1.9 (95% CI, 1.5-2.5), 3.0 (95% CI, 2.0-4.5), 1.5 (95% CI, 1.0-2.3), 2.9 (95% CI, 1.1-7.2), and 2.0 (95% CI, 1.62.4) of being exposed to alcohol, medications, cigarette smoking, X-rays, or to any of these, respectively, during the first trimester of pregnancy. CONCLUSIONS: Unintended pregnancies are more likely to occur among young women with a lower household monthly income level. Prenatal counseling should be especially recommended for women with unintended pregnancies in order to evaluate whether they have been exposed to potential teratogenic agents.     

Selection bias in Teratology Information Service pregnancy outcome studies.

BACKGROUND: Pregnancy outcome studies conducted through Teratology Information Services (TIS) rely on volunteer subjects. If these subjects tend to have different risk profiles than the population from which they are drawn, the results of TIS studies may have limited generalizability. METHODS: We selected all subjects who enrolled in the California Teratogen Information Service (CTIS) pregnancy outcome study for prenatal exposure to carbamazepine or valproic acid between 1990 and 1997 and who received prenatal care through Kaiser Permanente of Southern California (n = 13). We compared these subjects to Kaiser patients identified through the Maternal Serum Alpha Fetoprotein Program with exposure to carbamazepine or valproic acid but who had not enrolled in the CTIS project. The controls were matched by Kaiser location and pregnancy year using a 2:1 ratio (n = 26). Medical records were reviewed and the prevalence of 14 pregnancy risk factors was compared between the two groups. RESULTS: There were no significant differences between the groups on any one risk factor; however, a notably higher proportion of women who did not enroll in the CTIS study used tobacco or had a positive family history of congenital anomalies. CONCLUSIONS: Although the sample was small, and results may not apply to other exposures in different health care environments, these data provide some evidence that women who enroll in TIS pregnancy outcome studies do not have a substantially different pregnancy risk profile than women who do not. Efforts to address possible selection bias should be incorporated in future TIS study design.     

Exposure to ionizing radiation during pregnancy: perception of teratogenic risk and outcome

We quantified the perception of teratogenic risk in women attending the Motherisk program for counseling about diagnostic radiation in pregnancy (n = 50) and compared it with a control group of women exposed to nonteratogenic drugs and chemicals (n = 48). Before receiving known information about the specific exposure, women exposed to radiation assigned themselves a significantly higher teratogenic risk compared with the control group (25.5 +/- 4.3% versus 15.7 +/- 3.0% for major malformations, P less than 0.01). The post-consultation perception of teratogenic risk did not differ between the two groups. Special consideration and attention should be given when counseling pregnant women exposed to low-dose ionizing radiation, as their misperception of teratogenic risk may lead them to unnecessary termination of their pregnancy.     

Determinants of recall and recall bias in studying drug and chemical exposure in pregnancy

Case-control studies on effects of drugs in pregnancy rely heavily on maternal recall. At the Motherisk Program in Toronto we counsel women during early pregnancy on the risk of drug and chemical exposure; subsequently, we follow up the outcome of pregnancy after birth. This cohort has given us an opportunity to assess the magnitude of recall of early pregnancy exposure and determinants likely to affect it in 145 consecutive cases. The mean recall of exposure identity was 62%, while accurate recall of timing of exposure was 37% and of dosage 24%. Exposures that prompted the clinic visit, chronic therapeutic exposures, environmental agents, and known teratogens were recalled significantly better than were other exposures. Accurate report of smoking was significantly higher than of alcohol use (79.4% vs. 59%, respectively, P = .0002). The number of agents consumed by the pregnant woman negatively correlated with her recall; mean recall of 1 agent was 85% vs. only 40% recall of 4 agents. Women greater than or equal to 30 years of age recalled significantly worse (mean +/- SEM, 52 +/- 4%) than women younger than 30 (70 +/- 4%), P = .002) despite a similar mean number of exposures. No difference in mean recall was found between women having normal (n = 112) or adverse pregnancy outcome (n = 33). There was a recall bias in reporting alcohol consumption; postnatally, women with adverse outcome tended to report significantly less than the amount initially reported by them.     

Funding for teratology information services: Up, down, and all around

Funding for Teratology Information Services has been an ongoing struggle over the 25 years of its existence. Traditional and novel funding mechanisms have been explored with varying success. The importance of providing teratology risk assessment and counseling to all women of reproductive age is now an established health care objective. Sufficient and stable funding for these services is essential. Birth Defects Research (Part A) 94:660-663, 2012. ? 2012 Wiley Periodicals, Inc.     

ABCDXXX: The obscenity of postmarketing surveillance for teratogenic effects

Our current system of postmarketing surveillance, which is based on voluntary reporting of suspected teratogenic effects, is a failure. Postmarketing surveillance should, at a minimum, provide reassurance that every approved drug treatment does not produce a teratogenic effect as great as thalidomide embryopathy or fetal alcohol syndrome. This means that postmarketing surveillance should be able to detect a twofold or greater increase in the frequency of major congenital anomalies, a fivefold or greater increase in the frequency of intellectual disability, or a characteristic pattern of minor anomalies and functional abnormalities that occurs with a frequency of at least 10% among the children of women who were treated with the drug during pregnancy. Effective surveillance for teratogenic effects could be accomplished through a complementary set of mechanisms that includes pregnancy exposure registries or cohorts as well as direct examination of a small subset of infants whose mothers received the treatment during various periods of pregnancy. If this routine surveillance reveals a "signal" (i.e., an indication suggesting a possible teratogenic effect), further study would be needed to establish whether the observed effect is real and causal. Once a signal of possible teratogenicity in humans has been recognized, validating or refuting it would become an urgent matter. Birth Defects Research (Part A) 94:670-676, 2012. ? 2012 Wiley Periodicals, Inc.     

Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence

Drugs that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are widely used to manage hypertension and heart failure. Adequate functioning of the RAS is essential for normal fetal kidney development. The potential for ACEIs and ARBs to impair fetal and neonatal renal function if taken after the first trimester of pregnancy has been well documented. Although these drugs were not found to be teratogenic in animals, until recently little was known about the teratogenic effects of ACEIs and ARBs in humans when exposure was limited to the first trimester of pregnancy. New evidence from epidemiologic studies indicates that there may be an elevated teratogenic risk when these drugs are taken during the first trimester of pregnancy. However, this elevated risk does not appear to be specific to ACEIs and ARBs, but is instead related to maternal factors and diseases that typically coexist with hypertension in pregnancy, such as diabetes, advanced maternal age, and obesity. Women who become pregnant while being treated with an ACEI or ARB should be advised to avoid exposure to these drugs during the second and third trimesters of pregnancy by switching to a different class of antihypertensive drugs between weeks 8 and 10 after conception. Birth Defects Research (Part A) 94:576-598, 2012. ? 2012 Wiley Periodicals, Inc.     

Women's perspectives on counseling about risks for medication‐induced birth defects

PURPOSE : This qualitative study explored women's experiences with counseling about medication‐induced birth defects, as well as how and when they would like to receive information on medication‐induced birth defects from their health care providers (HCPs). METHODS : We conducted four focus groups with 36 women of reproductive age (18–45 years old) in Pittsburgh, Pennsylvania. Twenty‐one women were using medications to treat a chronic health condition, and two were pregnant. Content analysis was performed by three independent coders using a grounded theory approach. Discrepancies were resolved by consensus. RESULTS : Women reported depending on their HCPs for information about the risks of teratogenic effects of medications on a pregnancy, but felt the information they had been provided was not always comprehensive. Women want HCPs to initiate discussions about potentially teratogenic medications at the time the medications are prescribed, regardless of whether the woman is sexually active or planning a pregnancy. Women want clear information about all potential outcomes for a fetus. Factors women reported as being critical to effective teratogenic risk counseling included privacy, sufficient time to discuss the topic, and a trusting relationship with their HCP. CONCLUSIONS : Women of reproductive age think that providing information about the possible teratogenic effects of medications could be improved by routine discussions of teratogenic risks at the time medications are prescribed. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

The perception of teratogenic risk of cocaine.

While there has been a substantial increase in recreational use of cocaine by young adults, conclusive evidence for cocaine teratogenicity in humans is lacking, and even those believing the drug is teratogenic agree that the rates are quite small. While counseling pregnant women on their teratogenic risk, it was our impression that there is an unrealistically high perception of reproductive risk of cocaine. We wished to quantify the perception of teratogenic risk of cocaine by the public, physicians, and by pregnant women who were counseled following gestational exposure to the drug. Women taking cocaine during the first trimester of pregnancy (n = 54), controls with post secondary education (n = 30), and physicians (n = 30) were asked, using a visual analogue scale, to quantify the teratogenic risk of cocaine and the tendency to terminate/continue the pregnancy after first trimester exposure; in the case of the "public" and physicians this was a hypothetical question. Both physicians and the controls perceived cocaine to be teratogenic (13.4 +/- 11% risk of major malformations by physicians, and 56.5 +/- 22.8% by the "public"). The controls believed cocaine to be as hazardous as thalidomide (57.2 +/- 25.6% risk for thalidomide). Asked whether they would wish to terminate such pregnancy in their family, most physicians (56%) and the controls (70%) had a greater than 50% tendency to terminate.(ABSTRACT TRUNCATED AT 250 WORDS)