Birth Defects In Women Research Articles

Prepregnancy overweight and obesity as risk factors for birth defects: a cross-sectional study over a 30-year period

Overweight and obesity are public health problems worldwide despite being modifiable conditions. The association between birth defects and pregestational maternal body mass index is not entirely clear. We aimed to assess the prevalence and estimate the risk of birth defects related to pregestational body mass index and other maternal factors. We explored a 30-year time series database in a cross-section study. We analysed 40,217 cases, among them 2.8% had birth defects. Bivariate analysis showed a higher prevalence of birth defects with increased pre-pregnancy body mass index and in extremes of maternal age, white skin colour, and primiparity. Multivariable logistic regression showed a higher chance of birth defects in women with pre-pregnancy overweight/obesity (OR:1.19 [CI95%:1.01–1.41]), maternal age ≥ 40 years (OR:1.68 [CI95%:1.11–2.54]), and white skin colour (OR:1.44 [CI95%:1.19–1.75]). Maternal weight is a modifiable risk factor that must be considered and addressed in preconception counselling to minimise possible deleterious effects on embryogenesis. IMPACT STATEMENT What is already known on this subject? Previous studies have linked some maternal factors with birth defects. However, the association with prepregnancy maternal body mass index is not clear. What do the results of this study add? Our findings provide support for the association of prepregnancy maternal overweight and obesity with birth defects and highlight that BMI is a modified risk factor. What are the implications of these findings for clinical practice and/or further research? Maternal body mass index is a modifiable risk factor, highlighting the importance of preconception counselling for the prevention and possible reduction of factors that increase the risk of birth defects.

Impact of communication on the awareness of birth defects among adult women in Nigeria

Objectives: Birth defects are universal problems associated with poor management outcomes in children, especially in developing countries where its burden is enormous. Media advocacy is believed to help in reducing these poor outcomes. This study assessed the level of awareness of birth defects in women and the impact of the media in Nigeria. Material and Methods: This was a descriptive cross-sectional study of 778 women, conducted in the outpatient clinics of two major referral hospitals in Ibadan, Nigeria, from March to October 2019. Results: Of the 778 women, 768 were administered a structured questionnaire and 10 women whose children have been managed for a congenital anomaly before were interviewed using an in-depth interview guide. Of the 768 respondents, 600 (78.1%) were in the third and fourth decades of life and 577 (75.1%) women have heard about birth defects before. A total of 348 (60.3%) and 134 (23.2%) women heard about it from the hospital and mass media, respectively, with 65.0% of them believing that the media were helping in educating people about birth defects. There was a statistically significant relationship between the awareness levels and the respondents’ occupation (χ2 = 28.914, P < 0.001), educational status (χ2=43.325, P < 0.001), religion (χ2 = 10.376, P = 0.016), antenatal clinic attendance (χ2 = 5.035, P = 0.025), and history of previous mid-trimester abortion (χ2 = 7.689, P = 0.006). Conclusion: The level of awareness about birth defects is good but not enough; there is a need for greater media involvement in disseminating information on the occurrence of birth defects.

Editors' note: Reducing birth defects in women with epilepsy: Research leading to results

In “Reducing birth defects in women with epilepsy: research leading to results,” Pennell and Meador discuss: (1) the need for neurologists to carefully consider selection of antiepileptic drugs (AEDs) in women of childbearing age and (2) the impact of EURAP—a prospective registry of women on AEDs in 42 countries—on facilitating further understanding of the risks of congenital malformations and neurodevelopmental abnormalities associated with AEDs. Braillon and Bewley comment that (1) increased advocacy is needed to ensure whether EURAP's findings affect practice expediently and (2) to make the results more meaningful, EURAP should include detailed data on other risk factors for congenital malformations and neurodevelopmental abnormalities. Finally, the findings of EURAP should have influence on regulatory agencies to improve drug safety. Sethi further notes that it is particularly important for steps to be taken to ensure whether EURAP's findings be used to improve AED prescribing practices in low- and middle-income countries. Pennell and Meador respond that it is challenging to change practice, but partnership with governmental and regulatory organizations and performance of meta-analyses can help disseminate information about medications associated with of congenital malformations and neurodevelopmental abnormalities. Pennell further notes that the International League against Epilepsy is working to facilitate education of all specialists who care for women with epilepsy using knowledge acquired from EURAP in an effort to decrease the frequency of congenital malformations and neurodevelopmental abnormalities in patients on AEDs. In “Reducing birth defects in women with epilepsy: research leading to results,” Pennell and Meador discuss: (1) the need for neurologists to carefully consider selection of antiepileptic drugs (AEDs) in women of childbearing age and (2) the impact of EURAP—a prospective registry of women on AEDs in 42 countries—on facilitating further understanding of the risks of congenital malformations and neurodevelopmental abnormalities associated with AEDs. Braillon and Bewley comment that (1) increased advocacy is needed to ensure whether EURAP's findings affect practice expediently and (2) to make the results more meaningful, EURAP should include detailed data on other risk factors for congenital malformations and neurodevelopmental abnormalities. Finally, the findings of EURAP should have influence on regulatory agencies to improve drug safety. Sethi further notes that it is particularly important for steps to be taken to ensure whether EURAP's findings be used to improve AED prescribing practices in low- and middle-income countries. Pennell and Meador respond that it is challenging to change practice, but partnership with governmental and regulatory organizations and performance of meta-analyses can help disseminate information about medications associated with of congenital malformations and neurodevelopmental abnormalities. Pennell further notes that the International League against Epilepsy is working to facilitate education of all specialists who care for women with epilepsy using knowledge acquired from EURAP in an effort to decrease the frequency of congenital malformations and neurodevelopmental abnormalities in patients on AEDs.

Reader response: Reducing birth defects in women with epilepsy: Research leading to results.

Pennell and Meador rightly expressed concern about reducing birth defects in women with epilepsy with their editorial endorsing the EURAP registry (a prospective registry of women with epilepsy on AEDs, involving 42 countries across 4 continents).1,2 However, this was a missed opportunity to acknowledge the role of patients in better decision-making processes in regulatory activities.3

Reader response: Reducing birth defects in women with epilepsy: Research leading to results.

I read with interest the results reported by the EURAP study group1 and the accompanying editorial by Drs. Pennell and Meador.2 It is now well established that valproate use should be avoided in pregnancy and in woman with epilepsy (WWE) of child-bearing age. Broad spectrum anticonvulsants such as lamotrigine and levetiracetam should be used instead. Although the research has certainly yielded results in high-income countries in North America and Europe, the unmet needs of pregnant WWE in low- and middle-income countries in Asia and Africa remain high. In most state-run hospitals in these countries, the drugs available on formulary are restricted to phenobarbital, phenytoin, carbamazepine, and valproate. In these countries, the care of pregnant WWE is not well organized. As a result, maternal and fetal mortalities during childbirth remain high. We need to bring the findings from the EURAP registry to the attention of healthcare policymakers and planners in these countries so that, in accordance with utilitarian ethics, the research translates into results for not just a few but all pregnant WWE.

Author response: Reducing birth defects in women with epilepsy: Research leading to results.

We could not agree more with the comment on our editorial1 submitted by Dr. Sethi. Drs. Tomson, Meador, and I are members of the International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy. Our first goal has been education of healthcare providers across a variety of specialties and disciplines, especially because epilepsy care is often delivered by generalist MDs and non-MD providers in low- and middle-income countries in Asia and Africa. We have placed emphasis on the known different levels of risk between the antiseizure medicines and the importance of pregnancy planning, with optimization of the medicine and vitamin regimen before conception. Dr. Sethi's suggestion of also bringing it to the attention of healthcare policy makers and planners is an equally important endeavor. One approach could be to highlight that by restricting AED access to save money, the ultimate national costs in the loss of productivity in patients with epilepsy, and in supporting the healthcare and educational needs of children of women with epilepsy, are probably far greater. The ILAE is aware of this problem and is working to understand and solve this difficult dilemma.

Author response: Reducing birth defects in women with epilepsy: Research leading to results.

Author response: Reducing birth defects in women with epilepsy: Research leading to results.

Maternal factors and the risk of birth defects after IVF and ICSI: a whole of population cohort study.

To assess the contribution of maternal factors to major birth defects after in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and natural conception. Retrospective cohort study in South Australia for the period January 1986 to December 2002. A whole of population study. A census of all IVF and ICSI linked to registries for births, pregnancy terminations, and birth defects (diagnosed before a child's fifth birthday). Odds ratios (ORs) for birth defects were calculated among IVF, ICSI, and natural conceptions for maternal age, parity, pre-pregnancy BMI, smoking, pre-existing diseases, and conditions in pregnancy, with adjustment for confounding factors. Birth defects classified by International Classification of Diseases (ninth revision) and British Paediatric Association (ICD9-BPA) codes. There were 2211 IVF, 1399 ICSI, and 301 060 naturally conceived births. The unadjusted prevalence of any birth defect was 7.1, 9.9, and 5.7% in the IVF, ICSI, and natural conception groups, respectively. As expected, the risk of birth defects increased with maternal age among the natural conceptions. In contrast, for IVF and ICSI combined, relative to natural conceptions, births to women aged ≤29 years had a higher risk (adjusted odds ratio, aOR 1.42; 95% confidence interval, 95% CI 1.04-1.94), births to women aged 35-39 years had no difference in risk (aOR 1.01; 95% CI 0.74-1.37), and births to women aged ≥40 years had a lower risk of defects (aOR 0.45; 95% CI 0.22-0.92). Defects were also elevated for nulliparity, anaemia, and urinary tract infection in births after ICSI, but not after IVF. The usual age-birth defect relationship is reversed in births after IVF and ICSI, and the associations for other maternal factors and defects vary between IVF and ICSI. Risk of birth defects in women over 40 years is lower after infertility treatment than for natural conceptions.

First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis.

Metformin is generally considered a non-teratogenic drug; however, only a few studies specifically designed to assess the rate of congenital anomalies after metformin use have been published in the literature. The objects of the present study were to review all of the prospective and retrospective studies reporting on women treated with metformin at least during the first trimester of their pregnancy and to estimate the overall rate of major birth defects. Databases were searched for English language articles until December 2013. Inclusion criteria for the meta-analysis were: a case group of women with PCOS or pre-pregnancy type 2 diabetes and first-trimester exposure to metformin; a disease-matched control group which was not exposed to metformin or other oral anti-diabetic agents; and a list of the major anomalies in both the study and the control groups. A random effects model was used for the meta-analysis of data, using odds ratios. Studies not fulfilling the inclusion criteria for the meta-analysis but reporting relevant data on major malformations in women diagnosed with PCOS were then used to estimate the overall birth defects rate. Meta-analysis of nine controlled studies with women affected by PCOS detected that the rate of major birth defects in the metformin-exposed group was not statistically increased compared with the disease-matched control group and that there was no significant heterogeneity among the studies. The metformin-exposed sample was composed of 351 pregnancies and the OR of major birth defects was 0.86 (95% confidence interval: 0.18-4.08; Pheterogeneity = 0.71). By evaluating all of the non-overlapping PCOS studies reported in the literature, even those without an appropriate control group, the overall rate of major anomalies was 0.6% in the sample of 517 women who discontinued the therapy upon conception or confirmation of pregnancy and 0.5% in the sample of 634 women who were treated with metformin throughout the first trimester of their pregnancy. Regarding type 2 diabetic women, we did not identify a sufficient number of studies with metformin exposure during the first trimester to proceed with the meta-analysis. There is currently no evidence that metformin is associated with an increased risk of major birth defects in women affected by PCOS and treated during the first trimester. However larger ad hoc studies are warranted in order to definitely confirm the safety and efficacy of this drug in pregnancy.

Antiretroviral therapy, pregnancy, and birth defects: a discussion on the updated data

An increasing number of HIV-infected women of childbearing age are initiating antiretroviral therapy (ART) worldwide. This review aims to discuss updated data of the eligible ART regimens and their role in inducing birth defects in utero. Zidovudine and lamivudine plus a non-nucleoside reverse-transcriptase inhibitor or protease inhibitor (PI) is the first-line regimen applied. The role of zidovudine exposition monotherapy or associated with other ART in inducing birth defects remains inconclusive. The main organ systems involved are genitourinary and cardiovascular. For HIV-infected pregnant women, World Health Organization (WHO) guidelines up to 2010 recommend the same group of drugs that are prescribed to nonpregnant women. The exception is efavirenz, which has been associated with an increase in the risk of teratogenicity. Increased rates of birth defects were found in large cohorts and computational studies conducted recently in infants exposed to efavirenz-containing regimens. The combination of zidovudine and lamivudine and lopinavir/ritonavir is one of the most used ART regimens for prevention of mother-to-child-transmission. Conflicting data about the role of PI exposure in utero and birth defects have been reported. However, a reduced number of studies evaluating the role of PI in inducing birth defects in women are available. An association between prematurity and PI exposure in pregnancy was extensively described. Some questions arise due to the tendency of initiating ART early in the life of HIV-infected individuals or those at risk of infection. Longtime exposure to different ART regimens and the potential effect of birth-defect induction in pregnancy are not completely understood. Developing regions harbor the highest numbers of women of reproductive age exposed to ART. Most of the largest and expressive data come from developed countries, and could not be sufficiently representative of pregnant women living in developing countries.

Emergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients

Hundreds of thousands of women in their reproductive years are diagnosed with cancer each year. As the number of female patients who survive cancer increases, the demand for effective and individualized fertility preservation options grows. Currently there are limited clinical options for fertility preservation, and the paucity of publications describing clinical experience and outcomes data has limited accessibility to these options. Decision making for patients diagnosed with cancer requires up-to-date knowledge of the efficacy and safety of available techniques. This article describes a step-by-step approach to evaluation of the cancer patient and presents an accumulation of clinical experience with challenges unique to patients with breast cancer and leukemia. Current data on reproductive outcomes of fertility preservation techniques are examined, demonstrating increasing evidence that these techniques are becoming effective enough to offer routinely to patients facing gonadotoxic cancer therapies, including those still considered to be "experimental."

Safety and effectiveness of efavirenz versus nevirapine-based regimens in resource-limited settings

639–641Keywords: efavirenz, effectiveness, modelling, nevirapine, safety,sub-Saharan AfricaCombination antiretroviral therapy (ART) with eitherefavirenz (EFV) or nevirapine (NVP), both nonnucleo-side reverse transcriptase inhibitors (NNRTIs), and twonucleoside reverse transcriptase inhibitors (NRTI) isrecommended by the WHO as first-line therapy inresource-limited countries [1]. Compared with NVP,EFV is easier to monitor, is relatively well tolerated, hasless frequent and less severe rash and hepatic toxicity thanNVP, and can be administered once daily. Whereas NVPandEFVhavegenerallycomparableclinicalandvirologicefficacy [2–5], because of lower drug–drug interactions,EFV-based ART is associated with superior virologicoutcome compared with NVP-based ART in individualswith tuberculosis (TB) receiving anti-TB therapycontaining rifampicin. Therefore, efavirenz is theNNRTI antiretroviral drug of choice of TB-coinfectedindividuals [6–9]. However, there have been concernsregarding potential for central nervous system birthdefects with first-trimester exposure to EFV based onstudiesinpregnantrhesusmacaquesandretrospectivecasereportsinhumansthathavelimitedEFVuseinwomenofchildbearing age. This is a problem in many resource-limitedsettings,wherewomenconstitute50%or moreofHIV-infected individuals and TB is endemic, but there islimited access to contraception or women may wish tobecome pregnant.In this issue, Ouattara and colleagues use a computersimulation model to evaluate the risks and benefits ofusing EFV and NVP in women of childbearing age inresource-limited countries [10]. Using the previouslyvalidated Cost-Effectiveness of Preventing AIDS Com-plications (CEPAC) International model, the authorssimulated the trade-off between potential excess birthdefects and potential long-term clinical benefits forwomen starting EFV-based versus NVP-based ART inCote d’Ivoire. In a ‘hypothetical’ cohort of 100000women starting ARTwith EFV, the authors found that adrug with lower toxicity and requiring less regimenswitching led to approximately 911 more women aliveafter 10 years compared with those starting with NVP, animprovement in survival of approximately 1%. However,over thesameperiod,therewere59morebirthdefectsinwomen initiating EFV-based ART than those startingwith NVP. The authors concluded that in Cote d’Ivoire,initiating ART with EFV instead of NVP is likely to

Projecting the clinical benefits and risks of using efavirenz-containing antiretroviral therapy regimens in women of childbearing age

To project the outcomes of using either efavirenz or nevirapine as part of initial antiretroviral therapy (ART) in women of childbearing age in Côte d'Ivoire. We used an HIV computer simulation model to project both the mother's survival and the birth defects at 10 years for a cohort of women who started ART with either efavirenz or nevirapine. The primary outcome was the ratio at 10 years of the difference in the number of women alive to the difference in the cumulative number of birth defects in women who started ART with efavirenz compared with nevirapine. In the base case analysis, the birth defect rate was 2.9% on efavirenz and 2.7% on nevirapine. In sensitivity analyses, we varied all inputs across confidence intervals reported in the literature. In the base case analysis, for a cohort of 100 000 women, the additional number of women alive initiating ART with efavirenz at 10 years was 15 times the additional number of birth defects (women alive: nevirapine 67 969, efavirenz 68 880, difference = 911; birth defects: nevirapine 1128, efavirenz 1187, difference = 59). In sensitivity analysis, the teratogenicity rate with efavirenz had to be 6.3%, or 2.3 times higher than the rate with nevirapine, for the excess number of birth defects to outweigh the additional number of women alive at 10 years. In Côte d'Ivoire, initiating ART with efavirenz instead of nevirapine is likely to substantially increase the number of women alive at 10 years with a smaller potential number of birth defects.

Safety of Oseltamivir in Pregnancy

Pregnant women with influenza are at increased risk of morbidity, particularly due to respiratory complications. A high excess mortality rate among pregnant women has been observed in previous influenza pandemics and healthcare agencies have provided recommendations on the use of oseltamivir to treat pregnant women who are infected with the pandemic (H1N1) 2009 virus. This article reviews pre-clinical and clinical data to assess the safety of oseltamivir administered during pregnancy, in the context of the effects of influenza on adverse pregnancy outcomes and fetal malformations. The effects of influenza during pregnancy, whether mediated directly by the virus or by fever or other events secondary to the underlying infection, are not yet well understood, but some data indicate an increased risk of birth defects in women infected with influenza during the first trimester. Animal and toxicology studies do not suggest that clinically effective dosages of oseltamivir have the potential to produce adverse effects on fetal development. Additionally, transplacental transfer of the drug and its active metabolite was very limited and not detectable at normal therapeutic doses in an ex vivo human placenta model. To investigate the safety of oseltamivir in pregnancy, the Roche oseltamivir safety database was searched for all exposures to oseltamivir during pregnancy in the 9 years up to 14 December 2008. In addition, a search of the literature was carried out. Of 232 maternal exposures to oseltamivir in the Roche database, pregnancy outcomes were known for 115 of these exposures. The incidence of adverse pregnancy outcomes was as follows: spontaneous abortions 6.1% (7/115), therapeutic abortions 11.3% (13/115) and pre-term deliveries 2.1% (2/94 live births), values that are not higher than background incidence rates. Fetal outcomes were known in 100 of the 232 exposures. For the nine cases of birth defect that were reported, the timing of oseltamivir exposure in relation to the sensitive period for inducing the birth defect was analysed. Two cases of ventricular septal defect, a more common birth defect, and one case of anophthalmos, an uncommon birth defect, were consistent with exposure to oseltamivir during the sensitive period for these birth defects. For other birth defects, there was either no exposure to oseltamivir during the sensitive period for the defect or insufficient information for assessment. These findings were consistent with other reports in the published literature, including a series of 79 Japanese women exposed to oseltamivir during the first trimester. Together with the other evidence reviewed herein, review of the company safety database suggests that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but available data are limited. Clinicians who use oseltamivir in pregnant women should consider the available safety information, the pathogenicity of the circulating influenza virus strain, the woman's general health and the guidance provided by health authorities. Roche will continue to monitor all reports of oseltamivir use during pregnancy.