Risk Of Congenital Malformations Research Articles

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetes in adolescence.

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetes in adolescence.

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

Maternal and neonatal outcomes in pregnancies with type 2 diabetes in First Nation and other Manitoban people: a population-based study.

First Nation people living in Canada experience a high prevalence of type 2 diabetes in pregnancy. In this study, we aimed to describe maternal and neonatal outcomes in First Nation and all other females with type 2 diabetes living in Manitoba, Canada. This was a population-level retrospective cohort study using linked administrative data from Manitoba (2012-2017). We compared First Nation females with type 2 diabetes with all other Manitoban females with type 2 diabetes, using relative risks (RRs) and 95% confidence intervals (CIs). A total of 2181 females with type 2 diabetes were included, and 1218 (55.8%) were First Nation. First Nation females with type 2 diabetes were significantly more likely to experience stillbirth (RR 2.14, 95% CI 1.11-4.13) and perinatal death (RR 2.39, 95% CI 1.37-4.17) than all other Manitoban females with type 2 diabetes. Offspring of First Nation females with type 2 diabetes had a higher risk of most neonatal complications than offspring of all other Manitoban females with type 2 diabetes, including a higher risk of congenital malformations (RR 1.97, 95% CI 1.30-2.99), but First Nation people did not have a higher risk of most maternal complications. First Nation pregnant individuals living with type 2 diabetes experienced a higher risk for adverse pregnancy outcomes than all other Manitoban females with type 2 diabetes. Additional studies are needed to identify both high-risk and protective factors for pregnancy complications in First Nation people living with type 2 diabetes in pregnancy.

Maternal obesity: new placental paradigms unfolded.

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.

Prevalence of Old and New Torch Infection in Pregnant Women from Mombasa and Kisumu Counties in Kenya in 2017

Introduction: Toxoplasma gondii, Rubella, Cytomegalovirus (CMV) and Herpes simplex viruses, known briefly as TORCH are infectious agents that lead to the development of a maternal infection and may enter the intrauterine circulation at any gestational age increasing the risk of congenital malformations and abortion. Despite this, the testing for these infections is not commonly included in antenatal screenings nationwide in Kenya because it is quite costly and is also considered less prevalent in our population by obstetricians. It is mainly tested to confirm the cause of recurrent unexplained pregnancy losses in mothers with a bad obstetric history. Objectives: Through this study, we aim to confirm the prevalence current and old TORCH infections in the pregnant women in two largely populated counties of Kenya. This would give us estimated of successful vaccination coverage of the MMR vaccine, the lowest age with exposure to the infections, and the possible benefit for conducting the test in all pregnant women. Also to identify possible biographic factors correlated with increased risk of positivity to infection in the population. Methodology: Using stratified method of randomization and selection of centers, one of the largest centers with antenatal clinics (ANC) was chosen in each county and all their patients attending their ANC were screened for the infection using the On-Site TORCH Panel Rapid Test CTK Biotech, Inc. (San Diego, CA 92121, USA) with a specificity of between 85% and 97%. Positive results for IgM were verified using ELISA. Results: There was extremely low prevalence of confirmed active infection of TORCH in the population (only 2 cases which did not have any complications in pregnancy as a result), but presence of old infection was at about 30% for Toxoplasma, 50% for Rubella and HSV-1, 20% for HSV-2 and 10% for CMV. There seems to be an interruption in effective Rubella vaccination around the year 1987 which would be worth investigating. Conclusion: Testing pregnant women for TORCH is not of much benefit in pregnancy in Kenya due to low prevalence. However, the test can be used to screen populations at risk as is being conducted currently.

Neonatal outcomes after gamma-aminobutyric acid analog use during pregnancy: a meta-analysis of cohort studies.

Gamma-aminobutyric acid (GABA) analogs are being used by an increasing number of reproductive-age women. However, there is concern regarding the teratogenic potential of GABA analogs. We performed this systematic review and meta-analysis to assess the relationship between GABA analog exposure and risk of adverse neonatal outcomes. Eight cohort studies were included in the meta-analysis.Exposure to a GABA analog during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 1.19, 95% confidence interval [CI] 0.96-1.46, P = 0.106) or a small for gestational age (SGA) infant (OR 1.99, 95% CI 0.78-5.1, P = 0.152) compared to no exposure. However, exposure to a GABA analog was associated with an increased risk of preterm birth (PB) (OR 1.56, 95% CI 1.04-2.35, P = 0.033), spontaneous abortion (SA) (OR 1.64, 95% CI 1.14-2.38, P = 0.008), or termination of pregnancy (TOP) (OR 3.02, 95% CI 2-4.56, P < 0.001). Exposure to GABA analogs during pregnancy does not appear to be associated with congenital malformation, although there was some evidence of a higher risk of several other negative neonatal outcomes. Given the few studies included, larger prospective studies controlling for important confounders are needed to verify our findings.

A prospective comparative study of metabolic and haematological profile of infants born to mothers with pregestational and gestational diabetes mellitus

Background: Diabetes mellitus during pregnancy has long been associated with maternal and neonatal morbidity and mortality. Gestational and pregestational diabetes make up the most common maternal metabolic disorder of pregnancy. Suboptimal control of blood glucose has the potential for serious neonatal adverse effects. Neonates of pregestational diabetic mothers are at risk for congenital malformations, perinatal mortality, preeclampsia, preterm birth, increased birthweight, neonatal hypoglycaemia.Methods: 100 neonates born to diabetic mothers were enrolled in the study during 1January 2019 to 30June 2020 at Mediciti institute of medical sciences, Telangana. Gestational age, birth weight, relevant antenatal history of mothers with diabetes mellitus and examination findings were collected and recorded. Blood samples were collected to perform relevant biochemical tests and managed as per unit protocol.Results: Of the 100 neonates, 93% were born to mothers with GDM, while the remaining 7% were born to mothers with PGDM. 39% (39/100) of mothers had poor glycemic control. Mean birth of neonates born to PGDM mothers was lower when compared to GDM and was statistically significant (p=0.02). Hyperbilirubinemia was the most common abnormality seen in 53% of neonates. Incidence of hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, hyperbilirubinemia, were higher in infants born to mothers with PGDM and was statistically significant. Conclusions: Among the pregnancies complicated by diabetes, PGDM continues to have a major contribution. Metabolic and haematological complications are more in neonates born to mothers with PGDM. Hypocalcemia and hyperbilirubinemia was the most common complications in IDM.

Prégabaline et malformations congénitales : une fausse alerte

Pregabalin is frequently prescribed for neuropathic pain, generalized anxiety disorder and, to a lesser extent, epilepsy. On the basis of the analysis of a study conducted in 4 European countries, the European Medicines Agency and the French National Agency for the Safety of Medicines and Health Products considered that this drug should be avoided in pregnant women. An alarmist interpretation of these study results retains an increased risk of major congenital malformations in case of in utero exposure to pregabalin during the first trimester of pregnancy. Our analysis of this study and the overall evaluation of the data available on this drug in pregnant women do not lead us to the same conclusion.

First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy.

There is limited information about the effects of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection during the first trimester of pregnancy on the risk of major congenital malformations (MCMs). The International Registry of Coronavirus Exposure in Pregnancy (IRCEP) was designed to estimate the relative risk of adverse perinatal outcomes among women with Coronavirus Disease 2019 (COVID‐19) at specific times during gestation. Adult women were eligible to enroll if they had a SARS‐CoV‐2 test, regardless of the results, or clinically confirmed COVID‐19 during pregnancy. Self‐administered questionnaires collected data on SARS‐CoV‐2 infection, pregnancy outcomes (including detailed questions on MCMs), and potential confounders. The analysis of MCMs includes women with either a positive SARS‐CoV‐2 PCR test or a clinical diagnosis of COVID‐19 during the first trimester (exposed group) or a negative SARS‐CoV‐2 test (reference) that enrolled while pregnant. Sensitivity analyses were restricted to participants who enrolled before the availability of informative prenatal screening tests and extended to those enrolled after end of pregnancy. Generalized linear models were used to estimate relative risks (RR) and 95% confidence intervals (CI). Of 17,163 participants enrolled between June 2020 and July 2021, 1727 had a SARS‐CoV‐2 infection during the first trimester, of whom 1,675 enrolled during pregnancy. Of 10,235 controls with a negative test during pregnancy, 4,172 enrolled during pregnancy. Restriction to participants with complete follow‐up reduced the sample size to 92 exposed and 292 unexposed reference pregnancies. MCMs were reported in 3 (3.3%) exposed and 8 (2.7%) unexposed (RR 1.2; 95% CI 0.32–4.2) newborns. The RR was 2.5 (95%CI 0.23–27) among those enrolled before prenatal screening, and 2.2 (95%CI 0.89–5.3) in the overall study population including those enrolled post‐pregnancy. No specific pattern of malformations was observed. Although results are compatible with no major teratogenic effects associated with maternal SARS‐CoV‐2 infection, RR estimates were imprecise and larger studies are warranted.

Valproate Teratogenicity: A Moving Target.

Within several years after receiving U.S. Food and Drug Administration (FDA) approval in the late 1970s, valproate was shown to increase the risk for major congenital malformations and learning disabilities in the offspring of women who used the drug during pregnancy. Nonetheless, its use in pregnant women has persisted for more than four decades, recently resulting in numerous lawsuits and, in countries other than the United States, criminal indictments of the manufacturers of valproate. The use of valproate in pregnancy persisted and extended beyond its original indication for the treatment of epilepsy. Several recent studies indicate that the drug is more often prescribed to treat pregnant women with bipolar depression and migraine than for seizure control. Especially concerning is the absence of valproate from the list of more than 60 drugs for which the FDA has implemented Risk Evaluation and Mitigation Strategies to prevent or limit untoward consequences associated with specific drugs. Until this step is taken, avoidance of the teratogenic effects of valproate will rely on the vigilance of those caring for women and people with the potential to get pregnant.

Risk of major malformations in infants after first-trimester exposure to benzodiazepines: Results from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent. The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications prospectively enrolls pregnant women with psychiatric illness who take one or more psychiatric medications. Participants are interviewed twice during pregnancy and at 12 weeks postpartum. Women taking any benzodiazepine during the first trimester of pregnancy were compared with a group of women taking psychiatric medication(s) other than benzodiazepines during pregnancy. A total of 1053 women were eligible for this analysis; N = 151 women who had taken a benzodiazepine during the first trimester, and the comparison group was N = 902 women. There were 5 (3.21%) major malformations in the exposure group and 32 (3.46%) in the comparison group (odds ratio 0.92; 95% confidence interval 0.35-2.41). This ongoing pregnancy registry offers reassurance that benzodiazepines do not appear to have major teratogenic effects. The precision of relative risk estimate will improve as the number of participants increases. This and other pregnancy registries will better inform the reproductive safety of benzodiazepines.

Exposure to selective noradrenalin reuptake inhibitors during the first trimester of pregnancy and risk of congenital malformations: A meta-analysis of cohort studies

Selective serotonin-noradrenalin reuptake inhibitors (SNRIs) are used to treat depression and anxiety during pregnancy; however, information regarding their foetal safety is limited. Cohort studies concerning congenital malformations in infants born to mothers exposed to SNRIs during the first trimester of pregnancy were identified. Eight studies were included in the analysis. In general, the use of SNRIs was not associated with an increased risk of overall congenital malformations when compared with no exposure (rate ratio [RR] = 1.07, 95% confidence interval [CI] = 0.94–1.22; P = 0.31), exposure to SSRIs (RR = 1.12, 95% CI = 0.97–1.31; P = 0.12) and no exposure with clinical indication (RR = 1.04, 95% CI = 0.9–1.2; P = 0.564). A significantly increased risk of cardiac malformations was observed (RR = 1.33, 95% CI = 1.15–1.53; P < 0.001); however, this association was not statistically significant when the reference group comprised mothers exposed to SSRIs (RR = 1.1, 95% CI = 0.85–1.43; P = 0.47) or no exposure with clinical indication (RR = 1.17, 95% CI = 0.95–1.42; P = 0.13). The evidence shows no increased risk of congenital malformations and argues against a substantial cardiac teratogenic effect of SNRIs.

Maternal pregestational diabetes as an factor in the genesis of congenital malformations of the fetus

This review article summarizes the results of modern clinical studies performed domestically or abroad, which provide information on maternal pregestational diabetes (type 1 or 2) shaping a spectrum of congenital malformations of the fetus. Advances in the treatment of diabetes mellitus have reduced the risk of fetal congenital malformations in pregnant women with the disease, but an increase in its incidence among women of childbearing age indicates that this cause of congenital malformations is becoming more relevant every year. This review article presents four diabetes-mediated pathways for the genesis of fetal congenital malformations: those associated with metabolic imbalance or oxidative stress, genetically mediated and caused by insufficient inhibition of apoptosis. Thus, based on clinical studies and meta-analysis over the past ten years, it has been demonstrated that women with pregestational diabetes mellitus are at the highest risk of developing fetal congenital malformations. Achievement of diabetes compensation and physiological nutritional status in such patients determines the favorable course of all stages of pregnancy.

Association Between Maternal Exposure to SO2 and Congenital Ear Malformations in Offspring: A Population-Based Case-Control Study in Liaoning Province, China.

Objectives: To examine associations between maternal sulfur dioxide (SO2) exposure and congenital ear malformations risk in offspring. Methods: We surveyed 1676 cases with congenital ear malformations and 7950 controls from the Maternal and Child Health Certificate Registry of Liaoning Province between 2010 and 2015. SO2 concentrations were obtained from the Municipal Environment Protection Bureau of Liaoning Province. Multivariable logistic regression models and Restricted cubic splines (RCS) model were used to assess the aforementioned association. Results: There were significant associations between maternal SO2 exposure and congenital ear malformations risk during the 3 months before conception (OR Q4 vs. Q1 = 1.93, 95% CI = 1.43–2.59) and the 3 months after conception (OR Q4 vs. Q1 = 1.63, 95% CI = 1.22–2.18). Similar results were obtained in the analysis of single-month exposure windows, except for the third month before conception and the third month after conception. Moreover, these findings were broadly consistent across subgroups and robust in sensitivity analyses. There were non-linear dose-response associations between SO2 exposure and congenital ear malformations based on restricted cubic spline model analysis. Conclusion: Maternal SO2 exposure is associated with increased congenital ear malformations risk in offspring.

Long-Term Morbidity and Mortality in Children After In Utero Exposure to Maternal Cancer.

In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero. This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis. Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy. Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.

The Use of Antiepileptic Drugs During Pregnancy and Fetal Outcomes.

Epilepsy affects approximately 1 percent of the population and roughly 1 million women of childbearing age. Estimates suggest that 0.3-0.7 percent of pregnancies occur in women with epilepsy. Epilepsy itself increases the risk of congenital malformation and medications add to this risk. Also, approximately one-half of the use of medications for epilepsy are used for other indications, possibly increasing exposure in some women. As controlled trials with these medications are not performed during pregnancy, data has been accumulated primarily through databases and case studies. This review is intended to update the practitioner about the use and concerns of antiepileptic medications in the presnant woman and the potential effects on the fetus and neonate.

Study of certain congenital malformations due to low-level radiation exposures from high background radiation areas

The coastal regions of some states (Kerala, Tamil Nadu, Andhra Pradesh and Orissa) in India are known to have plenty of thorium-rich minerals, therefore possess high external gamma radiation fields, and are identified as Natural High Background Radiation Areas. There are concerns about congenital malformations due to the high background radiation prevailing in the region.Therefore, scientists find interest to study the possible biological effects of low-level exposures on the local populace who are living with generations under these extraordinary radiation fields. The present study is an attempt to find the correlation between the incidences of certain congenital malformations through a 1:3 matched case-control study. A total of 75 subjects (58 mental retardation cases and 17 Cleft lip/palate cases) along with 225 controls were selected for the investigations. Indoor and outdoor gamma dose rates were measured using a halogen-quenched GM tube-based survey meter, while the indoor inhalation dose rates were measured based on the radon and progeny measurements using the twin cup dosimeters equipped with LR-115 Type II solid-state nuclear track detectors. Conditional logistic regression analysis was used to find out the correlation between the radiation dose with congenital malformation. This study found an insignificant risk of cleft lip/palate (but not for mental retardation) from the exposures to natural high external gamma radiation fields in the study area. Therefore, the results of the investigation indicate no explicit risk of congenital malformations by the high background natural radiation prevailing in the region.

Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis.

The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.

Pregnancy Outcomes With Exposure to Second-Generation Antipsychotics During the First Trimester.

Objective: To investigate the risk of major congenital malformations associated with exposure to second-generation antipsychotics (SGAs) in the first trimester.Methods: Pregnant women who received consultation on drug exposure from the Japan Drug Information Institute in Pregnancy from October 2005 to December 2016 were asked to complete a questionnaire at 1 month after the expected delivery date. The questionnaire included items on pregnancy outcome, date of delivery, gestational age at delivery, malformations in the infant that were confirmed by the pediatrician's report, and the following parameters at birth: height, weight, head circumference, and chest circumference. Odds ratios (ORs) for major congenital malformations among live-born children of pregnant women with SGA exposure during the first trimester (SGA group) relative to children of women not exposed to SGAs and medications known to be teratogenic (comparison group) were estimated using an inverse probability of treatment weighting approach.Results: Of 404 women with SGA exposure during the first trimester, there were 351 live births, 3 stillbirths, 34 spontaneous abortions, and 16 elective abortions. The rate of major congenital malformations among live-born children was 0.9% (3/351) in the SGA group and 1.8% (70/3,899) in the comparison group. No statistically significant differences were observed in the adjusted OR for major congenital malformations (adjusted OR = 0.44; 95% CI, 0.12-1.48; P = .179).Conclusions: SGA exposure during the first trimester is not associated with an increased risk of major congenital malformations. These findings might be reassuring for pregnant women who require SGAs.

Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and Other Neurodevelopmental Outcomes Associated With Antipsychotic Drug Exposure During Pregnancy.

Between 0.3%-4.6% of women use antipsychotic (AP) drugs during pregnancy. Two large, retrospective, population-based cohort studies, conducted in Nordic countries and in the US, examined the risk of neurodevelopmental disorders (NDDs) following gestational exposure to APs. The Nordic study found that, in unadjusted analyses, exposure to APs during pregnancy was associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring; that the risk all but disappeared after adjusting for covariates; and that the risk appeared to be related to maternal major mental illness rather than to gestational exposure to APs. The US study also found that, in unadjusted analyses, gestational exposure to APs was associated with an increased risk of almost all of the study-specified NDDs in offspring; however, after adjusting for covariates, the risks were no longer meaningfully increased and, importantly, were no longer statistically significant for ADHD and ASD. Thus, these 2 studies suggest that gestational exposure to APs is a marker of NDD risk in offspring rather than a potential cause. Whereas a small but significantly increased risk was identified for aripiprazole in the US study, the signal was inconsistent across analyses, and confounding due to maternal mental illness was not ruled out. Previous studies have suggested that the use of APs during pregnancy is not associated with an increased risk of major congenital malformations and other adverse gestational outcomes. Considering the potential harm and suffering associated with major mental illness and the very low risks associated with AP use during pregnancy, initiation or continuation of APs appears to carry a favorable risk-benefit ratio in pregnant women who need these drugs; however, decision-making should be shared between patients, their caregivers, and the treating team.