Etiological diagnosis in limb reduction defects and the number of affected limbs:A population-based study in the Northern Netherlands

Limb reduction defects (LRDs) that affect multiple limbs are considered to be more often heritable, but only few studies have substantiated this. We aimed to investigate if an etiological diagnosis (genetic disorder or clinically recognizable disorder) is more likely to be made when multiple limbs are affected compared to when only one limb is affected. We used data from EUROCAT Northern Netherlands and included 391 fetuses and children with LRDs born in 1981-2017. Cases were classified as having a transverse, longitudinal (preaxial/postaxial/central/mixed), intercalary, or complex LRD of one or more limbs and as having an isolated LRD or multiple congenital anomalies (MCA). We calculated the probability of obtaining an etiological diagnosis in cases with multiple affected limbs versus one affected limb using relative risk (RR) scores and Fisher's exact test. We showed that an etiological diagnosis was made three times more often when an LRD occurred in multiple limbs compared to when it occurred in one limb (RR 2.9, 95% CI 2.2-3.8, p <0.001). No genetic disorders were found in isolated cases with only one affected limb, whereas a genetic disorder was identified in 16% of MCA cases with one affected limb. A clinically recognizable disorder was found in 47% of MCA cases with one affected limb. Genetic counseling rates were similar. We conclude that reduction defects of multiple limbs are indeed more often heritable. Genetic testing seems less useful in isolated cases with one affected limb, but is warranted in MCA cases with one affected limb

Maternal first trimester COVID-19 vaccination and risk of major non-genetic congenital anomalies

Background: Information regarding the risk of early pregnancy COVID-19 vaccination on the development of major congenital anomalies in the offspring is still limited. Here, we study the association between any COVID-19 vaccination during the 1st trimester and at least one major non-genetic congenital anomaly in the offspring.Methods: We used data from the Dutch Pregnancy Drug Register, an ongoing cohort study. We selected participants with a pregnancy that ended after at least 20 weeks gestation. Pregnant participants self-reported their COVID-19 vaccination status and the presence of congenital anomalies in the offspring. We used logistic regression analyses to study the association between 1st trimester COVID-19 vaccination (gestational week 2 + 0 to 12 + 6) and the risk of at least one major non-genetic congenital anomaly in the offspring. Clustering of anomalies on the ICD10 level by 1st trimester COVID-19 vaccination status was explored using Fisher exact tests.Results: We included 3721 participants of whom 795 (21.4%) were COVID-19 vaccinated during the 1st trimester. The percentage of participants who gave birth to a child with at least one major non-genetic congenital anomaly was comparable between participants who were 1st trimester vaccinated (1.1%) and participants who were not (1.2%) (adjusted odd ratio 0.78 [95% confidence interval 0.35–1.71]). We found no clustering of major non-genetic congenital anomalies by 1st trimester COVID-19 vaccination status (p &gt;.05).Conclusions: There were no indications of an increased risk of major non-genetic congenital anomalies in the offspring after maternal 1st trimester COVID-19 vaccination. Our findings suggest COVID-19 vaccines are safe during early pregnancy.</p

When the Right (Drug) Should Be Left:Prenatal Drug Exposure and Heterotaxy Syndrome

Background: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. Methods: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. Conclusion: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. (C) 2016 Wiley Periodicals, Inc.</p

Effect of prenatal screening on trends in perinatal mortality associated with congenital anomalies before and after the introduction of prenatal screening:A population-based study in the Northern Netherlands

BACKGROUND: Perinatal mortality in foetuses/children with congenital anomalies remains high. Prenatal diagnosis, essential for risk assessment and organisation of perinatal/postnatal care, offers parents the opportunity to consider the termination of pregnancy. In times of quick changes in prenatal screening programmes, it is relevant to evaluate the effect of prenatal screening on perinatal mortality rates. OBJECTIVES: The objective of this study was to study trends in early foetal and perinatal mortality associated with congenital anomalies before/after the introduction of the Dutch prenatal screening programme. METHODS: This population‐based cohort study included 8535 foetuses/neonates with congenital anomalies born in the Northern Netherlands between 2001 and 2017. Total deaths were defined as sum of early foetal (before 24 weeks’ gestation) and perinatal deaths (from 24 weeks’ gestation till day 7 post‐partum). Foetal deaths were categorised into spontaneous or elective termination of pregnancy for foetal anomalies (TOPFA). Trends in total mortality as well as early foetal and perinatal mortality were studied. Joinpoint regression was used to calculate the average annual percentage chance (AAPC) and identify linear trends in mortality within subperiods. RESULTS: Total and perinatal mortality were 17% and 4%. Total mortality was higher in abnormal karyotype and central nervous system anomalies. We observed an increase in total mortality over time: 11.9% in 2001 versus 21.9% in 2017 (AAPC 2.6, 95% confidence interval [CI] 1.5, 3.7), caused by an increase in early foetal mortality from 5.5% to 19.2% (AAPC 8.7, 95% CI 4.7, 12.9) and a decrease in perinatal mortality from 6.4% to 2.7% (AAPC −5.6, 95% CI −10.0, −1.0). The increase in early foetal mortality reflects an increase in TOPFA from 3.6% to 16.9% (AAPC 8.3, 95% CI 4.2, 12.7), mostly occurring at 13–14 and 20–23 weeks’ gestation. CONCLUSIONS: The introduction of the prenatal screening programme led to a decrease in perinatal mortality among foetuses and neonates with congenital anomalies and a marked increase in early foetal mortality before 24 weeks’ gestation due to higher rates of TOPFA

Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics:A retrospective comparative study in EudraVigilance

AIM: To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP) MATERIAL AND METHODS: A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologics (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment). RESULTS: ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus null in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. CONCLUSION: No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n= 64), anakinra (n= 20), belimumab (n= 93), ixekizumab (n= 29), rituximab (n=57), secukinumab (n= 128), tocilizumab (n= 124) and ustekinumab (n= 215). Regarding observed CCAs in the vedolizumab group (n= 113) no firm conclusions can be made based on available information

Impact of Muscarinic M3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients:A Case-Controlled Study

Background M-3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion. Objective Our objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M-3 muscarinic receptor antagonism (AD_ antaM(3) and AD_nonantaM(3), respectively). Methods We designed a case-control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994-2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM. Results A total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD_antaM(3) was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18-2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group ( Conclusion Our results suggest that exposure to AD_antaM(3) was associated with the development of T2DM among antidepressant users

Maternal occupational exposure and oral clefts in offspring

BACKGROUND: Previous studies suggest that periconceptional maternal occupational exposure to solvents and pesticides increase the risk of oral clefts in the offspring. Less is known about the effect of occupational exposure to metals, dust, and gases and fumes on development of oral clefts. METHODS: This case-malformed control study used data from a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2013. Cases were defined as non-syndromic oral clefts. The first control group had chromosomal/monogenic defects, and the second control group was defined as non-chromosomal/non-monogenic malformed controls. Maternal occupational exposure was estimated through linkage of mothers' occupation with a community-based Job Exposure Matrix (JEM). Multivariate logistic regression was used to estimate the effect of occupational exposures. Odds ratios were adjusted (aORs) for relevant confounders. RESULTS: A total of 387 cases, 1135 chromosomal and 4352 non-chromosomal malformed controls were included in this study. Prevalence of maternal occupational exposures to all agents was 43.9% and 41.0%/37.7% among cases and controls, respectively. Oral clefts had significantly increased ORs of maternal occupational exposure to pesticides (aOR = 1.7, 95% confidence interval [CI] 1.0-3.1) and dust (aOR = 1.3, 95% CI 1.1-1.6) when using non-chromosomal controls. Subgroup analysis for CL(P) stratified by gender showed a significantly increased risk for male infants exposed to 'other solvents' and exposure to mineral dust for female infants. CONCLUSION: Our study showed that maternal occupational exposure to pesticides and dust are risk factors for oral clefts in the offspring. Larger studies are needed to confirm this finding