Risk Of Oral Clefts Research Articles

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US

Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Influence of Domestic Exposure to Polycyclic Aromatic Hydrocarbons on Women's Periconceptional Stage and Associated Risk of Oral Cleft in Offspring.

Background:Polycyclic aromatic hydrocarbons (PAHs) constitute a group of chemicals with an omnipresence in the environment and our surroundings. With their genotoxicity and carcinogenic nature, it has been proven to be monstrous in our daily life and, especially for pregnant women and their newborn.Aim:This questionnaire study was done to verify the influence of domestic exposure to polyaromatic hydrocarbons on women's periconceptional stage and risk of oral cleft in offspring in the suburban and the rural population of Mysore.Methodology:Two hundred pregnant women as patients from four different hospitals in Mysore were given a questionnaire to be filled with 24 parameters ranging from the knowledge to various means of exposure to the pregnant women with the PAH and the severity and the extent of the orofacial defect in the newborn.Results:It was determined that exposure of pregnant women to the smoke emanating from the method of cooking or heating to smoking (first or passive) and the direct inhalation of gas had the maximum effects on the association of cleft palate (60.7%) in unilateral followed by 90.9% in bilateral, 65.0% in soft tissue, and 76.2% in hard tissue cleft palate.Conclusion:The deleterious effects of the cooking and water heating measures practiced in the suburban and the rural population predisposed the pregnant women to significantly higher chances of offspring with the varied extent of the orofacial defect. There is an influence of domestic exposure to polycyclic aromatic hydrocarbons on women's periconceptional stage and risk of oral cleft in offspring.

Maternal exposure to sulfur dioxide and the risk of oral clefts in Liaoning Province, China: a population-based case-control study.

There is limited and equivocal epidemiological evidence relating to the association between maternal sulfur dioxide (SO2) exposure and the risk of oral clefts (OCs) in offspring. We performed a population-based case-control study in Liaoning province to evaluate aforementioned relationship during 3 months before conception, the first trimester of pregnancy, and their single months. The study involved 3086 patients with OCs and 7950 controls. Data relating to SO2 concentration was acquired from air monitoring stations throughout the study period. We used a multivariable logistic regression model to evaluate the association between exposure to SO2 and the risk of OCs during the exposure windows. Maternal SO2 exposure was positively related to OCs during the 3 months before conception (odds ratio = 1.38, 95% confidence interval: 1.15-1.65; P for trend < 0.01). Positive relationships were obtained from the first and second months before conception and the first month of pregnancy. Thus, our research reflects a relationship between SO2 exposure and the risk of OCs. Future studies are now required to verify the association between SO2 exposure and OCs during pregnancy and indicate the most relevant vulnerable exposure time windows.

Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study

ObjectiveTo evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure.DesignPopulation based cohort study.SettingNationwide sample of publicly and...

Hydroxychloroquine early in pregnancy and risk of birth defects

BackgroundHydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative.ObjectiveThe study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis.Study DesignWe performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000–2014) and IBM MarketScan Research Database (MarketScan, 2003–2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.ResultsOverall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27–1.81). Patient characteristics were balanced in the restricted, propensity score–matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04–1.54); it was 1.33 (95% confidence interval, 1.08–1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60–1.50) for a daily dose of <400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified.ConclusionOur findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.

Folic acid antagonist use before and during pregnancy and risk for selected birth defects.

Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study. We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier. We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null. Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.

Maternal preconception and first trimester exposure to PM10 and the risk of oral clefts in offspring: a population-based, case–control study

BackgroundCurrent literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of...

Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.

ObjectiveTo examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.DesignPopulation based cohort study.SettingA cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.ParticipantsPregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.InterventionsUse of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.Main outcome measuresRisk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.ResultsThe study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.ConclusionsOral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy

(JAMA. 2018;320 (23):2425–2426) Nausea and vomiting during the first trimester of pregnancy is often unresponsive to conservative treatment and commonly requires antiemetic pharmacotherapy. First line agents, as per the American College of Obstetricians and Gynecologists’ treatment algorithm, are pyridoxine, alone or in combination with doxylamine. However, while the safety of pyridoxine has been well established, there remain concerns regarding potential effects of other antiemetic drugs on fetal development. In particular, the study by Huybrechts et al addressed concerns about potential associations between ondansetron, a serotonin receptor agonist and third-line agent, and fetal congenital malformations. The study found no significant associations between ondansetron and cardiac abnormalities [adjusted risk difference (aRR), −0.8; 95% confidence interval (CI), 0.92-1.06] and overall congenital anomalies. A small but significantly increased risk of oral clefts with first-trimester exposure to ondansetron was found (aRR, 1.24; 95% CI, 1.03-4.08).

Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring

Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting during pregnancy, is limited and conflicting. To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations. A retrospective cohort study nested in the 2000-2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1 816 414 pregnancies contributed by 1 502 895 women enrolled in Medicaid from 3 months before the last menstrual period through 1 month or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders. Ondansetron dispensing during the first trimester, the period of organogenesis. Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts. Among 1 816 414 pregnancies (mean age of mothers, 24.3 [5.8] years), 88 467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14 577 of 1 727 947 unexposed and 835 of 88 467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was -0.8 (95% CI, -7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, -7.3 to 18.2 per 10 000 births). Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts.

Maternal Folic Acid Supplementation and the Risk of Oral Clefts in Offspring.

There is controversial evidence from the literature regarding the protective effect of folic acid supplementation during pregnancy against orofacial clefts. The authors undertook this meta-analysis to assess whether folate supplementation during pregnancy can reduce the risk of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) in infants. Eligible articles were identified by searching databases, including PubMed, Medline, Scopus, ISI (Web of Knowledge) to September 2017. A meta-analysis was performed to evaluate the effects of maternal supplementation on oral clefts. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using Stata software. Publication bias was assessed by the Begg and Egger test. (Registration ID: CRD42018083922) RESULTS:: Out of the 1630 articles found in the authors' initial literature searches, 6 cohort studies, and 31 case-control studies were included in the authors' final meta-analysis. The results of the main analysis revealed that maternal folate supplementation was associated with a modest but statically significant decreased risk of all cleft subtypes (OR = 0.69, 95% CI: 0.60, 0.78). Folic acid intake alone was inversely associated with CL/P (OR = 0.73, 95% CI: 0.62-0.85,) but to a lesser extent than CPO (OR = 0.75, 95% CI = 053-1.04). Multivitamin intake had a significant protective effect for CL/P (OR = 0.65 95% CI = 0.55-0.80) as well as CPO (OR = 0.69, 95% CI = 0.53-0.90). Our results indicate that maternal supplementation in early pregnancy reduces the risk of nonsyndromic CL/P and CPO in infants. These data can serve to reassure women planning a pregnancy to consume multivitamins during the periconception period to protect against oral clefts.

Maternal exposure to ambient air pollutant and risk of oral clefts in Wuhan, China

Maternal exposure to ambient air pollution has been related to oral clefts in offspring; however, the epidemiologic evidence is equivocal. Especially, the association between high levels of exposure to ambient air pollution during pregnancy and oral clefts remains unclear. The objective of this study was to evaluate whether high levels of maternal exposure to PM2.5, PM10, O3, CO and SO2 are related to increased risk of oral clefts in Wuhan, China. A population-based study was conducted using cohort of 105,927 live-born infants, fetal deaths, and stillbirths during a two-year period from 2011 to 2013. For each participant, weekly and monthly averages of daily mean concentrations for each pollutant were estimated. Multiple logistic regression analyses were constructed to quantify the adjusted odds ratios (aORs) for the relationship between each air pollutant and oral clefts while controlling for key covariates. Using monthly averages, a cleft lip with or without cleft palate (CLP) was associated with PM2.5 (aORs 2nd month = 1.34, CI:1.19–1.49; aORs 3rd month=1.14, CI:1.02–1.28), PM10 (aORs 2nd month = 1.11, CI:1.00–1.23) and CO (aORs 2nd month = 1.31, CI:1.14–1.51; aORs 3rd month = 1.17, CI:1.03–1.33). A cleft palate only (CPO) was associated with PM2.5 (aORs 2nd month = 1.24, CI: 1.03–1.48), and O3 (aORs 2nd month = 1.21, CI: 1.03–1.42; aORs 3rd month = 1.18, CI: 1.02–1.37). Our findings reveal an association between air pollutants exposure and the risk of oral clefts. Future studies are needed to confirm these associations, and clarify the causality related to specific pollutants during the most relevant vulnerable exposure time windows for oral clefts during pregnancy.

Spotlight on the January 23 issue

#### Notable in Neurology this week This issue features an article that illustrates the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy and another that reports an increased risk of oral clefts associated with maternal use of high-dose topiramate early in pregnancy. A featured Medical Hypothesis article outlines the theory that exposure to low-dose organochlorine pesticides explains the difference in the association of midlife and late-life obesity with dementia risk. ### MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study In this study, the authors identified …

Pregnancy outcomes of women with spina bifida

Purpose: To assess the pregnancy outcomes of women with spina bifida.Materials and methods: We analyzed a population-based cohort of 397 pregnant women with spina bifida and 1,083,211 without spina bifida who delivered infants in hospitals in Quebec, Canada, 1989-2013. Outcomes included maternal and infant morbidity and mortality at delivery. We used log-binomial regression models to estimate prevalence ratios (PR) and 95% confidence intervals (CI) for the association of maternal spina bifida with pregnancy outcomes, accounting for maternal characteristics.Results: Women with spina bifida had a higher prevalence of several adverse outcomes compared with women who had no birth defects. Maternal risks were highest for intensive care unit admission during the delivery hospitalization (PR 3.41, CI 95% 1.56–7.43) and respiratory morbidity (PR 9.46, CI 95% 3.31–26.99). Infant risks were greatest for intracranial hemorrhage (PR 6.85, CI 95% 2.23–21.08), birth hypoxia (PR 1.64, CI 95% 1.21–2.22), and hospital length of stay ≥14 days (PR 2.56, CI 95% 1.58–4.15). After adjustment for confounders, maternal spina bifida was associated with risk of oral clefts and abdominal wall defects in infants.Conclusions: Women with spina bifida have an increased risk of severe maternal and infant complications at delivery, compared with no spina bifida.Implications for RehabilitationA growing number of women with spina bifida achieve pregnancy, but pregnancy outcomes are poorly understood.In a large pregnancy cohort, women with spina bifida had a high risk of severe maternal and infant morbidity at delivery.Women with spina bifida may benefit from enhanced periconceptional counseling and obstetric monitoring by health professionals.Guidelines should be developed for rehabilitation care providers to improve the obstetric management of women with spina bifida.

Maternal exposures and risk of oral clefts in South Vietnam.

Oral clefts are among the most common congenital anomalies. Most studies on risk factors of oral clefts have been carried out in developed countries. We investigated the associations between maternal exposures in the first trimester and oral clefts in South Vietnam. We conducted a hospital-based case-control study during October 2014-November 2015. Cases included 170 patients with nonsyndromic cleft lip with or without cleft palate and those with cleft palate only. Controls were 170 children without oral clefts, matched to each case by age and gender. Mothers were interviewed using structured questionnaire. We performed conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Passive smoking was associated with increased risk of oral clefts in univariate analysis, but not in multivariable analysis (adjusted OR [aOR] = 1.68; 95% CI, 0.53-5.37). No association was observed between liver intake and oral clefts. Compared with nondrinkers, mothers who reported consumption of caffeine-containing beverages were more likely to have an infant with oral cleft (aOR = 5.89; 95% CI, 1.08-32.00). Periconceptional use of folic acid and multivitamins supplementation was associated with reduced risk of oral clefts (aOR = 0.01; 95% CI, 0.00-0.09 and aOR = 0.03; 95% CI, 0.01-0.13, respectively). The results suggest no associations of maternal passive smoking or liver intake with oral clefts. Periconceptional use of folic acid or multivitamins may protect against oral clefts. Further studies are warranted to examine the roles of caffeine consumption in pregnant mothers on occurrence of oral clefts in offspring.

Risk of oral cleft from topiramate exposure increases with dosage

Risk of oral cleft from topiramate exposure increases with dosage

Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study.

To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications. This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted. The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group. The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

Individual deprivation, regional deprivation, and risk for oral clefts in Argentina

ABSTRACTObjective.The aim of this study was to analyze the effects of individual low socioeconomic status (SES) and deprived geographical area (GA) on the occurrence of isolated cleft lip with or without cleft palate (CL±P) in Argentina.Methods.This case-control study included 577 newborns with isolated CL±P and 13 344 healthy controls, born between 1992 and 2001, from a total population of 546 129 births in 39 hospitals in Argentina. Census data on unsatisfied basic needs were used to establish the degree of geographical area deprivation. An SES index for each individual was established, using maternal age, gravidity, low paternal and maternal education, and low-level paternal occupation. Logistic regression was used to assess the effects of low SES and of deprived GA on CL±P.Results.A slightly increased risk of CL±P was observed in mothers with a low SES, while a deprived GA showed no effect. Native ancestry, acute maternal illnesses, and poor prenatal care were significant risk factors for CL±P for the mothers with low SES, after using propensity scores to adjust for the demographic characteristics in cases and controls.Conclusions.Low individual SES slightly increased the risk for CL±P, but a deprived GA did not have that effect. There was no interaction between individual SES and deprived GA. Factors related to low individual SES—including poor prenatal care, low parental education, lack of information, and lifestyle factors—should be primarily targeted as risk factors for CL±P rather than factors related to a deprived place of residence.

Abstract: Maternal Tobacco Exposure and Risk of Orofacial Clefts in the Child

INTRODUCTION: While a relationship between maternal tobacco exposure and development of orofacial clefts in the child has been established for some time, the actual degree of risk conferred is not well quantified.1–3 A better understanding of this risk would benefit prenatal specialists in the counseling of prospective parents.4 The purpose of this study was to quantify the risk for cleft lip and/or cleft palate (CLP) associated with maternal tobacco exposure. METHODS: A case-control study was conducted at the Cleft Hospital and the Bashir Hospital in Gujrat, Pakistan from December 2015 to December 2016. All new cases of CLP at the Cleft Hospital were included in the study. Infants and children of three years of age or less at the Bashir Hospital were concurrently chosen to serve as control cases if they had no congenital malformations, were born or living in the same area as the patients in the study with CLP, and were of comparable socioeconomic standing to those patients. Bivariate analyses were performed to identify risk factors associated with CLP. These variables were then included alongside maternal tobacco exposure (whether one or both parents smoke) in a multiple logistic regression to calculate the adjusted odds ratio of developing CLP associated with tobacco exposure. RESULTS: A total of 329 patients with CLP and 131 controls were included in the study. Upon bivariate analysis, the following factors were associated with CLP: maternal tobacco exposure (p<0.001), complications during pregnancy (p<0.001), maternal hypertension (p=0.01), mother not on any medications (p<0.001), mother not receiving vaccinations (p<0.001), and lower socioeconomic status (p<0.001). After adjustment for these variables, having a smoking parent was associated with a 2.09 times increased odds of the child developing CLP (95% CI 1.22–3.58). Complications during pregnancy (OR=2.38, 95% CI 1.45–3.90), mother receiving vaccinations (OR = 0.32, 95% CI 0.16–0.64), and higher socioeconomic status (OR = 0.15, 95% CI 0.04–0.63) were also associated with CLP. CONCLUSION: While previous studies have consistently shown maternal tobacco exposure to be associated with development of orofacial clefts in the child, this study identifies and accounts for possible confounding variables in a case-control design, thereby providing a quantified estimate of the risk conferred by maternal tobacco exposure. This finding will be of value to providers in the context of perinatal counseling. Reference Citations: 1. Wyszynski DF, Duffy DL, Beaty TH. Maternal Cigarette Smoking and Oral Clefts: A Meta-analysis. Cleft Palate-Craniofacial J. 1997;34(3):206–210. doi:10.1597/1545–1569(1997)034<0206:MCSAOC>2.3.CO;2. 2. Little J, Cardy A, Munger RG. Tobacco smoking and oral clefts: a meta-analysis. Bull World Health Organ. 2004;82(3):213–218. 3. Xuan Z, Zhongpeng Y, Yanjun G, et al. Maternal active smoking and risk of oral clefts: a meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(6):680–690. doi:10.1016/j.oooo.2016.08.007. 4. Elahi MM, Jackson IT, Elahi O, et al. Epidemiology of cleft lip and cleft palate in Pakistan. Plast Reconstr Surg. 2004;113(6):1548–1555. doi:10.1097/01.PRS.0000117184.77459.2B.