Risk Of Cardiac Malformations Research Articles

Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations

This pharmacoepidemiology study uses Medicaid data to estimate associations between first-trimester use of intravenous ondansetron and risk of cardiac malformations and oral cleft in children of exposed mothers.

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

(JAMA. 2018;320(23):2429–2437) Ondansetron, a 5-HT3 receptor antagonist, has become the most frequently prescribed drug for nausea and vomiting during pregnancy. However, this medication is not formally approved for this use, and available evidence regarding ondansetron and fetal safety is limited or conflicting. The American College of Obstetricians and Gynecologists has concluded that further studies are warranted. Therefore, the authors of the present study investigated potential associations between ondansetron exposure during the first trimester of pregnancy and the risk of cardiac malformations and/or oral clefts in neonates.

Cardiomyopathies and Congenital Heart Disease in Pregnancy.

Pregnancy-associated diseases of the cardiovascular system occur in up to 10% of all pregnancies and the incidence is increasing. Besides congenital heart disease or pre-existing cardiomyopathy in the mother, the clinical focus has moved especially to peripartum cardiomyopathy (PPCM) because of the conditionʼs dramatic clinical course and the identification of the underlying mechanisms. This review article concentrates therefore on PPCM, which occurs either in the last month of pregnancy or in the first 6 months following delivery in women with previously healthy hearts. The global incidence is estimated today at roughly 1 : 1000 pregnancies. The condition is heterogeneous, ranging from mild disease to severe acute heart failure with cardiogenic shock and sudden cardiac death of the mother. Important risk factors are pregnancy-associated hypertensive complications, multiple pregnancy and greater maternal age. The pathogenesis comprises cleavage, induced by increased oxidative stress, of the lactation hormone prolactin into a toxic hormone fragment that damages blood vessels, known as the 16-kDalton protein fragment. The lactation-blocking drug bromocriptine prevents prolactin release and promotes healing of PPCM in combination with pharmacological heart failure therapy; it appears to prevent recurrence in subsequent pregnancies. Uncomplicated pregnancy is possible in most patients with congenital heart disease. The foetal complications include an increased abortion rate, prematurity and smallness for gestational age, as well as an increased risk of cardiac malformations. The maternal risk comprises mainly arrhythmias, progressive heart failure and thrombembolic complications, with the risk of vessel dissection with a low mortality risk of < 1% in the case of aortopathies. Individual risk assessment and corresponding close monitoring of the pregnancy are required.

Is the risk of cardiac malformations significantly increased among infants born to women who took SSRIs during the first trimester?

Is the risk of cardiac malformations significantly increased among infants born to women who took SSRIs during the first trimester?

Lithium Use in Pregnancy and the Risk of Cardiac Malformations

(N Engl J Med. 2017;376(23):2245–2254) Lithium is a first-line treatment for bipolar disorder in women of reproductive age in the United States, and has even been reported to reduce the risk of mood-episode recurrence during pregnancy and the postpartum period. However, infants born to mothers treated with lithium early in pregnancy are at increased risk for cardiac defects, although some small studies have shown conflicting results. Consequently, the authors of this large, retrospective cohort study evaluated the records of pregnant women nested in the US Medicaid Analytic eXtract (MAX), to provide evidence of the association between increased risk of neonatal cardiac malformations and maternal use of lithium in the first trimester.

Lithium Use in Pregnancy and the Risk of Cardiac Malformations

BackgroundThere has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein’s anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited. MethodsWe conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders. ResultsCardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of th...

Chronic hypertension in pregnancy and the risk of congenital malformations: a cohort study

Chronic hypertension is a common medical condition in pregnancy. The purpose of the study was to examine the association between maternal chronic hypertension and the risk of congenital malformations in the offspring. We defined a cohort of 878,126 completed pregnancies linked to infant medical records using the Medicaid Analytic Extract. The risk of congenital malformations was compared between normotensive controls and those with treated and untreated chronic hypertension. Confounding was addressed using propensity score matching. After matching, compared with normotensive controls, pregnancies complicated by treated chronic hypertension were at increased risk of congenital malformations (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.2-1.5), as were pregnancies with untreated chronic hypertension (OR 1.2; 95% CI, 1.1-1.3). In our analysis of organ-specific malformations, both treated and untreated chronic hypertension was associated with a significant increase in the risk of cardiac malformations (OR, 1.6; 95% CI, 1.4-1.9 and OR, 1.5; 95% CI, 1.3-1.7, respectively). These associations persisted across a range of sensitivity analyses. There is a similar increase in the risk of congenital malformations (particularly cardiac malformations) associated with treated and untreated chronic hypertension that is independent of measured confounders. Studies evaluating the teratogenic potential of antihypertensive medications must control for confounding by indication. Fetuses and neonates of mothers with chronic hypertension should be carefully evaluated for potential malformations, particularly cardiac defects.

Research round-up

Research round-up

First-trimester exposure to bupropion and risk of cardiac malformations

Bupropion is a drug uniquely used both to treat depression and as an aid to smoking cessation. We investigated previously reported associations between first-trimester exposure to bupropion and cardiac defects. Using data gathered since 2003 by the Slone Epidemiology Center's Case-control Birth Defects Study, we classified subjects with cardiac defects into subgroups. Exposure categories included first-trimester bupropion alone or in combination with other antidepressants, first-trimester antidepressants other than bupropion, and no exposure to any antidepressant at any time from 2 months prior to pregnancy through delivery. We calculated odds ratios and 95% confidence intervals, controlling for confounding using logistic regression. There were 8611 non-malformed infants and 7913 infants with cardiac defects. Eight cardiac subgroups had sufficient subjects (two or more exposed cases) for analysis. The adjusted odds ratio (aOR) for first-trimester bupropion use in relation to ventricular septal defect (VSD) was slightly elevated (1.6, 95% confidence interval 1.0-2.8); for exposure to bupropion alone, the aOR was 2.5 (95% confidence interval 1.3-5.0). Risks were not materially elevated for bupropion in relation to the other seven cardiac subgroups. We did not confirm previously reported associations for left-sided defects overall but had too few exposed cases to evaluate specific defects in this category. We did observe an elevated risk of VSD following first-trimester bupropion use, particularly when used without other antidepressants. This pattern for bupropion alone was observed in all our risk comparisons and was not explained by higher doses or gestational timing.

Prenatal Exposure to Antidepressants: How Safe Are They?

Prenatal Exposure to Antidepressants: How Safe Are They?

A Triple Threat: Down Syndrome, Congenital Central Hypoventilation Syndrome, and Hirschsprung Disease

Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS. Given the systemic nature of DS-related features, it is natural to attribute neonatal complications to the chromosomal aberration. We describe a biracial male infant with DS who had significantly delayed defecation and required continuous ventilator support, but had no primary cardiac or lung disease. Subsequent evaluations confirmed total colonic aganglionosis. Because we were unable to safely extubate the infant, a diagnosis of congenital central hypoventilation syndrome (CCHS) was considered and confirmed by molecular analysis of the PHOX2B gene, revealing a heterozygous polyalanine repeat-expansion mutation containing 27 repeats (normal gene contains 20 repeats). HSCR coexisting with CCHS is known as Haddad syndrome. This is the first reported case with co-occurrence of DS, CCHS, and HSCR.

Paroxetine Use During Pregnancy and Perinatal Outcomes Including Types of Cardiac Malformations in Quebec and France: A Short Communication

Antidepressants, more specifically SSRIs, represent one example of a widely prescribed class of medications in pregnant women for which less than adequate pregnancy data have been available since the first drug in this class was marketed 20 years ago. Moreover, findings from studies performed after 2005, when health governmental authorities issued warnings regarding first trimester exposure to paroxetine and the risk of cardiac malformations, may be the result of detection bias if physicians were investigating more their pregnant patients that used paroxetine than the others. To estimate the prevalence of 1) paroxetine use during pregnancy, and 2) diagnosed cardiac malformations in the Quebec and France populations. Two distinct pregnancy databases were used for this ecologic study: the Quebec Pregnancy Registry and the French EFEMERIS database. In Quebec, among the 109,344 eligible pregnancies, 1,612 (1.5%) were exposed to paroxetine. Prevalence of paroxetine use during pregnancy increased from 0.7% to 1.2% between 1998 and 2003, simultaneously to the increase of the prevalence of cardiac malformation diagnoses. In France, among 40,317 eligible pregnancies, 173 (0.4%) were exposed to paroxetine; between 2004 and 2008 the number of paroxetine fillings and cardiac malformation diagnoses remained constant. Despite differences in the Quebec and French healthcare systems, increase in paroxetine prevalence use during pregnancy was already consistent with an increase in the prevalence of cardiac malformations, even before the warning on the risk of cardiac malformations in newborns in 2005-2006, limiting the possibility of detection bias.

Do Drug Warnings and Market Withdrawals Have an Impact on the Number of Calls to Teratogen Information Services?

IMAGe provides information on risks and benefits of medication use during pregnancy and lactation. The aim of this study was to determine the impact of Health Canada warnings on the number of calls received at IMAGe. We analyzed calls received between January 2003 and March 2008. The impact of the following warning/withdrawal were studied: paroxetine and risk of cardiac malformations (09/29/2005), selective serotonin reuptake inhibitors (SSRIs) and risk of persistent pulmonary hypertension of the newborn (PPHN) (03/10/2006), and impact of rofecoxib market withdrawal (09/30/2004). Interrupted auto-regressive integrated -moving average (ARIMA) analyses were used to test the impact of each warning on the number of calls received to IMAGe. 61,505 calls were analyzed. The paroxetine warning had a temporary impact increasing the overall number of calls to IMAGe, and an abrupt permanent effect on the number of calls related to antidepressant exposures. The PPHN warning had no impact but we observed a significant increase in the number of calls following rofecoxib market withdrawal. Health Canada needs to consider the increase in the demand of information to IMAGe following warnings on the risk of medication use during pregnancy.

Maternal obesity predict isolated birth defects in live births in Eastern Province of Saudi Arabia

Objective: There is no research on the predictors of birth defects in Al Ahsa Governorate in the Eastern Province of Saudi Arabia. The aim of this research was to detect the predictors of isolated structural birth defects in live births. Methods: We conducted this study from April 2006 to 2010. Live births with isolated birth defects represented our sample for this retrospective case control study. Univariate analysis was done for all possible risk factors. Logistic regression analysis was done for all predictors in relation to different birth defects. Results: Out of 37168 live births, isolated structural birth defects were found in 318 cases. Obesity ( body mass index > 30) was a significant predictor for increased nervous system anomalies ( odds ratio (OR): 7.83, CI: 3.9–15.4), facial defects (OR: 5.92, CI: 2.8–12.4), genitourinary anomalies (OR: 4.6 CI: 1.9–11.1), and cardiac malformations (OR: 2.7 CI: 1.3–5.7). Consanguinity increased the risk for cardiac malformations (OR: 3.32, CI: 1.54–7.17). Low socio-economic status increased the risk for nervous system anomalies (OR: 2.09, CI: 1.18–3.7), facial defects (OR: 2.33, CI: 1.25–4.33) and musculoskeletal anomalies (OR: 2.3, CI: 1.29–4.09). Conclusion: Maternal obesity represented the most common predictor for certain categories of isolated structural birth defects including nervous system, facial, genitourinary and cardiac.

PW01-259 - Paroxetine use during pregnancy and adverse pregnancy outcomes in the absence of detection bias

ObjectiveTo quantify the prevalence of adverse pregnancy outcomes associated with gestational exposure to paroxetine before the FDA warnings on the risk of cardiac malformations in newborns associated with the use of paroxetine during gestation were issued in 2005.MethodsData on all pregnancies included in the Quebec Pregnancy Registry were analysed to estimate the prevalence of planned/spontaneous abortions and deliveries during 1998-2004, before the warnings were issued. All study outcomes including congenital malformations are physician-based, and made prospectively and routinely as part of health care management; exposure to paroxetine is based on automated prescription fillings. Trends in the frequency of gestational use of paroxetine during the study period were compared to the trends in the prevalence of cardiac malformations.ResultsAmong the 109,344 eligible pregnancies, 1,612 (1.5%) were exposed to paroxetine. Amongst paroxetine users, 49% had a planned abortion, 7% a spontaneous abortion, and 44% a delivery. Amongst those who delivered, 3% had a baby with a cardiac malformation. The most prevalent cardiac malformations were atrial and ventricular septal defects (74%). During the study period, an increase in the prevalence of paroxetine use during pregnancy was correlated with an increase in the rate of cardiac malformations.ConclusionParoxetine use during gestation is associated with an important risk of adverse pregnancy events above baseline rates. Before the warnings on paroxetine were issued, the increase in the prevalence of paroxetine use during pregnancy was already correlated with an increase in the rate of cardiac malformations, excluding the possibility of detection bias.

Paroxetine exposure during pregnancy and the risk of cardiac malformations: What is the evidence?

Paroxetine exposure during pregnancy and the risk of cardiac malformations: What is the evidence?

First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage

Conflicting findings with regard to the teratogenic risks of first trimester use of paroxetine have prompted the FDA, Health Canada, and the manufacturer of the drug to issue warnings against its use during pregnancy. Given that untreated depression during pregnancy can lead to deleterious effect on the mother and her unborn fetus, data on the relationship between the dose and the range of malformations is warranted. This study attempts to quantify the association between first trimester exposure to paroxetine and congenital cardiac malformations, adjusting for possible confounders, and to quantify the dose-response relationship between paroxetine use and cardiac defects. The Medication and Pregnancy registry was used. This population-based registry was built by linking three administrative databases (RAMQ, Med-Echo, and ISQ), and includes all pregnancies in Quebec between 01/01/1997 and 06/30/2003. Date of entry in the registry is the date of the first day of the last menstrual period. To be eligible for this study, women had to: 1) be 15-45 years of age at entry; 2) be covered by the RAMQ drug plan >or=12 months before and during pregnancy; 3) be using only one type of antidepressant during the first trimester; and 4) have a live birth. Two nested case-control studies were carried out comparing the prevalence of paroxetine use in the first trimester of pregnancy to the prevalence of other antidepressant exposures during the same time period. Cases were defined as: 1) any major malformations; or 2) any cardiac malformations diagnosed in the first year of life; controls were defined as no major or minor malformations. Multivariate logistic regression techniques were used to analyze data. Among the 1,403 women meeting inclusion criteria, 101 infants with major congenital malformations were identified; 24 had cardiac malformations. Adjusting for possible confounders, the use of paroxetine (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 0.49-3.92), and the use of other SSRIs (OR = 0.89, 95% CI = 0.28-2.84) during the first trimester of pregnancy did not increase the risk of congenital cardiac malformations compared with the use of non-SSRI antidepressants. When considering the dose, however, a dose-response relationship was observed, thus women exposed to >25 mg/day of paroxetine during the first trimester of pregnancy were at increased risk of having an infant with major congenital malformations (adjusted [adj] OR = 2.23, 95% CI = 1.19, 4.17), or major cardiac malformations (adj OR = 3.07, 95% CI = 1.00, 9.42). Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day.

How successful is fetal echocardiographic examination in the first trimester of pregnancy?

Transvaginal echocardiography is still rarely incorporated into the first-trimester ultrasound examination, despite the fact that heart defects are the most frequently encountered congenital malformation. This study was undertaken to explore the possibilities of fetal echocardiography in the late first trimester. In 85 women with uncomplicated singleton pregnancies, three transvaginal ultrasound examinations between 11+0 and 13+6 weeks' gestation were performed. The examinations were carried out at weekly intervals and visualization of several echocardiographic planes was attempted (four-chamber view, aortic root, long axis of the aorta, pulmonary trunk with three-vessel view, cross-over of the great arteries). The diameter of the aorta and pulmonary trunk were measured to establish reference ranges. The success rate of visualization of the different parameters increased with gestational age. The ability to perform a full cardiac examination increased from 20% in week 11 to 92% in week 13. Longitudinally derived growth curves of the aorta and the pulmonary trunk were constructed and both showed a linear increase with gestational age. The best time in the first trimester to perform transvaginal echocardiography is at 13+0 to 13+6 weeks' gestation. In this period, a full cardiac examination is possible in 92% of cases. The increase of success rate compared to earlier studies is likely to result from the use of better resolution, high-frequency transvaginal probes. First-trimester echocardiography provides an opportunity to examine the fetal heart early in gestation, especially in patients at risk for cardiac malformations because of a positive family history or in fetuses with increased nuchal translucency.