Jin-Ping Zhao

Sertraline use during pregnancy and the risk of major malformations

OBJECTIVE Given the current debate and growing public concerns on selective serotonin reuptake inhibitors (SSRIs) and birth defects generated by Food and Drug Administration warnings, we aim to quantify the association between first-trimester exposure to sertraline, a first-line treatment, and the risk of congenital malformations in a cohort of depressed women. STUDY DESIGN This was a population-based cohort study in Quebec, Canada, 1998 through 2010. From a cohort of 18,493 depressed/anxious pregnancies, sertraline-exposed, nonsertraline SSRI-exposed, non-SSRI exposed, and unexposed (reference category) women were studied. Major malformations overall and organ-specific malformations in the first year of life were identified. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Analyses were adjusted for potential confounders. RESULTS Among the 18,493 eligible pregnancies, 366 were exposed to sertraline, 1963 to other SSRIs, and 1296 to non-SSRI antidepressants during the first trimester of pregnancy. Sertraline use was not statistically significantly associated with the risk of overall major malformations when compared to nonuse of antidepressants. However, sertraline exposure was associated with an increased risk of atrial/ventricular defects specifically (risk ratio [RR], 1.34; 95% CI, 1.02-1.76; 9 exposed cases), and craniosynostosis (RR, 2.03; 95% CI, 1.09-3.75; 3 exposed cases). Exposure to SSRIs other than sertraline during the first trimester of pregnancy was associated with craniosynostosis (RR, 2.43; 95% CI, 1.44-4.11; 19 exposed cases), and musculoskeletal defects (RR, 1.28; 95% CI, 1.03-1.58; 104 exposed cases). CONCLUSION Sertraline use during the first trimester of pregnancy was associated with an increased risk of atrial/ventricular defects and craniosynostosis above and beyond the effect of maternal depression. Nonsertraline SSRIs were associated with an increased risk of craniosynostosis and musculoskeletal defects.

Circulating docosahexaenoic acid levels are associated with fetal insulin sensitivity.

Background Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies. Methods and Principal Findings In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity. Conclusion Low circulating DHA levels are associated with compromised fetal insulin sensitivity, and may be involved in perinatally “programming” the susceptibility to type 2 diabetes in the offspring of gestational diabetic mothers.

Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort

Objective Antidepressant use during gestation has been associated with risk of major congenital malformations but estimates can lack statistical power or be confounded by maternal depression. We aimed to determine the association between first-trimester exposure to antidepressants and the risk of major congenital malformations in a cohort of depressed/anxious women. Setting and participants Data were obtained from the Quebec Pregnancy Cohort (QPC). All pregnancies with a diagnosis of depression or anxiety, or exposed to antidepressants in the 12 months before pregnancy, and ending with a live-born singleton were included. Outcome measures Antidepressant classes (selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA) and other antidepressants) and types were individually compared with non-exposure during the first trimester (depressed untreated). Major congenital malformations overall and organ-specific malformations in the first year of life were identified. Results 18 487 pregnant women were included. When looking at the specific types of antidepressant used during the first trimester, only citalopram was increasing the risk of major congenital malformations (adjusted OR, (aOR) 1.36, 95% CI 1.08 to 1.73; 88 exposed cases), although there was a trend towards increased risk for the most frequently used antidepressants. Antidepressants with serotonin reuptake inhibition effect (SSRI, SNRI, amitriptyline (the most used TCA)) increased the risk of certain organ-specific defects: paroxetine increased the risk of cardiac defects (aOR 1.45, 95% CI 1.12 to 1.88), and ventricular/atrial septal defects (aOR 1.39, 95% CI 1.00 to 1.93); citalopram increased the risk of musculoskeletal defects (aOR 1.92, 95% CI 1.40 to 2.62), and craniosynostosis (aOR 3.95, 95% CI 2.08 to 7.52); TCA was associated with eye, ear, face and neck defects (aOR 2.45, 95% CI 1.05 to 5.72), and digestive defects (aOR 2.55, 95% CI 1.40 to 4.66); and venlafaxine was associated with respiratory defects (aOR 2.17, 95% CI 1.07 to 4.38). Conclusions Antidepressants with effects on serotonin reuptake during embryogenesis increased the risk of some organ-specific malformations in a cohort of pregnant women with depression.

Use of macrolides during pregnancy and the risk of birth defects: a population‐based study

Macrolides have been linked to the occurrence of congenital heart defects, but findings are inconsistent. We therefore aimed to estimate the risk of major congenital malformations (MCMs) after fetal exposure to macrolides, focusing on cardiac malformations.

Female fetus is associated with greater maternal insulin resistance in pregnancy

To explore the hypothesis that female fetus is associated with greater maternal insulin resistance during pregnancy.

Longitudinal circulating concentrations of long‐chain polyunsaturated fatty acids in the third trimester of pregnancy in gestational diabetes

Gestational diabetes mellitus is a common complication of pregnancy. Long‐chain polyunsaturated fatty acids (LCPUFA) are essential for fetal neurodevelopment. Docosahexaenoic acid (DHA) is the predominant n–3 LCPUFA in the brain and retina. Circulating absolute concentrations of total n–3 and n–6 LCPUFAs rise during normal pregnancy. It remains unclear whether gestational diabetes may affect the normal rise in circulating concentrations of LCPUFAs in the third trimester of pregnancy – a period of rapid fetal neurodevelopment. This study aimed to address this question.

SSRI and SNRI use during pregnancy and the risk of persistent pulmonary hypertension of the newborn

Aim The use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). Limited data are available on the risk of PPHN associated with serotonin norepinephrine reuptake inhibitors (SNRIs). We aimed to quantify both associations. Methods Using data from the Quebec Pregnancy Cohort between 1998 and 2009, we included women covered by the provincial drug plan who had a singleton live birth. Exposure categories were SSRI, SNRI and other antidepressant use; non‐users were considered as the reference category. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Confounding by indication was minimized by adjusting for history of maternal depression/anxiety before pregnancy. Results Overall, 143 281 pregnancies were included; PPHN was identified in 0.2% of newborns. Adjusting for maternal depression, and other potential confounders, SSRI use during the second half of pregnancy was associated with an increased risk of PPHN [adjusted odds ratio (aOR) 4.29, 95% CI 1.34, 13.77] compared with non‐use of antidepressants; SNRI use during the same time window was not statistically associated with the risk of PPHN (aOR 0.59, 95% CI 0.06, 5.62). Use of SSRIs and SNRIs before the 20th week of gestation was not associated with the risk of PPHN. Conclusions Use of SSRIs in the second half of pregnancy was associated with the risk of PPHN. Given our results on SNRIs and the lack of statistical power for these analyses, it is unclear whether SNRI use during pregnancy also increases the risk of PPHN.

Association between CYP2D6 Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy

Importance: Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by CYP2D6 genotype. Objective: To investigate the association between CYP2D6 genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal CYP2D6, Antidepressants, Depression during pregnancy. Setting: Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006–2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic. Main Outcomes and Measures: Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for CYP2D6 genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals. Results: A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, n = 204, 83%); 3.3% (n = 8) were ultrarapid metabolizers (UM), 5.7% (n = 14) poor metabolizers (PM), and 8.1% (n = 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptom in the first trimester (19.81 vs. 5.88%, P = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM). Conclusions and Relevance: Prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.

Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes

Objectives Leflunomide is known to be embryotoxic and teratogenic in rodents. However, there is less evidence in humans. We quantified the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans. Methods From a cohort of 289 688 pregnancies in Montreal, Quebec, Canada, from 1998 to 2015, first-trimester leflunomide exposure and other antirheumatic drug exposures were studied for their association with MCM and spontaneous abortions. Also second or third-trimester leflunomide exposures were examined for associations with prematurity and LBW. Logistic regression model-based generalised estimating equations were used. Results 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. Adjusting for potential confounders, use of leflunomide during the first trimester of pregnancy was not associated with the risk of MCM (adjusted OR (aOR) 0.97, 95% CI 0.81 to 1.16; 5 exposed cases). No association was found between second/third-trimester exposure to leflunomide and the risk of prematurity (aOR 4.03, 95% CI 0.91 to 17.85; 7 exposed cases) nor LBW (aOR 1.06, 95%CI 0.90 to 1.25; 8 exposed cases). Pregnancy exposure to leflunomide was also not associated with the risk of spontaneous abortion (aOR 1.09, 95% CI 0.90 to 1.32; 11 exposed cases). Conclusions Maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted.

Antiretroviral combination use during pregnancy and the risk of major congenital malformations

Objective: To quantify the risk of major congenital malformations (MCMs) associated with gestational combination antiretroviral use. Design: Population-based prospective cohort study. Methods: Using the Quebec Pregnancy Cohort from 1998 to 2015, we included women who were covered by the Quebec Drug Plan and had a singleton livebirth. All antiretroviral use alone or in combination were considered. MCMs overall and organ-specific malformations in the first year of life were identified. Results: In total, 214 240 pregnancies met inclusion criteria; 0.09% (n = 198) occurred while on antiretroviral combinations during the first trimester; 169 HIV-positive women without antiretroviral treatment were included. Compared with the general population in this cohort, the prevalence of MCMs was significantly higher in unexposed HIV-positive women (14.8 vs. 8.6%, P = 0.004) but not in antiretroviral-exposed HIV-positive women (10.3%, P = 0.41). Adjusting for potential confounders, including maternal HIV status, antiretroviral use during the first trimester was not associated with the risk of MCMs (adjusted odds ratio 0.59, 95% confidence interval 0.33–1.06). However, antiretroviral combination use during the first trimester was associated with an increased risk of defects of the small intestine (adjusted odds ratio 10.32, 95% confidence interval 2.85–37.38, P = 0.0004). Conclusion: Antiretroviral therapy during the first trimester was not associated with the risk of overall MCMs but may be associated with an increased risk of defects of the small intestine. However, HIV-positive pregnant women who are not treated with antiretrovirals during pregnancy seem to have a higher risk of malformations; this is not seen among those who are treated, which could indicate that the underlying condition puts women at risk and not the treatment.