Medically assisted reproduction and the risk of being born small and very small for gestational age: Assessing prematurity status as an effect modifier.

Over the last decade, the use of medically assisted reproduction (MAR) has steadily increased but controversy remains with regards to its risks. We aimed to quantify the risk of being born small for gestational age (SGA) and very SGA (VSGA) associated with MARs overall and by type, namely ovarian stimulators (OS) and assisted reproductive technology (ART). We conducted a cohort study within the Quebec Pregnancy Cohort. Pregnancies coinciding with Quebec's MAR reimbursement PROGRAM period (2010-2014) with a singleton liveborn were considered. MAR was first defined dichotomously, using spontaneous conception as the reference, and categorized into three subgroups: OS alone (categorized as clomiphene and non-clomiphene OS), ART, OS/ART combined. SGA was defined as being born with a birth weight below the 10th percentile based on sex and gestational age (GA), estimated using populational curves in Canada, while VSGA was defined as being born with a birth weight below the 3rd percentile. We then estimated odds ratios (OR) for the association between MAR and SGA as well as VSGA using generalized estimated equation (GEE) models, adjusted for potential confounders (aOR). Two independent models were conducted considering MAR exposure overall, and MAR subgroup categories, using spontaneous conceptions as the reference. The impact of prematurity status (less than 37 weeks gestation) as an effect modifier in these associations was assessed by evaluating them among term and preterm pregnancies separately. A total of 57,631 pregnancies met inclusion criteria and were considered. During the study period, 2,062 women were exposed to MARs: 420 to OS alone, 557 to ART, and 1,085 to OS/ART combined. While no association was observed between MAR and SGA nor VSGA in the study population, MAR was associated with an increased risk for SGA (aOR 1.69, 95% CI 1.08-2.66; 25 exposed cases) among preterm pregnancies; no increased risk of SGA was observed in term pregnancies. MARs are known to increase the risk of preterm birth and our results further confirm that they also increase the risk of SGA among preterm pregnancies.

The Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO): Comparisons between Quebec, Manitoba, Saskatchewan, and Alberta.

BACKGROUND: Given that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces. METHODS: CAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998-2015), Manitoba (1995-2019), Saskatchewan (1996-2020), and Alberta (2005-2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests. RESULTS: Almost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9-6.8%), LBW (4.0-5.2%), and multiplicity (1.0-2.5%) were statistically significant between provinces (p<0.001). Frequency of major malformations increased over time in Quebec (7-11%; p<0.001), Saskatchewan (5-11%; p<0.001), and Alberta (from 7-8%; p<0.001), and decreased in Manitoba (5-3%; p<0.001). Cardiovascular and musculoskeletal malformations were the most prevalent. INTERPRETATION: Medications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends.

Is in-utero exposure to cannabis associated with the risk of attention deficit with or without hyperactivity disorder? A cohort study within the Quebec Pregnancy Cohort.

IMPORTANCE AND OBJECTIVE: Prenatal cannabis effect on attention deficit with or without hyperactivity disorder (ADHD) remains to be determined. Our aim is to quantify the impact of in-utero exposure to cannabis on the risk of ADHD. DESIGN: Cohort study. SETTING: Questionnaires were mailed to women sampled from the Quebec Pregnancy Cohort (QPC). Data from questionnaires were then linked with their QPC (built with administrative health databases, hospital patient charts and birth certificate databases). PARTICIPANTS: Respondents who gave birth to a singleton live born between January 1998 and December 2003 and were continuously enrolled in the Régie de l'assurance maladie du Québec (RAMQ) medication insurance plan for at least 12 months before the first day of gestation and during pregnancy. EXPOSURE: In-utero cannabis exposure was based on mothers' answers to the question on cannabis use during pregnancy (yes/no) and categorised as occasionally, regularly exposed and unexposed if they chose one of these categories. OUTCOMES: ADHD was defined by a diagnosis of ADHD through the RAMQ medical services or MedEcho databases or a prescription filled for ADHD medication through RAMQ pharmaceutical services between birth and the end of the follow-up period. Follow-up started at the birth and ended at the index date (first diagnosis or prescription filled for ADHD), child death (censoring), end of public coverage for medications (censoring) or the end of study period, which was December 2015 (censoring), whichever event came first. RESULTS: A total of 2408 children met the inclusion criteria. Of these children, 86 (3.6%) were exposed to cannabis in-utero and 241 (10.0%) had an ADHD diagnosis or medication filled. After adjustments for potential confounders, no significant association was found between in-utero cannabis exposure (occasional (1.22 (95% CI 0.63 to 2.19)) or regular (1.22 (95% CI 0.42 to 2.79))) and the risk of ADHD in children. CONCLUSIONS: In-utero exposure to cannabis seemed to not be associated with the risk ADHD in children.

Prevalence and duration of prescribed opioid use during pregnancy: a cohort study from the Quebec Pregnancy Cohort.

BACKGROUND: Recent studies show a rapid growth among pregnant women using high potency opioids for common pain management during their pregnancy. No study has examined the duration of treatment among strong opioid users and weak opioid users during pregnancy. We aimed to investigate the prevalence of prescribed opioid use during pregnancy, in Quebec; and to compare the duration of opioid treatment between strong opioid users and weak opioid users. METHODS: Using the Quebec Pregnancy Cohort (1998-2015), we included all pregnancies covered by the Quebec Public Prescription Drug Insurance Program. Opioid exposure was defined as filled at least one prescription for any opioid during pregnancy or before pregnancy but with a duration that overlapped the beginning of pregnancy. Prevalence of opioids use was calculated for all pregnancies, according to pregnancy outcome, trimester of exposure, and individual opioids. The duration of opioid use during pregnancy was analyzed according to 8 categories based on cumulative duration (< 90 days vs. ≥90 days), duration of action (short-acting vs. long-acting) and strength of the opioid (weak vs. strong). RESULTS: Of 442,079 eligible pregnancies, 20,921 (4.7%) were exposed to opioids. Among pregnancies ending with deliveries (n = 249,234), 5.4% were exposed to opioids; the prevalence increased by 40.3% from 3.9% in 1998 to 5.5% in 2015, more specifically a significant increase in the second and third trimesters of pregnancy. Weak opioid, codeine was the most commonly dispensed opioid (70% of all dispensed opioids), followed by strong opioid, hydromorphone (11%), morphine (10%), and oxycodone (5%). The prevalence of codeine use decreased by 47% from 4.3% in 2005 to 2.3% in 2015, accompanied by an increased use of strong opioid, morphine (0.029 to 1.41%), hydromorphone (0.115 to 1.08%) and oxycodone (0.022 to 0.44%), from 1998 to 2015. The average durations of opioid exposure were significantly longer among pregnancies exposed to strong opioid as compared to weak opioid regardless of the cumulative duration or duration of action (P < 0.05). CONCLUSIONS: Given the differences in the safety profile between strong opioids and the major weak opioid codeine, the increased use of strong opioids during pregnancy with longer treatment duration raises public health concerns.

Chloroquine and Hydroxychloroquine Use During Pregnancy and the Risk of Adverse Pregnancy Outcomes Using Real-World Evidence.

Introduction: Chloroquine (CQ) and hydroxychloroquine (HCQ) are currently used for the prevention/treatment of malaria, and treatment of systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Although present data do not show their efficacy to treat COVID-19, they have been used as potential treatments for COVID-19. Given that pregnant women are excluded from randomized controlled trials, and present evidence are inconsistent and inconclusive, we aimed to investigate the safety of CQ or HCQ use in a large pregnancy cohort using real-world evidence. Methods: Using Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn, 1998-2015, (n = 233,748). The exposure time window for analyses on prematurity and low birth weight (LBW) was the second/third trimesters; was any time during pregnancy; only first trimester exposure was considered for analyses on major congenital malformations (MCM). The risk of prematurity, LBW, and MCM (overall and organ-specific) were quantified using generalized estimation equations. Results: We identified 288 pregnancies (0.12%) exposed to CQ (183, 63.5%) or HCQ (105, 36.5%) that resulted in liveborn singletons; CQ/HCQ was used for RA (17.4%), SLE (16.3%) or malaria (0.7%). CQ/HCQ was used for 71.8 days on average [standard-deviation (SD) 70.5], at a dose of 204.3 mg/d (SD, 155.6). We did not observe any increased risk related to CQ/HCQ exposure for prematurity (adjusted odds ratio [aOR] 1.39, 95%CI 0.84-2.30), LBW (aOR 1.11, 95%CI 0.59-2.06), or MCM (aOR 1.01, 95%CI 0.67-1.52). Conclusion: in this large CQ/HCQ exposed pregnancy cohort, we saw no clear increased risk of prematurity, LBW, or MCM, although number of exposed cases remained low.

Available medications used as potential therapeutics for COVID-19: What are the known safety profiles in pregnancy.

BACKGROUND: Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source. METHODS: Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998-2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations. RESULTS: Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11-3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31-1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01-4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41-2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25-4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00-1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51-4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02-2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02-1.19; 747 exposed cases) exposures were associated with MCM. CONCLUSIONS: Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.

Prevalence and determinants of attention deficit/hyperactivity disorder (ADHD) medication use during pregnancy: Results from the Quebec Pregnancy/Children Cohort.

AIMS: The use of attention deficit/hyperactivity disorder (ADHD) medications has grown over the past decade among pregnant women, but these treatments are not without risk. Updated prevalence of ADHD medication use and whether prescribed dosages follow guidelines are needed. The aim of this study is to describe the prevalence of ADHD medication use among pregnant women-dosages and switches-and identify determinants of ADHD medication use. METHOD: A population-based longitudinal cohort study within the Quebec Pregnancy/Children Cohort (QPC). Women aged 15-45 years old covered by the RAMQ prescription drug plan for at least 12 months before and during pregnancy from 1998 to 2015. ADHD medication exposure was assessed before and during pregnancy. We estimated odds ratios (ORs) for determinants of ADHD medication use during pregnancy with generalized estimating equations. RESULTS: Among 428,505 included pregnant women, 1,130 (0.26%) used ADHD medication. A 14-fold increase in the prevalence of ADHD medication use in pregnant women was observed, from 1998 (0.08%) to 2015 (1.2%). Methylphenidate was the most prevalent medication at 70.1%. ADHD medication fillings were at optimal dosage 91.8% of the time based on guidelines and 18.1% of women switched to another ADHD medication class during gestation. Main determinants of ADHD medication use during pregnancy were psychiatric disorders (aOR 2.19; 95% confidence interval [CI] 1.57, 2.96), mood and anxiety disorders (aOR 1.74; 95% CI 1.32, 2.24), and calendar year. CONCLUSIONS: The number of pregnancies exposed to ADHD medications has increased similarly to the increase reported in other countries between 1998 and 2015. In addition to the current literature, the use of ADHD medications during pregnancy is consistent with Canadian guidelines recommendations on dosage.

Maternal ADHD medication use during pregnancy and the risk of ADHD in children: Importance of genetic predispositions and impact of using a sibling analysis.

Attention deficit with hyperactivity disorder (ADHD) medications in pregnancy would be associated with ADHD in children, however, estimates can be confounded by genetic predispositions and environmental factors related to the mother-child pair. We aim to quantify the risk of ADHD in children associated with ADHD medication exposures during pregnancy. A prospective cohort study and sibling analysis conducted within The Quebec Pregnancy/Child Cohort (QPC). All full-term singleton live births covered by the provincial prescription drug insurance in Quebec from 1998 to 2015 were included. ADHD medication exposure during pregnancy was defined according to trimester of use and class-specific medication. ADHD in children was defined as having at least one diagnosis or one prescription filled for an ADHD medication. Cox proportional hazards regression models were used to calculate crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) in the overall cohort, the sub-cohort and the sibling analysis. Of 166,047 full-term singleton live births included, 25,454 (15.3%) had ADHD. In the overall cohort, maternal exposure to ADHD medication during pregnancy was associated with ADHD in children (aHR= 1.96, 95% CI 1.22-3.15). In the ADHD pregnant women sub-cohort (aHR= 1.56; 95% CI 0.93-2.62) and the sibling control analysis (aHR= 1.14; 95% CI 0.62-1.98), ADHD medications during pregnancy was not associated with an increased risk of ADHD in children. Our findings suggest that in utero exposure to ADHD medications was not associated with an increased risk of ADHD in children. This suggests that the association is due to genetic and/or family environmental factors.

Medically assisted reproduction and the risk of preterm birth: a case-control study using data from the Quebec Pregnancy Cohort.

BACKGROUND: The use of fertility treatments has been growing over the past decade, but these treatments are not without risk. We aimed to quantify the risk of preterm birth associated with the use of ovarian stimulators (OS) and assisted reproductive technologies (ART) overall and by type of fertility treatment. METHODS: We conducted a case-control analysis of data from the Quebec Pregnancy Cohort. We included singleton pregnancies ending in a live birth during the time when Quebec operated a universal reimbursement program for assisted reproduction (2010-2015). Fertility treatments were defined dichotomously, and pregnancies resulting from spontaneous conception were used as the reference. We categorized fertility treatments into subgroups: ovarian stimulators alone, ART alone and OS and ART combined. Preterm birth was defined as birth before 37 weeks' gestation. We estimated odds ratios (ORs) for the association between type of assisted reproduction and preterm birth using generalized estimating equation models and adjusted ORs for potential confounders. RESULTS: A total of 57 624 pregnancies were included in the study. During the study period, 2055 pregnancies were conceived through the use of OS, ART or both: 419 involved OS alone, 150 involved ART alone and 1486 involved both OS and ART. When we adjusted for potential confounders, conception with OS, ART or both was associated with an increased risk of preterm birth (adjusted OR 1.46, 95% confidence interval [CI] 1.25-1.72, 182 exposed cases). All types of assisted reproduction were associated with an increased risk of preterm birth compared with pregnancies conceived spontaneously (OS alone: adjusted OR 1.47, 95% CI 1.04-2.07; ART alone: adjusted OR 1.76, 95% CI 1.01-3.06; OS and ART combined: adjusted OR 1.43, 95% CI 1.19-1.73). Use of OS or ART or both was associated with an increased risk of late, moderate and extremely preterm birth (extremely preterm birth: adjusted OR 2.39, 95% CI 1.30-4.39). INTERPRETATION: Compared with pregnancies conceived spontaneously, pregnancies conceived through the use of OS, ART or both were associated with a 46% increased risk of preterm birth. Physicians should advise patients of the increased risks of late, moderate and extremely preterm birth so that they can make informed choices.

Antidepressant use during pregnancy and the risk of gestational diabetes mellitus: a nested case-control study.

OBJECTIVES: The aim of this study was to determine the association between antidepressant (AD) classes, types and duration of use during pregnancy and the risk of gestational diabetes mellitus (GDM). DESIGN AND SETTING: A nested case-control study was conducted within the Quebec Pregnancy Cohort (QPC), a Canadian provincial database which includes data on all pregnancies and children in Quebec from January 1998 to December 2015. PRIMARY OUTCOME MEASURES: Gestational diabetes mellitus. PARTICIPANTS: Cases of GDM were identified after week 20 of pregnancy and randomly matched 1:10 to controls on gestational age at index date (ie, calendar date of GDM) and year of pregnancy. AD exposure was assessed by filled prescriptions between the beginning of pregnancy (first day of last menstrual period) and index date. Conditional logistic regression models were used to estimate crude and adjusted odds ratios (aOR). RESULTS: Among 20 905 cases and 209 050 matched controls, 9741 (4.2%) women were exposed to ADs. When adjusting for potential confounders, AD use was associated with an increased risk of GDM (aOR 1.19, 95% CI 1.08 to 1.30); venlafaxine (aOR 1.27, 95% CI 1.09 to 1.49) and amitriptyline (aOR 1.52, 95% CI 1.25 to 1.84) were also associated with an increased risk of GDM. Moreover, the risk of GDM was increased with longer duration of AD use, specifically for serotonin norepinephrine reuptake inhibitors, tricyclic ADs and combined use of two AD classes. No statistically significant association was observed for selective serotonin reuptake inhibitors. CONCLUSION: The findings suggest that ADs-and specifically venlafaxine and amitriptyline-were associated with an increased risk of GDM.

The French Pregnancy Cohort: Medication use during pregnancy in the French population.

PURPOSE: We described the medication use during pregnancy in the French population using the French Pregnancy Cohort (FPC). METHODS: The FPC was built with the sampling of all pregnant women included in the French Echantillon généraliste des bénéficiaires (EGB), which is a 1/97th representative sample of the population covered by the French health insurance. The EGB includes anonymized information on the socio-demographic and medical characteristics of beneficiaries, and the health care services they have received such as diagnoses and procedure codes as well as data on filled reimbursed medication; EGB also includes data on hospital stays in all public and private French health facilities. Each filled prescription record contains information on drug brand and generic names, date of prescription and date of dispensing, quantity dispensed, mode of administration, duration of prescription, dosage, and prescribing physician specialty. FPC includes data on all pregnancies of women in the EGB (2010-2013). Date of entry in the FPC is the first day of pregnancy regardless of pregnancy outcome (spontaneous abortions or planned abortions (with or without medical reasons), deliveries), and data on women are collected retrospectively for a period of one year before pregnancy, and prospectively during pregnancy, and up to one year after delivery. The prevalence of prescribed medications before, during and after pregnancy was compared; comparison was also done between trimesters. Pregnancy outcomes are described and include spontaneous and planned abortions, livebirths, and stillbirths. RESULTS: FPC includes data on 36,065 pregnancies. Among them, 27,253 (75.6%) resulted in a delivery including 201 stillbirths (0.7%). The total number of spontaneous abortions was 6,718 (18.6%), and planned abortions 2,094 (5.8%). The prevalence of filled medication use was 91.1%, 89.9%, and 95.6% before, during and after pregnancy, respectively. Although there was a statistically significant decrease in the proportion of use once the pregnancy was diagnosed (first trimester exposure, 76.4% vs. exposure in the year prior to pregnancy, 91.1% (p < .01)), post-pregnancy medication use was above the pre-pregnancy level (95.6%). Maternal depression was the most prevalent comorbidity during pregnancy (20%), and post-partum depression was higher in those who delivered a stillborn infant (38.8%) as well as in those with a spontaneous (19.5%) or planned abortion (22.4%) compared to those with a liveborn (12.0%). CONCLUSION: FPC is an excellent tool for the study of the risk and benefit of drug use during the perinatal period. FPC has the advantage of including a representative sample of French pregnant women, and study medications only available in France in addition to others available worldwide.

New evidence for concern over the risk of birth defects from medications for nausea and vomitting of pregnancy.

OBJECTIVES: The aim of the study was to quantify the risk of major congenital malformations (MCM) associated with first-trimester exposure to antiemetics. STUDY DESIGN AND SETTING: Using the Quebec Pregnancy Cohort (1998-2015), first-trimester doxylamine-pyridoxine, metoclopramide, and ondansetron exposures were assessed for their association with MCM. Generalized estimating equations were used to estimate odds ratios (OR), adjusting for potential confounders (aOR). RESULTS: Within 17 years of follow-up, the prevalence of antiemetic use during pregnancy increased by 76%. Within our cohort, 45,623 pregnancies were exposed to doxylamine-pyridoxine, 958 to metoclopramide, and 31 to ondansetron. Doxylamine-pyridoxine and metoclopramide use were associated with an increased risk of overall MCM (aOR 1.07, 95% confidence interval [CI]: 1.03-1.11; 3,945 exposed cases) and (aOR 1.27, 95% CI: 1.03-1.57; 105 exposed cases), respectively. Doxylamine-pyridoxine exposure was associated with increased risks of spina bifida (aOR 1.87, 95% CI: 1.11-3.14; 23 exposed cases), nervous system (aOR 1.25, 95% CI: 1.06-1.47; 225 exposed cases), and musculoskeletal system defects (aOR 1.08, 95% CI: 1.02-1.14; 1,735 exposed cases). Metoclopramide exposure was associated with an increased risk of genital organ defects (aOR 2.26, 95% CI: 1.14-4.48; 10 exposed cases). No statistically significant association was found between ondansetron exposure and the risk of overall MCM. CONCLUSION: First-trimester doxylamine-pyridoxine and metoclopramide exposure was associated with a significantly increased risk of overall and specific MCM.

Impact of antidepressant use, discontinuation, and dosage modification on maternal depression during pregnancy.

Women tend to discontinue their antidepressants during pregnancy. This study compared the risk of depressive symptoms in the second-half of pregnancy in women who discontinue or continue with or without dosage modification their antidepressant during gestation. Women were eligible if they called MothertoBaby during 2006-2010 and within 14 completed weeks of pregnancy. A total of 367 pregnant women were included. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depression during the first and second half of pregnancy. Presence of depressive symptoms was defined as EPDS ≥13. Among participants, 149 did not use antidepressants, 38 used antidepressants at the beginning of pregnancy but discontinued before the end of second-trimester, and 180 used antidepressants continuously throughout pregnancy. Among continued users, 46 modified antidepressant dosage before the end of the second trimester, and 134 did not modify dosage. The majority of antidepressant users (150/218, 68.8%) had mild to moderate depression. Thirteen percent (13%) of women who continued antidepressant use throughout pregnancy without dosage modification remained depressed. Adjusting for potential confounders including maternal depression/anxiety before pregnancy, and compared to non-users, discontinued users were 5.95 times (95%CI: 1.54-23.02), and continued users without dosage modification 4.59 times (95%CI: 1.44-14.64) more at risk of depression in the second-half of pregnancy. Those with dosage modifications were at a similar risk of depression during pregnancy than non-users (adjusted odds ratio 0.58, 95%CI: 0.06-5.52). In conclusion, in a cohort of mild to moderate depressive pregnant women, discontinuing or continuing antidepressant use without dosage modification during pregnancy were associated with an increased risk of depression during the remaining gestational period.

Association Between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion.

Importance: Benzodiazepine use in early pregnancy is associated with spontaneous abortion (SA). However, to date, the association between specific benzodiazepine agent exposure and the risk of SA has not been examined. Objective: To quantify the risk of SA associated with gestational benzodiazepine incident use by drug class, duration of action, and specific benzodiazepine agent. Design, Setting, and Participants: This nested case-control study within the Quebec Pregnancy Cohort, Montreal, Quebec, Canada, includes all pregnancies covered by the Quebec Prescription Drug Insurance Plan from January 1, 1998, through December 31, 2015. Each case was randomly matched with up to 5 controls. Statistical analysis was performed from January 1, 1998, through December 31, 2015. Exposures: Benzodiazepine exposure was defined as 1 or more filled prescriptions between the first day of the last menstrual period and the index date (the calendar date of the SA diagnosis). Benzodiazepine exposure was categorized by overall use, long- or short-acting benzodiazepine, and specific benzodiazepine agents. Main Outcomes and Measures: Spontaneous abortion defined as a pregnancy loss between the beginning of the sixth week of gestation and the 19th completed week of gestation. Conditional logistic regression models were used to calculate odds ratios (OR) and 95% CIs. Results: Of the 442 066 pregnancies included in the Quebec Pregnancy Cohort, 27 149 (6.1%) ended with SA, with a mean (SD) maternal age of 24.2 (6.5) years. Among pregnancies ending with SA, 375 (1.4%) were among women exposed to benzodiazepines in early pregnancy compared with 788 (0.6%) of the 134 305 matched control pregnancies (crude OR, 2.39; 95% CI, 2.10-2.73). Adjusting for potential confounders, including maternal mood and anxiety disorders before pregnancy, and compared with nonuse, benzodiazepine exposure in early pregnancy was associated with an increased risk of SA (adjusted OR, 1.85; 95% CI, 1.61-2.12). The risk was similar among pregnancies exposed to short-acting (284 exposed cases; adjusted OR, 1.81; 95% CI, 1.55-2.12) and long-acting (98 exposed cases; adjusted OR, 1.73; 95% CI, 1.31-2.28) benzodiazepines during early pregnancy. All benzodiazepine agents were independently associated with an increased risk of SA (range of adjusted ORs, 1.13-3.43). Conclusions and Relevance: An increased risk of SA was observed among early pregnancies with incident exposure to short- and long-acting benzodiazepines and all specific benzodiazepine agents during early pregnancy. Insomnia, anxiety, and mood disorders are prevalent during pregnancy; clinicians should carefully evaluate the risk-benefit ratio of prescribing benzodiazepines in early pregnancy since alternative nonpharmacologic treatments exist.

Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies.

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.

Use of trimethoprim-sulfamethoxazole during pregnancy and risk of spontaneous abortion: a nested case control study.

AIMS: Data available on the fetal safety of trimethoprim-sulfamethoxazole (TMP-SMX) exposure during pregnancy remains scarce and inconclusive. A previous study assessing the link between TMP-SMX exposure during pregnancy and the risk of spontaneous abortion (SA) did not control for protopathic bias and indication bias. METHODS: We conducted a nested control study (n = 77 429 pregnancies including 7039 cases of SA and 70 390 controls) within the Quebec Pregnancy Cohort. For each case of SA, we selected 10 controls at the index date that were matched on gestational age and year of pregnancy. TMP-SMX exposure was defined as either having filled at least one prescription between the first day of gestation (1DG) and the index date, or as having filled a prescription before pregnancy but with a duration overlapping the 1DG (102 pregnancies exposed to TMP-SMX, including 25 cases of SA and 77 controls). RESULTS: Adjusting for potential confounders, TMP-SMX exposure was associated with an increased risk of SA (AOR 2.94, 95% C 1.89-4.57, 25 exposed cases). Similar results were found after controlling for indication bias and protopathic bias. CONCLUSION: Given that this drug is widely use in HIV patients to prevent opportunistic infections and malaria, there is an urgent need to identify potential data sources in Africa for analysis of early pregnancy exposure to TMP-SMX.

Risk of preterm birth following late pregnancy exposure to NSAIDs or COX-2 inhibitors.

Pregnant women may take nonsteroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase (COX)-2 inhibitors, or biological agents to relieve symptoms or manage disease flares in late pregnancy. We aimed to quantify the risk of prematurity associated with late pregnancy exposure to nonselective NSAIDs, selective COX-2 inhibitors, and biological agents. Using data from Quebec Pregnancy Cohort, we performed a population-based cohort study. We included all women who were covered by the Quebec Drug Plan and had a singleton live birth between January 1, 1998 and December 31, 2009. Late pregnancy exposure was defined as having filled at least 1 prescription for nonselective NSAIDs, selective COX-2 inhibitors, or biological agents in the 3 months before delivery. Prematurity was defined as <37 weeks of gestation. Crude and adjusted odds ratios (OR) were obtained using generalized estimation equation models. Covariates included maternal autoimmune diseases, demographics, concomitant drug use, history of pregnancy complications, and other comorbidities. A total of 156,531 pregnancies met inclusion criteria and were considered for analyses. In the 3 months before delivery, 391 pregnancies were exposed to nonselective NSAIDs, 55 to COX-2 inhibitors, and 12 to biological agents. After adjustment for maternal autoimmune diseases, concomitant medication use, and other risk factors, COX-2 inhibitor use in late pregnancy was associated with a 2.46-fold increased risk of prematurity (adjusted OR, 2.46; 95% confidence interval, 1.28-4.72) compared to nonuse; only late pregnancy exposure to celecoxib was found to increase the risk (adjusted OR, 3.41; 95% confidence interval, 1.29-9.02). In conclusion, celecoxib use during late pregnancy may increase the risk of prematurity.