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.

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.

Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study.

AIMS: Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed to quantify the association between exposure to gestational antibiotic and the risk of MCMs. METHODS: Using the Quebec pregnancy cohort (1998-2008), we included a total of 139 938 liveborn singleton alive whose mothers were covered by the "Régie de l'assurance maladie du Québec" drug plan for at least 12 months before and during pregnancy. Antibiotic exposure was assessed in the first trimester and MCMs were identified within the first year of life. RESULTS: After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95% CI 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95% CI 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95% CI 1.04-3.16, 13 exposed cases). Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95% CI 1.21-4.67, 9 exposed cases; aOR 2.46, 95% CI 1.21-4.99, 8 exposed cases; aOR 3.19, 95% CI 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group. CONCLUSIONS: Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ-specific malformations. Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs.

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.

Use of antibiotics during pregnancy and risk of spontaneous abortion.

BACKGROUND: Although antibiotics are widely used during pregnancy, evidence regarding their fetal safety remains limited. Our aim was to quantify the association between antibiotic exposure during pregnancy and risk of spontaneous abortion. METHODS: We conducted a nested case-control study within the Quebec Pregnancy Cohort (1998-2009). We excluded planned abortions and pregnancies exposed to fetotoxic drugs. Spontaneous abortion was defined as having a diagnosis or procedure related to spontaneous abortion before the 20th week of pregnancy. The index date was defined as the calendar date of the spontaneous abortion. Ten controls per case were randomly selected and matched by gestational age and year of pregnancy. Use of antibiotics was defined by filled prescriptions between the first day of gestation and the index date and was compared with (a) non-exposure and (b) exposure to penicillins or cephalosporins. We studied type of antibiotics separately using the same comparator groups. RESULTS: After adjustment for potential confounders, use of azithromycin (adjusted odds ratio [OR] 1.65, 95% confidence interval [CI] 1.34-2.02; 110 exposed cases), clarithromycin (adjusted OR 2.35, 95% CI 1.90-2.91; 111 exposed cases), metronidazole (adjusted OR 1.70, 95% CI 1.27-2.26; 53 exposed cases), sulfonamides (adjusted OR 2.01, 95% CI 1.36-2.97; 30 exposed cases), tetracyclines (adjusted OR 2.59, 95% CI 1.97-3.41; 67 exposed cases) and quinolones (adjusted OR 2.72, 95% CI 2.27-3.27; 160 exposed cases) was associated with an increased risk of spontaneous abortion. Similar results were found when we used penicillins or cephalosporins as the comparator group. INTERPRETATION: After adjustment for potential confounders, use of macro-lides (excluding erythromycin), quinolones, tetracyclines, sulfonamides and metronidazole during early pregnancy was associated with an increased risk of spontaneous abortion. Our findings may be of use to policy-makers to update guidelines for the treatment of infections during pregnancy.

Antidepressant Use in Pregnancy and the Risk of Attention Deficit with or without Hyperactivity Disorder in Children.

BACKGROUND: The association between antidepressant (AD) use during pregnancy and the risk of attention deficit with or without hyperactivity disorder (ADHD) in children is debated. We investigated the risk of ADHD associated with overall and class-specific antidepressant exposure in utero. METHODS: We designed a register-based cohort study using the Quebec Pregnancy/Children Cohort (QPC). A total of 144 406 singleton full-term live-born from 1998 to 2009 were included. Cox proportional hazards regression models were used to estimate unadjusted and adjusted hazard ratio with 95% confidence interval (CI). RESULTS: During 542 897 person-years of follow-up, 4564 (3.2%) infants were identified with ADHD. The mean age at first ADHD diagnosis was 6.3 ± 2.3 years (range 0-11 years), and the mean age at first ADHD medication use was 7.0 ± 1.5 years. Adjusting for potential confounders, including maternal history of depression/anxiety and ADHD, AD use during the 2nd or 3rd trimester of pregnancy was associated with an increased risk of (HR 1.3, 95% CI 1.0, 1.6; 134 exposed cases). More specifically, tricyclic use was associated with an increased risk of ADHD (HR 1.8, 95% CI 1.0, 3.1; 16 exposed cases); SSRI and SNRI use were not associated with increased ADHD risk. CONCLUSION: This study suggests that AD use during the 2nd and 3rd trimester of pregnancy, specifically tricyclics, is an independent risk factor for ADHD in children above and beyond the risk associated with maternal depression/anxiety or ADHD. However, residual confounding by indication severity could not be completely ruled out.

Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes.

BACKGROUND: Intranasal corticosteroid use during pregnancy has increased over the past decade. OBJECTIVE: We aim to estimate the safety of intranasal triamcinolone use during pregnancy, which was introduced for over-the-counter use in October 2013. METHODS: We designed a population-based prospective cohort study. From a cohort of 289,723 pregnancies in Montreal, Quebec, Canada, from 1998-2008, intranasal triamcinolone-exposed, other intranasal corticosteroid-exposed, and nonexposed women during the first trimester were studied for major congenital malformations (overall and organ specific) and spontaneous abortions and during the second/third trimesters for small-for-gestational age (SGA) newborns. The first trimester is the time window of interest for malformations and spontaneous abortion (organogenesis), and the second/third trimesters are the time windows of interest for SGA (fetal growth). Logistic regression model-based generalized estimating equations were used. RESULTS: Adjusting for potential confounders, use of intranasal triamcinolone during the first trimester of pregnancy was not significantly associated with the risk of overall congenital malformations (odds ratio [OR], 0.88; 95% CI, 0.60-1.28; 31 exposed cases) compared with nonexposure; however, it was associated with the risk of respiratory defects (OR, 2.71; 95% CI, 1.11-6.64; 5 exposed cases). Pregnancy exposure to intranasal triamcinolone was not significantly associated with the risk of spontaneous abortion (OR, 1.04; 95% CI, 0.76-1.43; 50 exposed cases). No association was found between second- or third-trimester exposure to intranasal triamcinolone and the risk of SGA (OR, 1.06; 95% CI, 0.79-1.43; 50 exposed cases). CONCLUSIONS: Maternal exposure to intranasal triamcinolone during pregnancy was not associated with the risk of SGA/spontaneous abortions/overall malformations. However, it has been shown to increase the risk of respiratory system defects. Chance finding cannot be ruled out.

Success of smoking cessation interventions during pregnancy.

BACKGROUND: Smoking during pregnancy is a modifiable risk factor associated with adverse pregnancy outcomes. Smoking during pregnancy has been shown to increase the risk of spontaneous abortion, prematurity, low birthweight, congenital malformations, and sudden infant death syndrome. Despite the fact that it is well known that smoking can lead to adverse pregnancy outcomes, 13-25% of pregnant women overall continue to smoke during this critical period. OBJECTIVE: The objective of the study was to evaluate the effect of gestational use of bupropion and nicotine patch replacement therapy on the risk of the following: (1) smoking cessation, (2) prematurity, and (3) small for gestational age. STUDY DESIGN: Women included in the Quebec Pregnancy Cohort who filled the annual autoadministered questionnaire between Jan. 1, 1998, and June 30, 2009, were studied. Smokers before gestation with a pregnancy resulting in a live birth comprised the study population. Three mutually exclusive study groups were formed among those who smoked at the beginning of pregnancy: gestational users of nicotine patch replacement therapy, bupropion, and smokers who did not use nicotine patch replacement therapy or bupropion. Rate of smoking cessation during pregnancy as well as the risk of prematurity and small for gestational age were studied. RESULTS: Of the 1288 women who met inclusion criteria, 900 were smokers, 72 were bupropion users, and 316 were nicotine patch replacement therapy users. Bupropion and nicotine patch replacement therapy use during pregnancy were associated with higher rates of smoking cessation: 81% in the bupropion group; 79% for nicotine patch replacement therapy; and 0% in those not using buproprion or nicotine patch replacement therapy. After discontinuing smoking cessation medications, 60% of bupropion users and 68% of nicotine patch replacement therapy users did not smoke again during and after pregnancy. Adjusting for potential confounders, nicotine patch replacement therapy use was associated with a lower risk of prematurity (adjusted odds ratio, 0.21, 95% confidence interval, 0.13-0.34), and small-for-gestational-age (adjusted odds ratio, 0.61, 95% confidence interval, 0.41-0.90) compared to smoking. Bupropion was associated with a lower risk of prematurity only (adjusted odds ratio, 0.12, 95% confidence interval, 0.03-0.50). CONCLUSION: Bupropion and nicotine patch replacement therapy have an impact on smoking cessation during and after pregnancy. Nicotine patch replacement therapy also decreased the risk of prematurity and small for gestational age.

Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study.

Perinatal psychological stress has been associated with unfavorable maternal and neonatal outcomes. We aimed to assess the impact of perinatal stress on infant development at 1 year of age. We recruited pregnant women calling North American Teratogen Information Services or attending outpatient clinics at CHU Sainte Justine (Montreal) between 2008 and 2010 and their spouses. To be part of our study, women had to be (1) >18 years of age, (2) <15 weeks of gestational age at recruitment, (3) living within 250-km radius of Montreal, and (4) taking antidepressants or non-teratogenic drugs. Stress was assessed using the telephone-administered four-item perceived stress scale during pregnancy in mothers and at 2 months postpartum in both parents. Child development at 1 year of age was evaluated with the Bayley III scales. Socio-demographic and potential confounders were collected through telephone interviews. Multivariable linear regression models were built to assess the association between perinatal parental stress and child development. Overall, 71 couples and their infants were included. When adjusted for potential confounders, maternal prenatal stress was positively associated with motor development (adjusted ß = 1.85, CI 95 % (0.01, 3.70)). Postpartum maternal and paternal stresses were negatively associated with motor and socio-emotional development, respectively (adjusted ß = -1.54, CI 95 % (-3.07, -0.01) and adjusted ß = -1.67, CI 95 % (-3.25, -0.10), respectively). Maternal and paternal postnatal stress seems to be harmful for the motor and socio-emotional development in 1-year-old children. No association was demonstrated between parental stress and cognitive, language, and adaptive behavioral development. However, prenatal maternal stress appears to improve motor skills.

Ovarian Stimulators, Intrauterine Insemination, and Assisted Reproductive Technologies Use and the Risk of Major Congenital Malformations-The AtRISK Study.

OBJECTIVE: To quantify the risk of major congenital malformations (MCMs) associated with the use of ovarian stimulators alone, intrauterine insemination (IUI), and assisted reproductive technologies (ARTs). METHODS: We conducted a case-control analysis using a birth cohort, built with the linkage of data obtained by a self-administered questionnaire, medical, pharmaceutic, and birth databases. Cases were pregnancies with at least one live birth with an MCM. Controls were pregnancies that did not result in major or minor congenital malformations. Multiple logistic regression models were used to calculate the odds ratios (ORs) and confidence intervals (CIs). RESULTS: Among the 5021 pregnancies identified, 825 were cases of MCM and 4196 were controls. Compared with spontaneous conception, the use of ART increased the risk of major urogenital malformations (adjusted OR, 3.11; 95% CI, 1.33-7.27). The use of IUI was associated with an increased risk of major musculoskeletal malformations (adjusted OR, 2.02; 95% CI, 1.10-3.71). Among the 471 women who used fertility treatments for conception, the use of ART was associated with an increased risk of any MCM (adjusted OR, 1.66; 95% CI, 1.00-2.79) and urogenital malformations (adjusted OR, 7.18; 95% CI, 1.59-32.53) when compared with ovarian stimulators used alone. CONCLUSIONS: The use of ART and IUI was associated with an increased risk of major musculoskeletal and urogenital malformations. ART was associated with a higher risk of MCM compared to ovarian stimulators used alone. Even the adjustment, a contribution of the underlying subfertility problems cannot completely ruled out given the differences in the severity of subfertility.

Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized and quasi-randomized trials.

BACKGROUND: It is known that antimalarial drugs reduce the risk of low birth weight (LBW) in pregnant patients. However, a previous Cochrane review did not evaluate whether the level of antimalarial drug resistance could modify the protective effect of antimalarial drugs in this regard. In addition, no systematic review exists comparing current recommendations for malaria prevention during pregnancy to alternative regimens in Africa. Therefore, we conducted a comprehensive systematic review and meta-analysis to assess the efficacy of antimalarial drugs for malaria prevention during pregnancy in reducing the risk of LBW. METHODS: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for articles published up to 21 November 2014, in English or French, and identified additional studies from reference lists. We included randomized and quasi-randomized studies reporting LBW as one of the outcomes. We extracted data and assessed the risk of bias in selected studies. All pooled analyses were based on a random effect model, and we used a funnel plot and trim and fill method to test and adjust for publication bias. RESULTS: A total of 25 studies met the inclusion criteria (37,981 subjects). Compared to no use, all combined antimalarial drugs were associated with a 27% (RR 0.73, 95% CI 0.56-0.97, ten studies) reduction in the risk of LBW. The level of antimalarial drug resistance modified the protective effect of the antimalarial drug used for prevention of LBW during pregnancy. Sulfadoxine-pyrimethamine was not associated with a reduction in the risk of LBW in regions where the prevalence of the dihydropteroate synthase 540E mutation exceeds 50% (RR 0.99, 95% CI 0.80-1.22, three studies). The risk of LBW was similar when sulfadoxine-pyrimethamine was compared to mefloquine (RR 1.05, 95% CI 0.86-1.29, two studies). CONCLUSION: Prophylactic antimalarial drugs and specifically sulfadoxine-pyrimethamine may no longer protect against the risk of LBW in areas of high-level resistance. In Africa, there are currently no suitable alternative drugs to replace sulfadoxine-pyrimethamine for malaria prevention during pregnancy.

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.

Association between ovarian stimulators with or without intrauterine insemination, and assisted reproductive technologies on multiple births.

OBJECTIVE: We sought to quantify the risk of multiple births associated with the use of different modalities of medically assisted reproduction. STUDY DESIGN: We conducted a case-control study using a birth cohort from 2006 through 2009. This cohort was built with the linkage of data obtained by a self-administered questionnaire and medical, hospital, pharmaceutical, birth, and death databases in Quebec. Cases were pregnancies resulting in multiple live births (International Classification of Diseases, Ninth Revision/International Statistical Classification of Diseases, 10th Revision codes). Each case was matched, on maternal age and year of delivery, with 3 singleton pregnancies (controls) randomly selected among all Quebec singleton pregnancies. Data on the use of different fertility treatments were collected by a self-administered questionnaire. Multiple logistic regression models, adjusted for body mass index, number of previous live births, ethnicity, family income, place of residence, marital status, subfertility, reduction of embryos, diabetes, metformin treatment, folic acid supplementation, and lifestyle factors, were used to calculate the odds ratios (ORs) and confidence intervals (CIs). We evaluated the associations between each type of fertility treatment (ovarian stimulators used alone, intrauterine insemination [IUI] used with ovarian stimulation, and assisted reproductive technologies [ART]) and the risk of multiple births. RESULTS: A total of 1407 cases of multiple births and 3580 controls were analyzed. More than half of multiple births following medically assisted reproduction (53.6%) occurred among women having used ovarian stimulation with or without IUI. The use of ovarian stimulators alone and IUI with ovarian stimulation increase the risk of multiple births (adjusted OR, 4.5; 95% CI, 3.2-6.4; and adjusted OR, 9.32; 95% CI, 5.60-15.50, respectively) compared to spontaneous conception. The use of invasive ART was associated with a greatly increased risk of multiple births. Among only the 465 women who used medically assisted reproduction for conception, the use of IUI with ovarian stimulation was associated with an increased risk of multiple births (adjusted OR, 1.98; 95% CI, 1.12-3.49) when compared to ovarian stimulators used alone. Invasive ART were associated with an increased risk of multiple births (adjusted OR, 6.81; 95% CI, 3.72-12.49) when compared to ovarian stimulators used alone. CONCLUSION: Although the risk of multiple births associated with invasive ART can be decreased by elective implementing of single embryo transfer, special attention should be paid to the greatly increased risk associated with ovarian stimulation used alone or with IUI.

Can drug effects explain the recent temporal increase in atonic postpartum haemorrhage?

BACKGROUND: Rates of postpartum haemorrhage and atonic postpartum haemorrhage have increased in several high-income countries. We carried out a study to examine if drug use in pregnancy, or drug and other interactions, explained this increase in postpartum haemorrhage. METHODS: The linked administrative and hospital databases of the Québec Pregnancy Cohort were used to define a cohort of pregnant women in Québec, Canada, from 1998 to 2009 (n = 138,704). Case-control studies on any postpartum haemorrhage and atonic postpartum haemorrhage were carried out within this population, with up to five controls randomly selected for each case after matching on index date and hospital of delivery (incidence density sampling). Conditional logistic regression was used to estimate the effects of drug use on postpartum haemorrhage and atonic postpartum haemorrhage. RESULTS: There was an unexpected non-linear, declining temporal pattern in postpartum haemorrhage and atonic postpartum haemorrhage between 1998 and 2009. Use of antidepressants (mainly selective serotonin reuptake inhibitors) was associated with higher rates of postpartum haemorrhage [adjusted rate ratio (aRR) 1.48, 95% confidence interval (CI) 1.23, 1.77] and atonic postpartum haemorrhage [aRR 1.40, 95% CI 1.13, 1.74]. Thrombocytopenia was also associated with higher rates of postpartum haemorrhage [aRR 1.52, 95% CI 1.16, 2.00]. There were no statistically significant drug interactions. Adjustment for maternal factors and drug use had little effect on temporal trends in postpartum haemorrhage and atonic postpartum haemorrhage. CONCLUSIONS: Although antidepressant use and thrombocytopenia were associated with higher rates of atonic postpartum haemorrhage, antidepressant and other drug use did not explain temporal trends in postpartum haemorrhage.

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

PURPOSE: 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. METHODS: From the Quebec Pregnancy Cohort (1998-2008), women exposed to a macrolide or penicillin in the first trimester and unexposed women were studied. There were 135 859 pregnancies included; 914 were exposed to azithromycin, 734 to erythromycin, 686 to clarithromycin, and 9106 to penicillin during the first trimester. Cases of MCMs were identified within the first year of life. RESULTS: After adjusting for potential confounders, azithromycin (RR = 1.19, 95%CI: 0.98, 1.44; 120 exposed cases), erythromycin (RR = 0.96, 95%CI: 0.74, 1.24; 66 exposed cases) and clarithromycin use (RR = 1.12, 95%CI: 0.99, 1.42; 79 exposed cases) during the first trimester of pregnancy were not statistically significantly associated with the risk of MCMs; no associations were observed for cardiac malformations. CONCLUSIONS: First trimester exposure to any of the macrolides was not associated with an increased risk of overall MCMs or cardiac malformations specifically.

Differential low uptake of free vitamin D supplements in preterm infants: the Quebec experience.

BACKGROUND: Vitamin D is essential for bone mineralization, particularly in premature infants. For nearly 20 years, Quebec has offered a program of free vitamin D supplements via its public medication insurance plan Régie de l'Assurance Maladie du Québec (RAMQ). The objective of this study is to evaluate the number of preterm infants that obtained at least one bottle (50 doses) of vitamin D supplement through this program and to determine if uptake varied by gestational age. METHODS: This was a retrospective cohort study of preterm infants covered by RAMQ and born from 1998 to 2008; all infants had 1 year of follow-up data regarding supplement use. Data were extracted from the Quebec Pregnancy Cohort, a linked administrative database and were stratified by early (<34 weeks) or late gestational age premature infants. The number of infants obtaining supplements was the primary outcome and their characteristics were compared across gestational age groups. Predictors for participation (obtaining at least 1 bottle) or adherence (2 or more bottles) were identified via logistic regression (GEE). RESULTS: 10288 infants were eligible; the percentage exposed to vitamin D was 24.5% (37.4%- early; 20.7%-late preterm infants, p < 0.001). The median number of bottles obtained was 2 for early and 1 for late preterms. For all premature infants, there was an apparent geometric decline in the infants obtaining subsequent bottles of supplements over the 12 month period. Additionally, there was a significant decline in program participation over time (OR = 0.90/year, 95% CI: 0.89-0.90) regardless of gestational age. Older or more educated mothers were positive predictors for participation. A prescription from a pediatrician significantly increased the odds of obtaining the supplement. CONCLUSION: Early preterm infants were more likely to obtain the supplement post-discharge; uptake was low and decreased with time for both age categories. Specifically, targeting late preterm infants and young mothers with less education could improve vitamin D uptake.

Programme to provide Quebec infants with free vitamin D supplements failed to encourage participation or adherence.

AIM: The aim of this study was to evaluate the uptake of a free vitamin D infant prescription programme and to determine the incidence of nutritional rickets. METHODS: This was a retrospective cohort study of infants from Quebec, Canada, involving term infants born between 1998 and 2008 and covered by the public insurance programme. Data were extracted from the Quebec Pregnancy Cohort. Predictors of programme participation were identified through logistic regression. RESULTS: A total of 123 018 infants were eligible, and the mean annual prevalence of supplemental vitamin D exposure was 17.9 ± 5.6%. The median age for obtaining the first bottle was 36 days and half only obtained one bottle of 50 doses. Mothers with higher socio-economic status, those who lived as a couple, older mothers or a prescription by a paediatrician significantly increased the odds of obtaining vitamin D. There was a decline in programme participation over time (OR 0.89/year, 95% CI = 0.88-0.90). The incidence of rickets was 23.9 cases per 100 000 live births, with an annual increase of 1.12 cases/year (95% CI = 1.01-1.24). CONCLUSION: Without educational measures, a free prescription programme for vitamin D failed to encourage participation or adherence. Moreover, participation decreased with time. New strategies, including educational support, need to be developed to increase vitamin D supplementation rates.

[Quebec Pregnancy Cohort: prevalence of medication use during gestation and pregnancy outcomes]. / La cohorte des grossesses du Québec : prévalences et conséquences de l'utilisation des médicaments durant la grossesse.

OBJECTIVE: Many women are exposed to medications during pregnancy. The Quebec Pregnancy Cohort (QPC) is a prospective population-based cohort which includes all data on pregnancies and children between January 1997 and December 2008. METHODS: We linked four administrative databases in Quebec, Canada: RAMQ (medical and pharmaceutical), MED-ECHO (hospitalizations), ISQ (births/deaths), and MELS (Ministry of Education). Pregnancies included were covered by the Quebec prescription drug insurance plan (36% of women aged 15-45 years) from 12 months prior until the end of pregnancy. RESULTS: We analyzed 97,680 pregnancies. Prevalence of medication use was 74% pre-pregnancy, 56% during pregnancy, and 80% post-pregnancy. Most frequently used medications during pregnancy were antibiotics (47%), antiemetic drugs (23%), and non-steroïdal anti-inflammatory drugs (NSAIDs) [17%]. Medication users were more likely to have spontaneous abortions, preterm births, children with congenital malformations and postpartum depression than non-users (p<0.01). CONCLUSION: Medications are commonly used during pregnancy. The QPC is a powerful tool for perinatal pharmacoepidemiological research.