Sharon Daniel

Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes.

OBJECTIVE Despite high rates of hypertension in pregnancy, the effects of hypertension have not been separated appropriately from the effects of the medications that are used. We evaluated the safety of exposure to antihypertensive medications during pregnancy, while accounting for disease effects. STUDY DESIGN A population-based retrospective cohort study was performed that compared all pregnancies of women with hypertension who were either exposed or unexposed to antihypertensive medications. A computerized database of the medications that were dispensed to pregnant women from 1998-2008 was linked with computerized databases that contained maternal and infant hospitalization records from the district hospital during the same period. RESULTS During the study period, 100,029 deliveries occurred; of those, 1964 pregnant women experienced chronic hypertension, and 620 neonates (0.6%) were exposed to at least 1 antihypertensive medication (methyldopa or atenolol) during pregnancy. A higher rate of intrauterine growth restriction (7.2% vs 2.1%, respectively; adjusted odds ratio [OR], 4.37; 95% confidence interval [CI], 3.00-6.36; P < .001), small for gestational age (3% vs 1.7%, respectively; adjusted OR, 2.23; 95% CI, 1.27-3.92; P = .005), and preterm deliveries (<37 weeks, 22.9% vs 8.0%, respectively; adjusted OR, 3.69; 95% CI, 2.90-4.69; P < .001) were noted among the pregnancies of women who were exposed to antihypertensive medications during the third trimester. Importantly, a similar association was detected when we compared women with chronic hypertension who were not treated during pregnancy (n = 1074) to women who had no chronic hypertension and who were unexposed to antihypertensive medications (n = 97,820). CONCLUSION Chronic hypertension with or without treatment during pregnancy is an independent and significant risk factor for adverse perinatal outcomes such as intrauterine growth restriction, small for gestational age, and preterm delivery.

Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy.

Objective. Nonsteroidal antiinflammatory drugs (NSAID) are among the most common medicines used by pregnant women. Published data are controversial regarding fetal safety following intrauterine exposure to NSAID. We investigated exposure to NSAID in the first trimester in a large cohort of infants and fetuses. Methods. A computerized database of medications dispensed from 1998 to 2009 to all women registered in the “Clalit” health maintenance organization in Southern Israel was linked with 2 computerized databases containing maternal and infant hospitalization records. Pregnancy terminations for medical reasons were analyzed. The following confounders were controlled for: parity, maternal age, ethnicity, maternal pregestational diabetes, maternal inflammatory disease, and year of birth or pregnancy termination. First trimester exposure to nonselective cyclooxygenase (COX) inhibitors and to selective COX-2 inhibitors as groups and to individual drugs was analyzed. Results. There were 110,783 pregnancies during the study period: 109,544 singleton births and 1239 pregnancy terminations for medical reasons. In total, 5267 mothers were exposed to NSAID during the first trimester of pregnancy: 5153 to nonselective COX inhibitors and 114 to COX-2 selective inhibitors. Exposure to NSAID in the first trimester, as groups (nonselective COX and selective COX-2 inhibitors) and as individual drugs, was not associated with an increased risk of major congenital malformations in general (adjusted OR 1.07, 95% CI 0.96−1.21 for nonselective; and adjusted OR 1.40, 95% CI 0.70−2.78, for selective COX-2 inhibitors), although an increased risk for musculoskeletal malformations was found following exposure to COX-2 selective inhibitors (adjusted OR 3.39, 95% CI 1.37−8.34). Conclusion. Intrauterine exposure to NSAID was not associated with increased risk for major congenital malformations. Further studies are needed to assess the risk for malformations after exposure to COX-2 selective inhibitors.

Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions

Background: Spontaneous abortion is the most common complication of pregnancy. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy. Published data are inconsistent regarding the risk of spontaneous abortion following exposure to NSAIDs. Methods: We performed a historical cohort study involving all women who conceived between January 2003 and December 2009 and who were admitted for delivery or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. We constructed time-varying Cox regression models and adjusted for maternal age, diabetes mellitus, hypothyroidism, obesity, hypercoagulation or inflammatory conditions, recurrent miscarriage, in vitro fertilization of the current pregnancy, intrauterine contraceptive device, ethnic background, tobacco use and year of admission. Results: The cohort included 65 457 women who conceived during the study period; of these, 58 949 (90.1%) were admitted for a birth and 6508 (9.9%) for spontaneous abortion. A total of 4495 (6.9%) pregnant women were exposed to NSAIDs during the study period. Exposure to NSAIDs was not an independent risk factor for spontaneous abortion (nonselective cyclooxygenase [COX] inhibitors: adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.99–1.22; selective COX-2 inhibitors: adjusted HR 1.43, 95% CI 0.79–2.59). There was no increased risk for specific NSAID drugs, except for a significantly increased risk with exposure to indomethacin (adjusted HR 2.8, 95% CI 1.70–4.69). We found no dose–response effect. Interpretation: We found no increased risk of spontaneous abortion following exposure to NSAIDs. Further research is needed to assess the risk following exposure to selective COX-2 inhibitors.

The fetal safety of clomiphene citrate: a population‐based retrospective cohort study

To evaluate whether exposure to clomiphene citrate (CC) for ovulation induction is associated with major malformations overall or with specific fetal anomalies.

NSAIDs and spontaneous abortions – true effect or an indication bias?

AIM The aim of the study was to characterize the extent of indication bias resulting from the excessive use of NSAIDs on the days preceding a spontaneous abortion to relieve pain. METHODS We used data from a retrospective cohort study assessing the risk for spontaneous abortions following exposure to NSAIDs. Three definitions of exposure for cases of spontaneous abortions were compared, from the first day of pregnancy until the day of spontaneous abortion and until 3 and 2 days before a spontaneous abortion. Statistical analysis was performed using multivariate time programmed Cox regression. RESULTS A sharp increase was observed in the dispensation of indomethacin, diclofenac and naproxen, and a milder increase was found in the use of ibuprofen during the week before a spontaneous abortion. Non- selective COX inhibitors in general and specifically diclofenac and indomethacin were found to be associated with spontaneous abortions when the exposure period was defined until the day of spontaneous abortion (hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04, 1.28; HR 1.31, 95% CI 1.08, 1.59 and HR 3.33, 95% CI 2.09, 5.29, respectively). The effect disappears by excluding exposures occurring on the day before the spontaneous abortion for non-selective COX inhibitors and on the last week before the spontaneous abortion for indomethacin. In general, decreasing HRs were found with the exclusion of exposures occurring on the days immediately before the spontaneous abortion. CONCLUSIONS The increased use of NSAIDs during the last few days that preceded a spontaneous abortion to relieve pain associated with the miscarriage could bias studies assessing the association between exposure to NSAIDs and spontaneous abortions.

Risk of major congenital malformations following first‐trimester exposure to vaginal azoles used for treating vulvovaginal candidiasis: a population‐based retrospective cohort study

To evaluate the risk for major malformations following first‐trimester exposure to vaginal azoles.

Seasonality of birth affects paediatric coeliac disease

This study investigated the seasonality of birth in children diagnosed with coeliac disease (CD) at a tertiary University hospital in Southern Israel.

The Fetal Safety of Enoxaparin Use During Pregnancy: A Population-Based Retrospective Cohort Study

IntroductionEnoxaparin is widely used during pregnancy as pregnancy is a hypercoagulable state; however, its fetal safety has scarcely been investigated.ObjectiveOur study aimed to examine fetal safety following enoxaparin exposure during pregnancy.MethodsA population-based, retrospective cohort study was performed by linking computerized databases, including the drug dispensing registries of Clalit Health Services in Israel and maternal and infant hospital records, between 1998 and 2009. Multivariate logistic regression models were used to examine associations between first- and third-trimester exposure to enoxaparin, major malformations, and other adverse birth outcomes, adjusted for confounders.ResultsFrom a total of 109,473 singleton pregnancies, 418 and 572 were exposed to enoxaparin during the first and third trimesters, respectively. Exposure to enoxaparin during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations [adjusted odds ratio (aOR) 1.1, 95% confidence interval (CI) 0.8–1.6], while exposure during the third trimester was not associated with an increased risk of low birth weight (aOR 1.1, 95% CI 0.8–1.4), low Apgar score (aOR 0.9, 95% CI 0.4–1.8), or risk of perinatal mortality (aOR 0.6, 95% CI 0.1–2.9).ConclusionExposure to enoxaparin during pregnancy was not associated with an increased risk of major malformations in general or according to organ systems. Nonetheless, risk for specific malformations cannot be ruled out.

Authors’ reply re: The fetal safety of clomiphene citrate: a population based retrospective cohort study

(CC dispensation from two months before conception through the first month of pregnancy), and cost-effective management of pregnancy-related physiological/metabolic aberrations. Interestingly, use of smokeless tobacco during pregnancy had an adverse effect on women’s reproductive physiology and the pregnancy outcome. Moreover, pooled analyses using patient-specific DNA/RNA/protein-based cell-/molecular-biology research studies involving human subjects along with in vitro cell-/cell-line-based research methodology and animal models of disease would be beneficial in the eventual design of safe CC drug-dose regimens at pre-conception and pregnancy stages during embryonic induction and fetal development. High-throughput chemopredictive drug-dosage pharmacogenetic and/or pharmacokinetic biological assays with standardised drug dosages coupled with gene-epidemiology-based studies with a specific subset of patients from ethnically disparate populations may be incorporated in future designs of cost-effective clinical research protocols so as to provide critical insights into CC exposure and fetal safety in pregnant women of diverse cultural backgrounds. Future multi-centric epidemiological research study protocols using metabolomics, transcriptomics, genomics, and proteomics are warranted to provide unbiased risk assessment in susceptible individuals (e.g. drug responders versus poor responders) and increase our current understanding of the pharmacological basis of CC-mediated adverse drug effects in maternal-fetal medicine, and subsequently aid in the identification ofpredictive and/orprognosticbiomarkers in the ever-expanding reproductive medicine field worldwide.&

Reply to 'Indication bias or protopathic bias?'.

We thank Dr Faillie for his letter 1. We also deliberated at length about the exact definition of bias in our study.