Flory T. Muanda

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.

Ovarian Stimulation, Intrauterine Insemination, Multiple Pregnancy and Major Congenital Malformations: A Systematic Review and Meta- Analysis- The ART_Rev Study

INTRODUCTION Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear. OBJECTIVE To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments). METHODS We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaborations tool for assessing risk of bias for RCTs and the Newcastle-Ottawa Scale for observational studies. RESULTS There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable. CONCLUSIONS The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed.

Paroxetine use during pregnancy and the risk of cardiac defects

We would like to thank Dr Bracken for his comments [1] on our meta-analysis, titled ‘The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis’ recently published in the British Journal of Clinical Pharmacology. [2] Our meta-analysis results are consistent with previously publishedmeta-analyses [3, 4] including that by Wurst et al. [3] which was funded by the maker of paroxetine. An observational study is not designed to address causality but associations, which we did with this meta-analysis. Additional criteria should be considered when assessing causality between paroxetine and birth defects, as was done previously by Bérard [5]. Although we agree that independence of data is important to avoiding potential bias in epidemiological studies, we disagree that this will necessarily lead to false results. Indeed, in recent years, advances in statistical analyses and programming have led researchers in the field of perinatal epidemiology to analyse dependent data (for example, multiple pregnancies per woman), and thus increase sample size and statistical power. We disagree that considerable overlap exists between studies from Denmark or Scandinavia. Although some overlap was reported in studies included in our metaanalysis, it is incorrect to assume that studies emerging from the same geographical area have the same underlying data [6]. Indeed, different database linkages, inclusion/exclusion criteria or calendar years considered could all result in different study cohorts [6], with minimal overlap, as was recognized in the Scandinavian and US studies in our metaanalysis. This is also postulated in the International Committee of Medical Journal Editors recommendations [7]. We further disagree that authors have included the entire country population in their study, for the same reasons listed above. Although overlapping data could be present, they would have a minimal effect on the point estimate and width of the confidence interval [6, 8]. If, however, updates on the same underlying cohort are performed, only the most recent peerreviewed update should be considered [6], as was done for the

Reply to ‘Comment on “Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study” by Muanda et al.’

We thank Acar et al. [1] for their comments on our study titled ‘Use of antibiotics during pregnancy and the risk of major congenital malformations: A population based cohort study’. Though we fully agree with Acar et al. that we could not completely rule out a chance finding as clearly stated in our study, there are important considerations that should be taken into account when interpreting our findings. First, most of our results were consistent with previous published studies on the risk of major congenital malformations following in utero exposure to antibiotics especially for penicillin, macrolides, quinolones, doxycycline, nitrofurantoin and metronidale as reported in our study [2]. Therefore, such replications of findings are more likely hypothesis-testing research rather than exploratory approach as stated by Acar et al. Second, biological plausibility has been reported for each association seen in our study which strengthen our findings [2]. Third, adjustment for multiple testing can provide misleading results especially in presence of rare outcomes such is the case in our study. Indeed, by reducing the type 1 error (α), multiple test adjustments may increase the type II error (i.e. the probability of not rejecting the null hypothesis when the alternative is true) for those associations that are not null [3, 4]. Therefore, the increase of the type II error (β) will decrease the ability of a study to detect a real difference between groups (power = 1 β). The American Hospital Formulary Service (AHFS) Pharmacologic-Therapeutic Classification which was developed by the American Society of Health-System Pharmacists (ASHP) was used to classify antibiotics as stated in our manuscript [2]. The AHFS classification allows the grouping of drugs with similar pharmacologic, therapeutic and/or chemical characteristics in a four-tier hierarchy [5]. Finally, no increased risk of major congenital malformations following in utero exposure to fluoroquinolone class has been reported in eight studies as stated in our manuscript [2]. Though, those previous studies, including published meta-analyses, were limited by several methodological flaws (low power, recall and indication bias) as pointed out in our paper, their findings were overall similar to ours [2]. Of the eight studies reported in our manuscript, only two studies were able to assess the risk of birth defect associated with the use of individual fluoroquinolone [6, 7]. The first study looked at the risk of major congenital malformations following in utero exposure to individual fluoroquinolone, and their findings were similar to ours as stated in our manuscript [2, 7]. Unlike us, they could not examine the risk of organ specific malformations [2, 7]. The second study investigated the risk ofmajor congenitalmalformations and organ specific malformations associated with the use of ciprofloxacin, and their findings were consistent with ours [2, 6]. Unlike us again, they did not assess the risk of major congenital malformations associatedwith other fluoroquinolone such as levofloxacin, ofloxacin, norfloxacin and moxifloxacin [2, 6]. Contrary to the statement by Acar et al., we were able to look at the risk of major congenital malformations overall as well as the risk of eight specific organ system anomalies following gestational exposure to 17 individual antibiotics including the five most used fluoroquinolones (ciprofloxacin, norfloxacin, moxifloxacin, ofloxacin, levofloxacin) [2]. Of interest, we have also recently reported that fluoroquinolone use in early pregnancy was increasing the risk of spontaneous abortion (a class effect) [8]. British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 1083–1084 1083

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

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.

Response to: “Maternal infection can cause spontaneous abortion”

We thank Dr. Zipursky and colleagues[1][1] for their letter about our article on the risk of spontaneous abortion associated with the use of antibiotics during pregnancy.[2][2] We agree that whether the association observed in our study supports causality remains a critical question. It is likely to

The authors respond to: “Optimal levels of DHEA for pregnancy may be reduced by antibiotics”

We thank Dr. Howard[1][1] for his letter about our article on the risk of spontaneous abortion associated with the use of antibiotics during pregnancy.[2][2] Dr. Howard hypothesized that antibiotics reduced arylsulfatase (dehydroepiandrosterone sulfate [DHEAS]), which in turn reduces availability of

The authors respond to “Underlying maternal infection likely cause of study findings”

We thank Dr. Elwood and Dr. Money[1][1] for their letter to the editor on our CMAJ article on the risk of spontaneous abortion associated with use of antibiotics during pregnancy.[2][2] We agree that maternal infection may pose a risk to the developing fetus and the mother as stated in our