Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis

Macrolides and Congenital Malformations 1 Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis Narmeen MALLAH, MS1,2, Hamid Reza TOHIDINIK, Ph.D1,3,4, Mahyar ETMINAN, PharmD, MS5, Adolfo FIGUEIRAS, PharmD, Ph.D1,2, Bahi TAKKOUCHE, MD, Ph.D1,2 Affiliations: 1Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; 2Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP), Madrid, Spain; 3HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran; 4Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; and 5Eye Care Center, University of British Columbia, Vancouver, Canada. Address correspondence to: Bahi Takkouche, Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain R/ San Francisco, s/n, 15782, [bahi.[email protected]], +34-881-812-268 ORCID: 0000-0002-0739-2241 Short title: Macrolides and Congenital Malformations Macrolides and Congenital Malformations 2 Abstract Introduction: Macrolides are widely used during pregnancy; however, their fetal safety remains uncertain. We performed a meta-analysis to assess the relation between prenatal exposure to macrolides and occurrence of congenital malformations. Methods: We searched MEDLINE, EMBASE and other databases until June 12th, 2019. We assessed the quality of the studies and checked for heterogeneity and publication bias. We performed 3 different analyses and compared the effect of macrolides to each of the following unexposed populations: Group 1: babies unexposed to any medicine before birth, Group 2: babies exposed to non-macrolides antibiotics/non-teratogens, and Group 3: mixed population of the first and second comparators. Results: A weak association between macrolides and congenital malformation of any type was observed when macrolides were compared to the mixed population [ORgroup 3: 1.06 (95%CI 1.01, 1.10)]. Subgroup analysis showed that this weak association is restricted to fetus exposure in the first trimester of pregnancy [OR: 1.06 (95%CI: 1.01, 1.11)] and to cohort studies [OR: 1.07 (95%CI: 1.02, 1.13). Digestive system malformations were found to be slightly associated with prenatal exposure to macrolides [ORgroup 3: 1.14 (95%CI: 1.02, 1.26)]. Musculoskeletal system was also found to be potentially affected [ORgroup 2: 1.21 (95%CI: 1.08, 1.35) and ORgroup 3: 1.15 (95%CI: 1.05, 1.26)]. European studies showed a slightly stronger association than American studies in these two comparisons. Conclusions: Our study suggests a weak association of macrolides’ prenatal use and congenital malformations, limited to exposure in early pregnancy, and musculoskeletal and digestive systems. In addition to studies with a larger control of confounding, risk-benefit research is needed to determine the usefulness of macrolides during pregnancy. Key words: macrolides, congenital malformations, meta-analysis, fetal safety. Macrolides and Congenital Malformations 3 Key Points • Macrolides are widely used during pregnancy, however knowledge about their fetal safety is uncertain. • This meta-analysis shows that macrolides intake during pregnancy is associated with a weak increase in the odds of congenital abnormalities, limited to some subgroups. • These findings along with additional assessment of the risks and benefits of macrolides are crucial to determine their usefulness during pregnancy. Macrolides and Congenital Malformations 4 1. Introduction Congenital abnormalities are malformations of organs or body parts during organogenesis, which mainly take place in the first trimester of pregnancy [1,2]. Some malformations may also occur in the second and third trimesters of pregnancy as the tissues and organs continue to develop [2]. Birth defects are the leading risk factor of infants’ mortality worldwide [1, 3-5]. However the causes of the occurrence of these defects are not well determined [1]. According to the Global Report on Birth Defects, the proportion of malformations due to genetic factors is small compared to the proportion of abnormalities due to exposure to teratogenic intra-uterine factors such as certain medicines [6]. It is remarkable that 97.7% of the drugs approved by the FDA between 2000 and 2010 have ‘‘undetermined’’ teratogenic risk in human pregnancy [7]. Antibiotics are frequently prescribed during pregnancy, mainly to treat urinary infections. Indeed, around one-fourth of pregnant women receive antibiotics during pregnancy, comprising thereby 80% of all prescriptions [8]. Some antibiotics used for this purpose were found to harm fetal formation [9]. Macrolides are among the most consumed antibacterial medicines [10-12]. The major types of macrolides include erythromycin, azithromycin, clarithromycin and roxithromycin. Data about the association of prenatal exposure to macrolides with birth defects are inconclusive [9, 13-16]. For instance, when used in early pregnancy, erythromycin was associated with anencephaly, transverse limb deficiency, pyloric stenosis and other congenital malformations, [9, 13] while no relation was found between clarithromycin and the risk of fetal malformations [16]. Except for a meta-analysis aimed at assessing general adverse child outcomes, which included a limited number of original studies, no comprehensive review was carried out on this topic so far [17]. Therefore, to determine if there is an effect of macrolides´ prenatal Macrolides and Congenital Malformations 5 exposure on congenital abnormalities and to study whether this effect varies according to the type of macrolide and to the exposure pregnancy term, we carried out a systematic review and meta-analysis. 2. Methods 2.1. Information sources and search strategy We retrieved published studies on the use of macrolide antibiotics during pregnancy and the development of congenital malformations, by searching MEDLINE from 1966 until June 12th, 2019. To identify the relevant articles, we used the following syntax: (macrolide* OR erythromycin OR roxithromycin OR clarithromycin OR azithromycin OR macrolide[MeSH Terms]) AND (((birth defect*) OR (congenital) OR "congenital abnormalities"[MeSH Terms] OR fetal OR fetus)))). The search was exclusive to studies involving humans. Our search was not limited to any language of publication. We excluded cross sectional studies from our search due to the impossibility of this design to infer any causal effect. We also conducted a search using the following terms as free text words: birth defects, congenital malformation, congenital abnormalities, pregnancy, macrolides, cohort, case-control and incidence. We adopted similar strategies to search EMBASE from 1980 until 2019; the five regional bibliographic databases of the World Health Organization (WHO): African Index Medicus (AIM), Latin American and Caribbean Health Science Literature Database (LILACS), Index Medicus for the Eastern Mediterranean Region (IMEMR), Index Medicus for South-East Asia Region (IMSEAR), Western Pacific Region Index Medicus (WPRIM); as well as the Open Access Thesis and Dissertations (OATD). We also searched for abstracts of scientific meetings using the Conference Proceedings Citation Index from inception in 1990 until June 2019. Finally, we manually examined the references of all obtained articles as well as those of related systematic reviews. Macrolides and Congenital Malformations 6 All searches were carried out independently by two epidemiologists (N.M. and B.T.) and the results were merged. We registered the review protocol of this study in the International prospective register of systematic reviews PROSPERO (Reference: CRD42017055131) [18]. 2.2. Eligibility criteria and study selection We included studies that fulfilled the following eligibility criteria: (1) reporting original data from randomized clinical trials, case-control or cohort studies; (2) examining the association between prenatal exposure to macrolides and the development of congenital malformation; (3) providing estimates of relative risk (RR) or odds ratios (OR) and their corresponding 95% confidence intervals (CIs) or presenting enough data to calculate them. Due to their limitation in inferring causal relationships, cross-sectional studies were excluded. We restricted our analysis to congenital malformations in live births only. We excluded articles on drugs that could be assimilated to macrolides such as ivermectin, nystatin and natamycin and limited our study to true macrolides. We also excluded studies that investigated the postnatal maternal and/or infant exposure to macrolides. Duplicate studies were detected by identifying the study population. Only the most updated study was included in the meta-analysis. In addition, for publications about different macrolides that were carried out by the same investigator in the same population, we calculated the pooled RRs or ORs of these different publications and presented them as a single study. When effect measures of maternal exposure to different types of macrolides and/or during distinct terms of pregnancy were reported in the same study, we analyzed each outcome separately. 2.3. Data extraction We scanned the titles and abstracts of the collected articles in order to exclude the irrelevant ones, and subsequently reviewed the full texts of the remaining articles to check their Macrolides and Congenital Malformations 7 eligibility. We recorded the following information from the eligible studies: (1) study name and source; (2) publication year; (3) study design (cohort study and case-control study); (4) study period; (5) sample size (number of cases and controls for case-control studies, or number of cases and cohort size for cohort studies); (6) type of control (unexposed to any drug, exposed to non-macrolides antibiotics or to non-teratogens, or a mixture of the unexposed and non-macrolide exposed fetuses), (7) study country; (8) ascertainment of macrolides exposure; (9) exposure dose; (10) exposure period; (11) effect measures and 95% confidence interval; (12) adjustment, matching, and restriction variables; (13) percentage of drop-outs in cohort studies; (14) response rate in case-control studies; (15) type of macrolide; and (16) use of individual or a mixture of macrolides. 2.4. Quality assessment We assessed the quality of the studies by using a seven-point scale extracted from the Newcastle Ottawa scale according to the requirements of this meta-analysis [19]. We assessed the following criteria: Macrolide exposure ascertainment: based on a clinical history or any other documented proof (1 point), else (0 points). Confounding assessment: results adjusted for maternal age and urinary tract infections (2 points, 1 point each), else (0 points). Exposure description: reported duration (1 point) and determined dose (1 point), else (0 points). To assess methodological issues that were not common to cohort studies and casecontrol studies, we used the following criteria: drop-out rate or losses to follow up in cohort studies: < 20% (2 points), between 20% and 40% (1 point), and > 40% or not explained (0 points) and participation rate in case-control studies: > 80% (1 point), < 80% or not reported (0 points). We carried out a pooled analysis on studies scoring more than 4 points and compared the results with those of studies with a lower quality score. Macrolides and Congenital Malformations 8 Both data extraction process and quality rating were independently performed by two epidemiologists [N.M. and H.T.] and discrepancies were resolved through discussion with a third party [B.T.]. 2.5. Data synthesis We extracted the adjusted odds ratios and their 95% CI from the studies included in our metaanalysis. We used the crude ORs if no adjusted estimate was provided or computed them from the data provided by the authors. Subsequently, we weighted the log RRs and log OR for cohort and case-control studies, respectively, by the inverse of their variance to obtain a pooled OR and its 95% CI. Odds Ratios were considered unbiased estimates of the Relative Risk [20]. We carried out three different analyses according to the characteristics of the unexposed population. In the first approach, we included all studies that used fetuses unexposed to any drug as a comparator (comparison group 1). The second approach encompassed studies that compared the effect of macrolides parental exposure to exposure to non-macrolides or nonteratogenic drugs (comparison group 2). The third analysis involved the combination of the studies of the two approaches described above (comparison group 3). We presented both fixed and random effects pooled estimates. We checked for heterogeneity using DerSimonian and Laird’s Q test. We quantified the heterogeneity by calculating the proportion of the total variance due to between study variance (Ri) [21]. Large values (>0.75) of Ri indicate large amount of heterogeneity, values between 0.4 and 0.75 suggest a moderate amount while small values (<0.4) indicate low heterogeneity. Subsequently, we restricted the analysis to subgroups defined by study characteristics such as adjustment factors, exposure period, anatomical location of congenital malformations and study design. Prior to data analysis, we contacted the authors in order to know whether abstracts retrieved in our search Macrolides and Congenital Malformations 9 were published later as a full paper and to have more information about the comparison group used in the studies [14, 16, 22-25]. We repeated the same analysis for the three categories of comparison populations. 2.6. Assessment of publication bias We assessed publication bias visually using funnel plots at first, and then, more formally, using Egger´s regression test [26]. Furthermore, we used the trim-and-fill method to correct for potential publication bias. We also performed a sensitivity analysis by assuming that the results of case-control studies are the least likely to be published when their results show no effect. Accordingly, we recalculated the pooled OR assuming that (1) the case-control studies retrieved in our search represent only half of the studies ever conducted, (2) the unpublished studies found a null association (OR = 1) between macrolides prenatal exposure and congenital malformation, and (3) the unpublished studies found the same prevalence of congenital malformation as the average of the published studies. We re-calculated the pooled odds ratio under these extreme assumptions. All subgroup analyses, including anatomic location of the malformation, type of macrolides and pregnancy term, were planned a priori and were identified and published in the protocol registered in PROSPERO. All analyses were carried out using the software HEpiMA version 2.1.3 [27], and STATA version 12 (Stata Corp, College Station, Tex). Macrolides and Congenital Malformations 16 chromosomal congenital abnormalities in previous studies and could represent potential confounders [9, 46]. However, it is worth mentioning that the results after restriction of the analysis to the fully adjusted studies did not differ from that of the incompletely adjusted studies. Misclassification of the outcome is highly improbable to occur for such a diagnosis. Misclassification of exposure to macrolides is also unlikely as it was well documented in more than half (13 out of 21) of the included studies in which the corresponding data were collected through medical records. In addition, although it is unlikely that recall bias may have affected our results, we recalculated the pooled OR by excluding the studies that assessed exposure using a questionnaire or an interview (and not medical records), and the results remained unaltered. However, exposure to macrolides might be misclassified if some women did not actually take the macrolides that were prescribed. Due to the absence of data in the original studies, the results of our meta-analysis are limited by the absence of dose-response analysis. In addition, due to unavailability of data, we did not consider malformation outcomes in abortions or stillbirths. Therefore, we cannot rule out a mutagenic effect of macrolides that could have caused abortions or stillbirths. 5. Conclusion In summary, our meta-analysis showed that the increase in the odds of birth defects among women who consumed macrolides during their pregnancy is very low. However, a harmful effect of macrolides cannot be ruled out, especially for the musculoskeletal and digestive systems. Risk-benefit research is needed to address the question of whether macrolide prescription should be restricted during pregnancy. Macrolides and Congenital Malformations 17 Authors´ contributions Conception and design of the study: Bahi Takkouche and Mahyar Etminan. Conceptualization of the manuscript and review and synthesis of the literature: Narmeen Mallah. Data extraction: Narmeen Mallah and Hamid Reza Tohidinik. Coordination and supervision of data extraction and analysis: Bahi Takkouche and Adolfo Figueiras. All authors made substantial contribution to the interpretation of data, critically reviewed the manuscript and approved its submission for publication. Compliance with Ethical Standards: Funding Source: No specific funding for this work. Dr Takkouche’s and Dr Figueiras’ work is funded by a grant from the Regional Ministry of Education, Universities and Vocational Training, Santiago de Compostela, Spain, ED431C 2018/20. Conflict of Interest: Narmeen Mallah, Hamid Reza Tohidinik, Mahyar Etminan, Adolfo Figueiras, and Bahi Takkouche declare that they have no conflict of interest. Data Sharing: All data generated or analyzed during this study are included in this published article and its supplementary information file (Online Resource 1). 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The association between race/ethnicity and major birth defects in the united states, 1999- 2007. Am J Public Health. 2014;104(9):e14-23. https://doi.org/10.2105/AJPH.2014.302098 45. Goossens H. Antibiotic consumption and link to resistance. Clinical Microbiology and Infection. 2009;15(Sup 3):12 - 5. https://doi.org/10.1111/j.1469-0691.2009.02725.x 46. Hollier LM, Leveno KJ, Kelly MA, DD MC, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol. 2000;96(5 Pt 1):701-6. https://doi.org/10.1016/S0029-7844(00)01019-X Figures Fig. 1 Flow chart of screening for literature about macrolides’ prenatal exposure and congenital malformation Fig. 2 Study specific and pooled odds ratios of prenatal exposure to macrolides and congenital malformations Fig. 3 Funnel plot of prenatal macrolides’ exposure and any congenital malformation Macrolides and Congenital Malformations 21 Supplemental Information Online Resource 1 (Table ESM_1). Dataset of extracted and calculated OR of general and specific congenital malformations classified by the comparator group, continent, OR adjustment status, quality assessment score, body systems, exposure period and type of macrolide. Online Resource 2 (Table ESM_2): represents the characteristics of cohort studies of macrolides´ intake and congenital malformations Online Resource 3 (Table ESM_3): represents the characteristics of case-control studies of macrolides´ intake and congenital malformations Macrolides and Congenital Malformations 22 Table 1 Pooled Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of macrolides’ intake and congenital malformations (comparison group 1: fetuses not exposed to any drug) Number of studies OR (95% CI) Fixed effects OR (95% CI) Random effects Ri* Q test (p value) Any congenital malformation All studies 14 1.05 (0.99, 1.12) 1.05 (0.99, 1.12) 0.00 0.81 Study Design Cohort 11 1.07 (0.99, 1.15) 1.07 (0.99, 1.15) 0.00 0.90 Case-control studies 3 1.02 (0.92, 1.14) 1.01 (0.88, 1.17) 0.39 0.21 Anatomic location Cardiovascular 8 1.03 (0.93, 1.14) 1.05 (0.90, 1.22) 0.48 0.07 Head and Neck 4 1.27 (0.94, 1.72) 1.27 (0.94, 1.72) 0.00 1.00 Musculoskeletal system 5 1.06 (0.91, 1.24) 1.06 (0.85, 1.31) 0.33 0.27 Digestive system 8 1.13 (0.97, 1.31) 1.12 (0.9, 1.33) 0.18 0.30 Urogenital system 5 1.00 (0.80, 1.24) 0.98 (0.71, 1.35) 0.43 0.17 Nervous system 4 1.14 (0.86, 1.52) 1.12 (0.81, 1.55) 0.19 0.28 Adjustment Full 2 1.04 (0.94, 1.15) 1.04 (0.94, 1.15) 0.00 0.50 Incomplete 12 1.06 (0.98, 1.15) 1.06 (0.98, 1.15) 0.00 0.75 Quality score ≥ 4 7 1.04 (0.95, 1.14) 1.04 (0.95, 1.14) 0.00 0.78 < 4 7 1.06 (0.98, 1.16) 1.06 (0.98, 1.16) 0.00 0.56 Macrolide exposure period First trimester 11 1.07 (1.00, 1.14) 1.07 (1.00, 1.14) 0.00 0.93 Third trimester 3 1.00 (0.79, 1.28) 1.08 (0.73, 1.59) 0.60 0.11 Geographic location Europe 6 1.10 (0.98, 1.23) 1.10 (0.98, 1.23) 0.00 0.71 North America 6 1.03 (0.96, 1.12) 1.03 (0.96, 1.12) 0.00 0.45 Type of treatment Erythromycin 7 1.05 (0.97, 1.15) 1.05 (0.97, 1.15) 0.00 0.46 Azithromycin 2 1.15 (0.97, 1.36) 1.15 (0.97, 1.36) 0.00 0.37 Clarithromycin 2 1.10 (0.88, 1.38) 1.10 (0.88, 1.38) 0.00 0.84 Roxithromycin 2 2.03 (0.75, 5.48) 2.03 (0.75, 5.48) 0.00 0.79 *Ri: Proportion of total variance due to between-study variance. Macrolides and Congenital Malformations 23 Table 2 Pooled Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of macrolides’ intake and congenital malformations. (comparison group 2: fetuses exposed to non-teratogenic drugs/non-macrolides) Number of studies OR (95% CI) Fixed effects OR (95% CI) Random effects Ri* Q test (p value) Any congenital malformation All studies 13 1.06 (1.00, 1.12) 1.06 (1.00, 1.12) 0.00 0.88 Study Design Cohort 11 1.07 (1.00, 1.15) 1.07 (1.00, 1.15) 0.00 0.86 Case-control studies 2 1.03 (0.93, 1.14) 1.03 (0.93, 1.14) 0.00 0.36 Anatomic location Cardiovascular 7 0.87 (0.81, 0.95) 0.93 (0.80, 1.07) 0.50 0.10 Head and Neck 4 1.08 (0.90, 1.29) 1.05 (0.78, 1.42) 0.54 0.12 Musculoskeletal system 4 1.21 (1.08, 1.35) 1.21 (1.08, 1.35) 0.00 0.85 Digestive system 5 1.14 (0.98, 1.33) 1.11 (0.90, 1.38) 0.44 0.15 Urogenital system 4 0.89 (0.76, 1.05) 0.92 (0.60, 1.39) 0.84 0.001 Nervous system 4 1.14 (0.92, 1.42) 1.05 (0.68, 1.62) 0.70 0.03 Adjustment Full 2 1.05 (0.96, 1.15) 1.05 (0.96, 1.15) 0.00 0.48 Incomplete 11 1.07 (0.99, 1.15) 1.07 (0.99, 1.15) 0.00 0.84 Quality score ≥ 4 8 1.08 (1.01, 1.15) 1.08 (1.01, 1.15) 0.00 0.74 < 4 5 1.02 (0.92, 1.13) 1.02 (0.92, 1.13) 0.00 0.86 Macrolide exposure period First trimester 9 1.05 (0.99, 1.12) 1.05 (0.99, 1.12) 0.00 0.83 Third trimester 2 1.33 (0.99, 1.79) 1.33 (0.99, 1.79) 0.00 0.34 Geographic location Europe 7 1.15 (1.01, 1.31) 1.15 (1.01, 1.31) 0.00 0.90 North America 6 1.04 (0.98, 1.11) 1.04 (0.98, 1.11) 0.00 0.81 Type of treatment Erythromycin 6 0.92 (0.86, 0.99) 0.99 (0.83, 1.18) 0.84 0.00 Azithromycin 6 1.08 (0.98, 1.19) 1.08 (0.98, 1.19) 0.00 0.63 Clarithromycin 4 0.92 (0.82, 1.04) 0.92 (0.82, 1.04) 0.00 0.95 Roxithromycin 3 1.50 (0.81, 2.77) 1.74 (0.69, 4.37) 0.53 0.13 *Ri: Proportion of total variance due to between-study variance. Macrolides and Congenital Malformations 24 Table 3 Pooled Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of macrolides’ intake and congenital malformations. (Comparison group 3: mixed population of unexposed fetuses) Number of studies OR (95% CI) Fixed effects OR (95% CI) Random effects Ri* Q test (p value) Any congenital malformation All studies 21 1.06 (1.01, 1.10) 1.06 (1.01, 1.10) 0.00 0.86 Study Design Cohort 17 1.07 (1.02, 1.13) 1.07 (1.02, 1.13) 0.00 0.93 Case-control studies 4 1.03 (0.95, 1.11) 1.02 (0.94, 1.12) 0.14 0.35 Anatomic location Cardiovascular 11 0.93 (0.87, 0.98) 1.03 (0.89, 1.18) 0.71 0.002 Head and Neck 5 1.13 (0.96, 1.32) 1.12 (0.93, 1.35) 0.19 0.31 Musculoskeletal system 6 1.15 (1.05, 1.26) 1.15 (1.05, 1.26) 0.00 0.40 Digestive system 9 1.14 (1.02, 1.26) 1.10 (0.94, 1.28) 0.44 0.08 Urogenital system 6 0.93 (0.81, 1.05) 0.96 (0.69, 1.34) 0.81 0.001 Nervous system 5 1.15 (0.97, 1.36) 1.02 (0.72, 1.47) 0.71 0.01 Adjustment Full 3 1.05 (0.98, 1.12) 1.04 (0.97, 1.12) 0.00 0.50 Incomplete 18 1.06 (1.00, 1.12) 1.06 (1.00, 1.12) 0.00 0.84 Quality score ≥ 4 12 1.07 (1.01, 1.13) 1.07 (1.01, 1.13) 0.00 0.78 < 4 9 1.04 (0.97, 1.12) 1.04 (0.97, 1.12) 0.00 0.70 Macrolide exposure period First trimester 16 1.06 (1.01, 1.11) 1.06 (1.01, 1.11) 0.00 0.95 Third trimester 4 1.12 (0.93, 1.35) 1.15 (0.85, 1.56) 0.62 0.05 Geographic location Europe 10 1.12 (1.03, 1.22) 1.12 (1.03, 1.22) 0.00 0.86 North America 9 1.03 (0.98, 1.09) 1.03 (0.98, 1.09) 0.00 0.74 Type of treatment Erythromycin 9 0.96 (0.91, 1.01) 1.00 (0.88, 1.14) 0.79 0.00 Azithromycin 6 1.09 (1.00, 1.19) 1.09 (1.00, 1.19) 0.00 0.73 Clarithromycin 5 0.96 (0.86, 1.07) 0.96 (0.86, 1.07) 0.00 0.97 Roxithromycin 5 1.63 (0.96, 2.75) 1.66 (0.95, 2.89) 0.08 0.36 *Ri: Proportion of total variance due to between-study variance. Macrolides and Congenital Malformations 25 Figure 1. Online Resource 2. Characteristics of cohort studies of macrolides´ intake and congenital malformations Source Type of Macrolide Country Type of malformation Exposure Period (months of pregnancy) Comparison Type and OR (95% CI) Cases/ Cohort Size General OR (95% CI) Adjustment, Matching, and Restriction Factors Muanda FT, et al. 2017 [1] azithromycin, erythromycin, clarithromycin Quebec Cardiac, digestive, head and neck, musculoskeletal, nervous, respiratory, urogenital 1 – 3 Unexposed to any antibiotic: 1.08 (0.95, 1.23) Exposed to nonmacrolide antibiotics: 1.04 (0.95, 1.14) 13, 852/139,938 1627/15469 1.05 (0.98, 1.14) Maternal age, urinary tract infections, sociodemographic variables, chronic maternal illness, endometriosis and other maternal infections, healthcare utilization, year of delivery, infant’s gender Lê Nguyên T, et al. 2017 [2] macrolides France Congenital malformations 1 – 3 Unexposed to any antibiotic: 1.02 (0.71, 1.46) Treated with penicillin: 0.93 (0.63, 1.37) 47/62,846 47/12,193 0.98 (0.75, 1.27) Maternal age, long-term maternal illness, gestity, parity, multiple pregnancy Källén B, et al. 2014 [3] erythromycin Sweden Any, cardiac 1 – 3 Unexposed to any antibiotic: 1.14 (0.96, 1.36) 70339/1575847 1.14 (0.96, 1.36) Maternal age, year of delivery, parity, smoking, obesity Lund M, et al. 2014 [4] azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, Denmark Infantile hypertrophic pyloric stenosis • 1 – 6 • 6 – 9 Unexposed to any antibiotic: 1.23 (0.85, 1.76) Exposed to nonmacrolide antibiotics: 1.23 (0.83, 1.83) 30/315569 159/60732 1.23 (0.94, 1.60) Birth order, infant’s sex, calendar period, current age of the infant Andersen JT, et al. 2013 [5] clarithromycin Denmark Cardiac, musculoskeletal, urogenital 1 – 3 Unexposed to any antibiotic: 1.03 (0.53, 2.00) 24817/705837 1.03 (0.53, 2.00) Maternal age, education, number of previous births, economical status Online Resource 2. Characteristics of cohort studies of macrolides´ intake and congenital malformations (continued) Source Type of Macrolide Country Type of malformation Exposure Period (months of pregnancy) Comparison Type and OR (95% CI) Cases/ Cohort Size General OR (95% CI) Adjustment, Matching, and Restriction Factors Dinur AB, et al. 2013 [6] azithromycin, clarithromycin, erythromycin, roxithromycin Israel Cardiac, digestive 1 – 3 Unexposed to any antibiotic: 1.07 (0.84, 1.38) ---/105492 1.07 (0.84, 1.38) Maternal age, year of delivery, parity, ethnicity, chronic maternal illness Bar-Oz B, et al. 2012 [7] azithromycin, roxythromycin, clarithromycin • Czech Republic • Germany • Israel • Italy • Netherlands Cardiac 1 – 3 Exposed to nonteratogenic agents: 1.42 (0.70, 2.88) 32/1146 1.42 (0.70, 2.88) Maternal age, smoking, alcohol consumption, previous abortions, previous child with structural anomaly, macrolide exposure Romøren M, et al. 2012 [8] erythromycin, azithromycin, clarithromycin, spiramycin Norway Any, Cardiac 1 – 3 Unexposed to any antibiotic: 1.02 (0.86, 1.23) Exposed to nonmacrolide antibiotics: 1.15 (0.96, 1.38) 8865/178142 413/9069 1.08 (0.95, 1.24) Maternal age, urinary tract infections, chronic maternal illness, parity, marital status, smoking, pregnancy supplement, previous abortions Cooper WO, et al. 2009 [9] azithromycin, erythromycin United States Any, digestive, head and neck, nervous, musculoskeletal, urogenital • 1 – 3 • 1 – 9 Unexposed to any antibiotic: 0.92 (0.73, 1.16) Exposed to nonmacrolide antibiotics: 1.03 (0.88, 1.21) 869/30,049 589/7471 0.99 (0.87, 1.13) Maternal age, year of delivery, race, rural residence, economical status, chronic maternal illness, filling of prescriptions of other known teratogens Bar-Oz B, et al. 2008 [10] azithromycin, roxythromycin, clarithromycin • Croatia • Israel Cardiac 1 – 3 Exposed to nonmacrolide antibiotics: 1.62 (0.68, 3.86) 32/1066 1.62 (0.68, 3.86) Unadjusted Online Resource 2. Characteristics of cohort studies of macrolides´ intake and congenital malformations (continued) Source Type of Macrolide Country Type of malformation Exposure Period (months of pregnancy) Comparison Type and OR (95% CI) Cases/ Cohort Size General OR (95% CI) Adjustment, Matching, and Restriction Factors Chun JY, et al. 2006 [11] roxythromycin South Korea Major 1 – 3 Unexposed to any teratogenic agent: 1.37 (0.07, 27.57) 3/187 1.37 (0.07, 27.57) Maternal age, gravity Sarkar M, et al. 2006 [12] azithromycin Canada Major 1 – 3 Exposed to any nonteratogen: 1.01 (0.20, 5.11) 6/227 1.01 (0.20, 5.11) Maternal age, gestational age at call, smoking, alcohol consumption Wolfgang P, et al. 2005 [13] roxithromycin Hungary Congenital anomalies 1 – 3 Unexposed to any antibiotic: 2.13 (0.75, 6.1) 15/275 2.13 (0.75, 6.1) Maternal age, gestational age at call Cooper WO, et al. 2002 [14] erythromycin, nonerythromycin, lincomycin, clindamycin, clarithromycin, azithromycin, dirithromycin United States Digestive • 6 – 9 • 1 – 9 Exposed to nonmacrolide antibiotics: 1.28 (0.96, 1.70) 679/260,799 1.28 (0.96, 1.70) Maternal age, education, geographic residence, use of other antibiotics, infant´s gender, infant´s race, birth order, year of delivery, infant´s postnatal prescriptions for erythromycin Mahon BE, et al. 2001 [15] macrolides United States Digestive 1 – 9 Unexposed to any antibiotic: 1.19 (0.6, 2.3) 43/14,876 1.19 (0.6, 2.3) Birth weights, gestational age Einarson A, et al. 1998 [16] clarithromycin Canada Major 1 – 3 Exposed to nonteratogenic antibiotics: 1.1 (0.44, 2.78) 19/266 1.1 (0.44, 2.78) Maternal age, smoking, alcohol consumption Wilton LV, et al. 1998 [17] azithromycin United Kingdom Congenital anomalies 1 – 3 Exposed to nonmacrolide antibiotics: 1.75 (0.01, 31.23) 14/556 1.75 (0.01, 31.23) Unadjusted References 1. Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and the risk of major congenital malformations: A population based cohort study. Br J Clin Pharmacol. 2017;83(11):2557-71. https://doi.org/10.1111/bcp.13364 2. Lê Nguyên T, Araujo M, Hurault-Delarue C, Lacroix I, Damase-Michel C, Sommet A. teratogenic risk of macrolides during the first trimester of pregnancy: a study with two complementary approaches within the efemeris database. Clinical Therapeutics. 2017; 39 (8)Sup:e11-e12 3. Kallen B, Danielsson BR. Fetal safety of erythromycin. An update of swedish data. Eur J Clin Pharmacol. 2014;70(3):355-60. https://doi.org/10.1007/s00228-013-1624-3 4. Lund M, Pasternak B, Davidsen RB, Feenstra B, Krogh C, Diaz LJ et al. Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: Nationwide cohort study. BMJ. 2014;348:g1908. https://doi.org/10.1136/bmj.g1908 5. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C et al. Clarithromycin in early pregnancy and the risk of miscarriage and malformation: A register based nationwide cohort study. PLoS One. 2013;8(1):e53327. https://doi.org/10.1371/journal.pone.0053327 6. Dinur AB, Koren G, Matok I, Wiznitzer A, Uziel E, Gorodischer R et al. Fetal safety of macrolides. Antimicrob Agents Chemother. 2013;57(7):3307-11. https://doi.org/10.1128/AAC.01691-12 7. Bar-Oz B, Weber-Schoendorfer C, Berlin M, Clementi M, Di Gianantonio E, de Vries L et al. The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: A prospective, multicentre, observational study. Drug Saf. 2012;35(7):589-98. https://doi.org/10.2165/11630920-000000000-00000 8. Romoren M, Lindbaek M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin - a population-based register study from norway. Br J Clin Pharmacol. 2012;74(6):1053-62. https://doi.org/10.1111/j.1365-2125.2012.04286.x 9. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer SM, Gideon PS et al. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol. 2009;23(1):18-28. https://doi.org/10.1111/j.1365-3016.2008.00978.x 10. Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I et al. Pregnancy outcome after gestational exposure to the new macrolides: A prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol. 2008;141(1):31-4. https://doi.org/10.1016/j.ejogrb.2008.07.008 11. Chun JY, Han JY, Ahn HK, Choi JS, Koong MK, Nava-Ocampo AA et al. Fetal outcome following roxithromycin exposure in early pregnancy. J Matern Fetal Neonatal Med. 2006;19(3):189-92. https://doi.org/V347283491478V77 12. Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006;6:18. https://doi.org/1471-2393-6-18 13. Wolfgang P, Schloemp S, Sterzik K, Stoz F, editors. Does roxithromycin affect embryo development? 33rd Annual Conference of the European Teratology Society; 3 - 7 Sep, 2005; Haarlem, The Netherlands: Reproductive Toxicology. 14. Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med. 2002;156(7):647-50. https://doi.org/poa10338 15. Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr. 2001;139(3):380-4. https://doi.org/S0022-3476(01)02879-7 16. Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol. 1998;15(9):523-5. https://doi.org/10.1055/s-2007-994053 17. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol. 1998;105(8):882-9. Online Resource 3. Characteristics of case-control studies of macrolides´ intake and congenital malformations Source Type of Macrolide Country Type of malformation Exposure Period (months of pregnancy) Comparison Type and OR (95% CI) Cases/Controls General OR (95% CI) Adjustment, Matching, and Restriction Factors Lin KJ, et al. 2013 [1] Any macrolide, erythromycin, nonerythromycin • Canada • United States Cardiac, digestive, head and neck, musculoskeletal, nervous, respiratory, urogenital • 1 – 3 • 3 – 6 • 6 – 9 Unexposed to any antibiotic: 0.99 (0.85, 1.16) 4867/6,952 0.99 (0.85, 1.16) Maternal age, calendar year when they were ascertained, race, education, geographic residence, obesity, family history of congenital malformations or diabetes mellitus, smoking, pregnancy supplement, multiple pregnancy, urinary tract infections, maternal chronic illness Crider KS, et al. 2009 [2] erythromycin United States Cardiac, digestive, head and neck, musculoskeletal, nervous, urogenital 1 – 3 Unexposed to any antibiotic: 1.12 (0.96, 1.32) Exposed to nonmacrolide antibiotics: 1.01 (0.91, 1.13) 13155/4941 1384/516 1.04 (0.95, 1.15) Maternal age, race, education, obesity, gestational age at call, pregnancy supplements, smoking, alcohol consumption Louik C, et al. 2002 [3] erythromycin • Canada • United States Digestive • 1 – 6 • 6 – 9 Unexposed to any antibiotic: 0.81 (0.57, 1.14) 1,044/1704 0.81 (0.57, 1.14) Maternal age, geographic region, study period, parity, infant´s gender, gestational age Czeizel AE, et al. 2000 [4] & Czeizel AE, et al. 1999 [5] erythromycin, spiramyicn, roxithromycin, oleandomycin, josamycin, Hungary Cardiac, head and neck, musculoskeletal, urogenital, nervous, others • 1 – 3 • 1 – 9 Exposed to other agents (not macrolides): 1.19 (0.92, 1.54) 22,865/38,151 1.19 (0.92, 1.54) Maternal age, urogenital disorders, birth order, maternal chronic illness, other drug uses References 1. Lin KJ, Mitchell AA, Yau WP, Louik C, Hernandez-Diaz S. Safety of macrolides during pregnancy. Am J Obstet Gynecol. 2013;208(3):221 e1-8. https://doi.org/10.1016/j.ajog.2012.12.023 2. Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects: National birth defects prevention study. Arch Pediatr Adolesc Med. 2009;163(11):978-85. https://doi.org/10.1001/archpediatrics.2009.188 3. Louik C, Werler MM, Mitchell AA. Erythromycin use during pregnancy in relation to pyloric stenosis. Am J Obstet Gynecol. 2002;186(2):288-90. https://doi.org/S0002937802042874 4. Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A case-control teratological study of spiramycin, roxithromycin, oleandomycin and josamycin. Acta Obstet Gynecol Scand. 2000;79(3):234-7. 5. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol. 1999;13(6):531-6. https://doi.org/S0890-6238(99)00046-5