Adverse Effects of Dipyrone (Metamizole) Use During Pregnancy on Offspring Health: A Systematic Review and Meta-Analysis

Adverse Effects of Dipyrone (Metamizole) Use During Pregnancy on Offspring Health: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adverse Effects of Dipyrone (Metamizole) Use During Pregnancy on Offspring Health: A Systematic Review and Meta-Analysis Gabriel Moreira Lino, Felipe Shoji Ishibashi, George Alessandro Maranhão Conrado, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4421640/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jul, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted 10 You are reading this latest preprint version Abstract Background This meta-analysis and systematic review aimed to review the health outcomes of offspring following dipyrone use during pregnancy. Methods A systematic literature search was conducted in MEDLINE, Embase, and the Cochrane Library to identify clinical trials or observational studies investigating women who used dipyrone during pregnancy published up to 22 March 2024. Two independent reviewers were responsible for the data extraction. The data were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) and a random effects model. Sensitivity analyses were performed using Bayesian Markov Chain Monte Carlo methods. Results Six case-control studies and four prospective cohort studies met the inclusion criteria. There was no evidence of associations with congenital anomalies (OR 1.18, 95% CI 0.80–1.63; I 2 = 33.73%; 3 cohorts and 1 case-control, n = 67,374), major congenital anomalies (OR 1.06, 95% CI 0.47–2.37; I 2 = 0%; 2 cohorts, n = 1,356), infant leukemia (OR 1.25, 95% CI 0.86–2.22; I 2 = 72.82%; 3 case-controls, n = 1,686), fetal death (OR 0.81, 95% CI 0.57–1.14; 3 cohorts, n = 6,380), prematurity (OR 0.99, 95% CI 0.80–1.21; I 2 = 0%; 3 cohorts, n = 6,194), low birth weight, constriction of the ductus arteriosus, or renal and cardiac disorders. There is insufficient evidence to exclude oligohydramnios and patent ductus arteriosus in second- and third-trimester exposures. All analyses were of very low certainty. Conclusion There is no evidence indicating that maternal use of dipyrone causes substantial harm to offspring. According to the sensitivity analyses, exposure during the first and second trimesters was not associated with any negative outcomes. Some observed outcomes, particularly in the third trimester of pregnancy, merit further research. Dipyrone Pregnancy Congenital anomalies Patent ductus arteriosus Infant leukemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1 INTRODUCTION Dipyrone (metamizole) is a nonopioid drug with significant antipyretic and analgesic properties. It is commonly used to manage pain in Spain, Brazil, and Germany in outpatient and inpatient care 1–3 . Dipyrone is a well-tolerated medication 1,2,4 , although drug-induced agranulocytosis reactions have led to its prohibition in some countries, including the UK and the US 5 . Currently, there is still uncertainty over its use during pregnancy. Studies have investigated potential myelotoxic, teratogenic, and endocrine-disruptive effects on fetuses in recent decades, but no conclusions have been reached 6,7 . Therefore, this systematic review and meta-analysis were conducted to investigate the safety and risk of dipyrone use during pregnancy to the health of offspring. 2 METHODS 2.1 Protocol and registration This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines 8 . The protocol was previously registered in PROSPERO (CRD42023453817). 2.2 Search strategy and eligibility criteria A systematic literature search (up to 22 March 2024) was conducted in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, and the Cochrane Library for articles reporting adverse effects from maternal exposure to dipyrone without language or date restrictions. The final search query is presented in Appendix S1. The study’s investigators designed the search. Publications that met the following predefined inclusion criteria were considered: clinical trials or observational studies (cohorts and case-controls) that studied women who had used dipyrone during pregnancy and assessed offspring health. When only some of the patients in a study fulfilled the mentioned criteria, only those patients were included in the review. Studies were excluded if there were no disaggregated data on the exposed group. Contact with the study’s authors by email was made in the case of exclusion. 2.3 Study selection and data extraction All found reports were registered in a prestructured formulary containing data about authorship, year, and journal of publication. Two reviewers (GML, FSI) independently accessed titles and abstracts and excluded duplicates, redundant publications, and reports that did not meet the inclusion criteria. Thus, the same two reviewers (GML, FSI) performed the full-text reading to exclude articles for which at least one exclusion criterion was met. Whenever disagreement was found between the reviewers in the abstract or full-text reading, a third reviewer (GAMC) was consulted. The data from the selected studies were searched and extracted independently by two reviewers (GML, FSI) for adverse outcomes related to the health of the offspring. Data on the study (design, country and period of enrollment, sample size, comparison groups, participant selection, allocation, certainty of outcome, confounding variables), exposure to dipyrone during pregnancy (mother’s age, daily dose, duration of therapy, trimester of pregnancy, over-the-counter or prescription use) and adverse outcomes related to the health of the offspring were collected. The following outcomes were found: spontaneous abortions, intrauterine death, stillbirths, birth weight, prematurity, oligohydramnios, patent ductus arteriosus, congenital anomalies, infant leukemia and nephroblastoma (including leukemia cases associated with MLL rearrangements and the NAT2 phenotype). Spontaneous abortions, intrauterine deaths, and stillbirths were analyzed conjunctly as fetal deaths. 2.4 Risk of bias assessment in included studies Two independent reviewers (GML, GAMC) used the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies. This tool was designed to analyze the quality of observational studies (cohort and case-control) based on study group selection, comparability, exposure (case-control), or outcome (cohort). A score above 6 on the NOS indicated high quality. 2.5 Statistical analysis Quantitative data were analyzed using R software, version 4.2.2, with the packages meta, metafor, bayesmeta, and tidyverse 9–12 . The outcomes are reported as dichotomous data and were compared using odds ratios (ORs) with 95% confidence intervals (CIs). The adjusted ORs (aORs) were extracted from studies to minimize confounding factors 13 . Heterogeneity was evaluated with tau and I 2 statistics; p values less than 0.10 and I 2 values > 25% were considered significant for heterogeneity. A random-effects restricted maximum likelihood (REML) model on the log-odds scale was used. Publication bias was analyzed using funnel plots. Sensitivity analyses were performed for significant outcomes in a Bayesian framework with Markov chain Monte Carlo (MCMC) methods utilizing weakly informative and noninformative priors. Zanrosso 2010 14 was not included in the statistical synthesis because the data reported were from the same population as one of the included studies. 2.6 Certainty of the evidence assessment The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) 15 was used to determine the quality of evidence of the analyses. In this evaluation, evidence can be divided into four grades based on how certain the outcomes are: high (we are very confident that the true effect lies close to that of the estimate of the effect), moderate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different), low (the true effect may be substantially different from the estimate of the effect) and very low (the true effect is likely to be substantially different from the estimate of effect). The tables were generated with GRADEpro GDT software 16 . 3 RESULTS From the 375 records initially identified, 41 duplicates were removed. Three hundred thirty-four abstracts were screened, and fifty-nine reports were selected for full-text reading. Ten studies were included in the systematic review, and seven were included in the meta-analysis (Fig. 1 ). The reasons for exclusion are described in the flowchart. The characteristics of the studies, exposure to dipyrone, and adverse outcomes related to the health of the offspring are summarized in Table 1 . There were six case-control studies 6,14,17–19,24 and four prospective cohorts 20–22 . Five studies were conducted in Brazil 6,14,18,21,24 , two in Germany 22 , one in Hungary 19, and two in multiple other countries (Italy, Israel, Greece, Egypt, Brazil, Chile, China, Hong Kong, and Japan) 17,20 . Only five studies reported the gestational age of exposure; among three, the exposure occurred during the first trimester. The health outcomes reported for the offspring were congenital anomalies (n = 4) 19–22 , infant leukemia (n = 4) 6,14,17,18 , fetal death (n = 3) 20–23 , prematurity (n = 3) 20–22 , birth weight (n = 3) 20–22 , oligohydramnios (n = 2) 19,23 , patent ductus arteriosus (n = 1) 23 , constriction or closure of ductus arteriosus (n = 1) 23 , renal disorders (n = 1) 23 , cardiac disorders (n = 1) 23 , and nephroblastoma (n = 1) 24 . Drug therapy was based almost exclusively on self-reported information. Table 1 – Characteristics of the included studies Author (Year) Country Study design Period Sample size: exposed/ not exposed Outcomes (child age) Pregnancy trimester of dipyrone use Drug therapy Source of information NOS Alexander et al. (2001) 17 Multiple countries Multicenter case-control 1996-ND 136:266 a ALL and AML (< 18 months) ND ND Self-reported 7 Couto et al. (2015) 18 Brazil Multicenter case-control 1999–2007 231:411 a ALL and AML (< 23 months) ND ND Self-reported 5 Pombo-de-Oliveira et al. (2006) 6 Brazil Multicenter case-control 1999–2005 202:440 a ALL and AML (< 21 months) ND ND Self-reported 6 Zanrosso et al. (2010) 14 Brazil Multicenter case-control 2000–2008 132:131 ALL (< 21 months) ND ND Self-reported 4 Banhidy et al. (2007) 19 Hungary Population-based case-control 1980–1996 22,843:38,151 CA, OLIGO First trimester 1.5 g (0.5–4.0mg)/ day of oral dipyrone for 2.5 weeks for cases and 2.8 weeks for controls Self-reported by women retrospectively identified in a dataset (81.1%) and medical records (18.9%) 6 Bar-Oz et al. (2005) 20 Israel and Italy Multicenter prospective cohort ND 108:108 CA, FD, PREM and BW First trimester 0.5–2 g/ day of oral dipyrone for 1–4 days Self-reported by women calling teratogen information services at the time of exposure 7 da Silva Dal Pizzol et al. (2009) 21 Brazil Multicenter prospective cohort 1991–1995 555:4,276 CA, FD, PREM and BW Second trimester (21st − 28th week) ND Self-reported in interviews 7 Dathe et al. (2017) 22 Germany Prospective cohort 2000–2015 446:887 CA, FD, PREM and BW First trimester Most therapies were short-term, further information not provided Self-reported by women who contacted the Embryotox institute 8 Dathe et al. (2022) 23 Germany Prospective cohort 2008–2017 1092:1154 a FD, OLIGO, PDA, constriction or closure of ductus arteriosus, renal and cardiac disorders Second and third trimesters Therapy was reported individually for all cases Self-reported by women who contacted the Embryotox institute 8 Sharpe et al. (1996) 24 Brazil Multicenter case-control 1987–1989 109:218 a Nephroblastoma ND ND Self-reported 4 ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BW: Birth weight; CA: congenital anomaly; FD: fetal death; ND: not determined; NOS: newcastle-ottawa scale; OLIG: oligohydramnios; PDA: patent ductus arteriosus; PREM: prematurity. a In these studies, exposures other than dipyrone were included in the total sample size. Five studies had a low risk of bias. The confounding variables and adjustment methods differed across studies (Table S1 ). The evaluation of the risk of bias in each study is presented in the supplementary file (Table S2 ). Regarding publication bias, funnel plots showed some visual asymmetry (Figures S1 and S2). 3.1 Congenital anomalies Four studies, including a total of 67,374 newborns, investigated the occurrence of congenital anomalies. There was an increased chance of congenital anomalies in the exposed group (OR 1.21, 95% CI 1.13–1.30, p < 0.0001; I 2 = 0%; 3 cohorts and 1 case-control, n = 67,374, very low certainty evidence) (Fig. 2 ). The pooled ORs with adjusted data were similar (aOR 1.19, 95% CI 1.10–1.29, p < 0.0001; I 2 = 0%; 2 cohorts and 1 case-control, very low certainty evidence) (Fig. 3 ). A total of 95% of the weight of these estimates can be attributed to the study of Banhidy et al., which revealed a statistically significant correlation between dipyrone exposure and diaphragmatic and cardiovascular congenital anomalies. Sensitivity analysis with MCMC revealed no evidence of an association for congenital anomalies (OR 1.18, 95% CI 0.80–1.63; I 2 = 33.73%). There was no evidence of risk in the subgroup analysis of major congenital anomalies (OR 1.06, 95% CI 0.47–2.37, p = 0.89; I 2 = 0%; 2 cohorts, n = 1,356, very low certainty evidence) (Fig. 4 ). Adjusted data on major congenital anomalies were not available. 3.2 Perinatal outcomes (fetal death, prematurity, low birth weight, oligohydramnios, patent ductus arteriosus, constriction of ductus arteriosus, renal and cardiac disorders) Four studies investigated fetal death 20–22 and did not observe an increase in risk with dipyrone exposure during pregnancy (OR 0.81, 95% CI 0.57–1.14, p = 0.22; I 2 = 0%; 3 cohorts, n = 6,380, very low certainty evidence) (Fig. 5 ). One study not included in the meta-analysis reported two cases of fetal death, from 72 exposed pregnancies that were unlikely to have been caused by dipyrone exposure, based on the World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality assessment 23 . Three studies investigated prematurity. There was no evidence of a risk of prenatal exposure to dipyrone for prematurity (OR 0.99, 95% CI 0.80–1.21, p = 0.90; I 2 = 0%; 3 cohorts, n = 6,194, very low certainty evidence) (Fig. 6 ). One study provided adjusted data, corroborating previous observations (aOR 0.77, 95% CI 0.58–1.02) 21 . Three studies reported birth weight. Only one study compared the chance of low birth weight between exposed and unexposed groups without significant findings (aOR 0.77, 95% CI 0.51–1.17; 1 cohort, n = 4,755, very low certainty evidence) 21 . The other two studies reported only the mean (3320 ± 540 g) 20 and median (3330, IQR 2995–3652.5 g) 22 birth weight in cohorts of pregnant women using dipyrone. Two studies investigated oligohydramnios. In Dathe 2022, which assessed 72 pregnancies exposed to dipyrone in the second and third trimesters, only two cases of oligohydramnios were possibly caused by dipyrone, based on the WHO-UMC causality assessment 23 . In comparison, there were 29/1154 patients in the comparison cohort. The second study found no evidence of an association with first-trimester exposures (RR 1.4, 95% CI 0.3–6.9) 19 . Dathe 2022 also investigated the outcomes of patent ductus arteriosus, constriction of ductus arteriosus, and renal and cardiac disorders following second- and third-trimester exposures. One study reported two cases of patent ductus arteriosus in premature infants and one in a full-term infant 23 . Comparatively, there were 10/1133 patients in the comparison cohort, including 5/117 in premature infants and 5/1010 in full-term infants. For the other outcomes, no patients were included in the exposed group. 3.3 Infant cancer (leukemia and nephroblastoma) Four case-control studies, including 1,949 patients, investigated infant leukemia patients. There was an increased chance of infant leukemia (OR 1.48, 95% CI 1.18–1.86, p = 0.0007; I 2 = 6%; 3 case-controls, n = 1,686, very low certainty evidence) (Fig. 7 ). The pooled ORs with adjusted data were similar (aOR 1.63, 95% CI 1.23–2.17, p = 0.0009; I 2 = 0%; 3 case‒controls, very low certainty evidence) (Fig. 8 ). The frequency of mixed lineage leukemia (MLL) gene rearrangements was greater in the exposed group (aOR of 2.69, 95% CI 1.23–5.88, p = 0.01; I 2 = 62%; 3 case-controls, very low certainty evidence). Sensitivity analysis with MCMC revealed no evidence of an association for infant leukemia (OR 1.25, 95% CI 0.86–2.22; I 2 = 72.82%) and a positive association for MLL gene rearrangements (OR 2.86, 95% CI 1.14–7.12; I 2 = 78.12%). One study analyzed the interaction of prenatal exposure to dipyrone with the NAT2 acetylation phenotype in mothers/children. The NAT2 slow-acetylation haplotype was associated with an increased chance of acute lymphoblastic leukemia without dipyrone exposure (OR 8.90; 95% CI, 1.71–86.7) 14 . In a case-control study with 109 patients and 218 controls, nephroblastoma was associated with dipyrone use in low-income pregnant women (aOR 10.9, 95% CI 2.40–49.90) but not in middle-income (aOR 0.66, 95% CI 0.17–2.60) or high-income women (aOR 2.56, 95% CI 0.72–9.12). 3.4 Quality of evidence The summary of the evidence following the GRADE approach indicated a very low certainty grade of evidence for all the analyses conducted (Table S3 ). 4 DISCUSSION 4.1 Main findings The findings of this study, summarized according to the GRADE recommendations (Table 2 ), indicate that there is no evidence of an association between maternal dipyrone exposure and congenital anomalies or major congenital anomalies in first- and second-trimester exposures or between maternal dipyrone exposure and infant leukemia, fetal death, prematurity, low birth weight, constriction of the ductus arteriosus, or renal and cardiac disorders in newborns. However, there is insufficient evidence to exclude patent ductus arteriosus and oligohydramnios in second- and third-trimester exposures, even though substantial risk is improbable based on the available information. Hence, there is currently no evidence that dipyrone during pregnancy is harmful to offspring. Table 2 Summary of findings Dipyrone compared to no dipyrone in pregnancy Patient or population : Pregnancy Setting: - Intervention : Dipyrone Comparison : No dipyrone Outcomes Anticipated absolute effects * (95% CI) Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments Risk with no dipyrone Risk with dipyrone Congenital anomaly 4 per 1 000 5 per 1 000 (3 to 6) OR 1.18 (0.80 to 1.63) 66850 (3 non-randomised studies) ⨁◯◯◯ Very low a,b,c Dipyrone may increase/have little to no effect on congenital anomaly but the evidence is very uncertain. Major congenital anomaly 19 per 1 000 20 per 1 000 (9 to 45) OR 1.06 (0.47 to 2.37) 1356 (2 non-randomised studies) ⨁◯◯◯ Very low a,b,c Dipyrone may increase/have little to no effect on major congenital anomaly but the evidence is very uncertain. Infant leukemia 361 per 1 000 414 per 1 000 (327 to 556) OR 1.25 (0.86 to 2.22) 569 cases 1117 controls (3 non-randomised studies) ⨁◯◯◯ Very low b,c,d Dipyrone may increase/have little to no effect on infant leukemia but the evidence is very uncertain. Patent ductus arteriosus 9 per 1 000 0 per 1 000 (0 to 0) not estimable 1205 (1 non-randomised study) ⨁◯◯◯ Very low b,e Dipyrone may increase/have little to no effect on patent ductus arteriosus but the evidence is very uncertain. Oligohydramnios 25 per 1 000 0 per 1 000 (0 to 0) not estimable 1226 (1 non-randomised study) ⨁◯◯◯ Very low b,e Dipyrone may increase/have little to no effect on oligohydramnios but the evidence is very uncertain. Fetal death 33 per 1 000 27 per 1 000 (19 to 38) OR 0.81 (0.57 to 1.14) 6380 (3 non-randomised studies) ⨁◯◯◯ Very low b,c,e Dipyrone may reduce/have little to no effect on spontaneous gestational loss but the evidence is very uncertain. Prematurity 147 per 1 000 145 per 1 000 (121 to 172) OR 0.99 (0.80 to 1.21) 6194 (3 non-randomised studies) ⨁◯◯◯ Very low b,c,e Dipyrone may reduce/have little to no effect on prematurity but the evidence is very uncertain. * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI : confidence interval; OR : odds ratio GRADE Working Group grades of evidence High certainty : we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty : we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty : our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty : we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. Explanations a. Most evidence comes from studies not at serious risk of bias. Two studies had a high quality NOS score (above 6) and one study had a score of six. b. Differences in interventions across participants cannot be assessed, once it relies on reported information. Lack of data on dose and length of therapy in most studies. c. 95% CI suggests both benefit and harm d. Evidence comes from studies at serious risk of bias. Only one study had a NOS score above six. e. All studies had a high Newcastle-Ottawa scale score (above 6) 4.2 Strengths and limitations To our knowledge, this is the first systematic review and meta-analysis to investigate the adverse effects of prenatal dipyrone exposure on offspring health. We included four prospective cohorts and six case-control studies, resulting in the analysis of more than 68,000 patients. There were no restrictions in terms of intervention, exposure, or outcome reported. Exposures were analyzed according to pregnancy trimester, and both adjusted and unadjusted data are presented. The quality of the evidence was summarized according to GRADE, which allows a better understanding of the clinical significance and generalizability of our results. Ultimately, the significant results presented were subjected to a sensitivity analysis with a random-effects Bayesian hierarchical model (Markov chain Monte Carlo), which estimates heterogeneity more adequately when few studies are included. There are limitations to the evidence discussed in this review. Only one study assessed the causality of suspected adverse drug reactions based on the WHO-UMC criteria. This implies that there could be a significant overestimation of the adverse events attributed to dipyrone in our review. Additionally, only four studies provided information about the dose or length of therapy, and only five studies reported the trimester of exposure. There are few published studies on these thematics in the literature, which was the principal challenge in the development of this review. Consequently, the small number of studies included was a substantial limitation in our review. Additionally, none of the included studies adjusted for possible teratogenic maternal infections, which could be the reason why the mother sought the medication. 4.3 Interpretation We estimated an increase of 20% in the chance of congenital anomalies with exposure to dipyrone in the first trimester, an estimate heavily influenced by a single study that did not address important sources of bias. No association was observed with major congenital anomalies. Thus, substantial harm is improbable in first-trimester exposure. We estimated a 25% increase in the likelihood of infant leukemia derived from retrospective studies at a high risk of bias. The evidence is very uncertain regarding any association between maternal dipyrone exposure and infant leukemia. Some patients were observed to have oligohydramnios and patent ductus arteriosus during second- and third-trimester exposures, but none were classified as certain or probable according to the WHO-UMC. In that sense, dipyrone use in late pregnancy may increase the risk for these outcomes, but not substantially. It may be prudent to avoid extended exposures in late pregnancy. For the other outcomes, there is no evidence that dipyrone could be a potential cause. Concerns about exposure to dipyrone during pregnancy have been discussed in the literature. Based on previous reports, the European Medicines Agency recommended against third-trimester use of dipyrone 25 . This recommendation was based on case reports that revealed acute renal failure, oligohydramnios, pulmonary hypertension, and ductus arteriosus constriction or closure after dipyrone therapy. In the cohort included in our review that investigated these outcomes during second- and third-trimester exposures, acute renal failure, pulmonary hypertension, and ductus arteriosus constriction or closure were not observed following dipyrone therapy. However, two cases of oligohydramnios were reported, which were classified as possibly caused by dipyrone. On the other hand, short-term therapies were considered acceptable in the first and second trimesters 25 . Our findings are mostly congruent with the assessment from the European Medicines Agency, as we did not observe certain substantial harm for any particular outcome during pregnancy. However, we did not find significant indications of fetotoxicity in the second- or third-trimester exposures. Historically, dipyrone has been considered a dangerous analgesic. However, contemporary understanding indicates that toxic effects, as in the case of agranulocytosis reactions, are not as frequent as presumed 5 . Moreover, our study revealed that the available evidence does not indicate substantial harm from prenatal exposure during pregnancy. Analgesia is a common necessity in pregnancy, and mothers in need of medications should be correctly informed about the evidence of harm from pharmacological interventions. This ensures that important interventions are not unnecessarily withheld. 5 CONCLUSION According to this systematic review and meta-analysis of observational studies, exposure to dipyrone during pregnancy does not seem to pose substantial risks to offspring. However, it may be ideal to avoid extended exposure regardless of the trimester of pregnancy. Postmarketing clinical trials of pharmacovigilance are recommended for investigating the use of dipyrone in reproductive-aged women and identifying possible adverse effects of prenatal dipyrone use on the health of offspring. Declarations Data availability The data of this study can be shared upon formal and reasonable request. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or nonfinancial interests to disclose. Contribution to Authorship GM Lino was responsible for the study search, selection, data extraction, data analysis, data synthesis, risk of bias and grade of evidence assessment, and writing of the manuscript; FS Ishibashi was responsible for the study search, selection, and data extraction; GAM Conrado was responsible for reviewing the study search, selection, data extraction, data synthesis, and risk of bias assessment; CC Bresani was responsible for reviewing the final manuscript; and PVM Galvão was responsible for the data analysis and reviewing the final manuscript. Ethics approval None. References Hoffmann F, Bantel C, von Rosen FT, Jobski K. Regional Differences in Prescribing Patterns of Metamizole in Germany Based on Data from 70 Million Persons. Int J Environ Res Public Health. Multidisciplinary Digital Publishing Institute; 2020 Jan;17(11):3892. 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Pregnancy, maternal exposure to analgesic medicines, and leukemia in Brazilian children below 2 years of age. Eur J Cancer Prev. 2015 May;24(3):245–252. Banhidy F, Acs N, Puho E, Czeizel AE. A population-based case-control teratologic study of oral dipyrone treatment during pregnancy. DRUG Saf. 2007;30(1):59–70. Bar-Oz B, Clementi M, Di Giantonio E, Greenberg R, Beer M, Merlob P, Arnon J, Ornoy A, Zimmerman D, Berkovitch M. Metamizol (dipyrone, optalgin) in pregnancy, is it safe? - A prospective comparative study. Eur J Obstet Gynecol Reprod Biol. 2005 Apr 1;119(2):176–179. da Silva Dal Pizzol T, Schueler-Faccini L, Mengue SS, Fischer MI. Dipyrone use during pregnancy and adverse perinatal events. Arch Gynecol Obstet. 2009 Mar;279(3):293–297. Dathe K, Padberg S, Hultzsch S, Meixner K, Tissen-Diabate T, Meister R, Beck E, Schaefer C. Metamizole use during first trimesterA prospective observational cohort study on pregnancy outcome. Pharmacoepidemiol Drug Saf. 2017 Oct;26(10):1197–1204. Dathe K, Frank J, Padberg S, Hultzsch S, Beck E, Schaefer C. Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort. BMC Pregnancy Childbirth. 2022 Aug 26;22(1). Sharpe C, Franco E. Use of dipyrone during pregnancy and risk of Wilms’ tumor. Epidemiology. 1996 Sep;7(5):533–535. European Medicines Agency. Metamizole containing medicinal products - referral [Internet]. Metamizole containing medicinal products - referral | European Medicines Agency. 2019 [cited 2024 Mar 9]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products Additional Declarations No competing interests reported. Supplementary Files FigureS1Funnelplotforthecongenitalanomaliesanalysis.docx FigureS2Funnelplotfortheinfantleukemiaanalysis.docx TableS1Methodologicalqualities.docx TableS2QualityassessmentusingtheNewcastleOttawascale.docx TableS3Evidenceprofile.docx APPENDIXS1Searchstrategy.docx Cite Share Download PDF Status: Published Journal Publication published 12 Jul, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted Editorial decision: Revision requested 08 Aug, 2024 Reviews received at journal 19 Jul, 2024 Reviews received at journal 01 Jul, 2024 Reviewers agreed at journal 27 Jun, 2024 Reviewers agreed at journal 20 Jun, 2024 Reviewers invited by journal 17 Jun, 2024 Editor invited by journal 20 May, 2024 Editor assigned by journal 16 May, 2024 Submission checks completed at journal 16 May, 2024 First submitted to journal 14 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4421640","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304594956,"identity":"1326e2cd-b37d-42f9-b65d-0c96c954c465","order_by":0,"name":"Gabriel Moreira Lino","email":"","orcid":"","institution":"University of Pernambuco","correspondingAuthor":false,"prefix":"","firstName":"Gabriel","middleName":"Moreira","lastName":"Lino","suffix":""},{"id":304594957,"identity":"2b2548ff-2926-4a62-b7c0-055f948013fb","order_by":1,"name":"Felipe Shoji Ishibashi","email":"","orcid":"","institution":"University of 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2","display":"","copyAsset":false,"role":"figure","size":28264,"visible":true,"origin":"","legend":"\u003cp\u003ePooled odds ratios of congenital anomalies in newborns of women who used dipyrone during pregnancy\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/3fd7903839ee8b2ba5f3ecf7.png"},{"id":57443776,"identity":"f6c08566-bbe5-41c2-8780-774cd801883c","added_by":"auto","created_at":"2024-05-30 18:52:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24430,"visible":true,"origin":"","legend":"\u003cp\u003ePooled adjusted odds ratios of congenital anomalies in newborns of women who used dipyrone during pregnancy\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/36e978325a34298303c4aa1f.png"},{"id":57443778,"identity":"dd0e2b57-767d-478b-bb70-696a9a0bb932","added_by":"auto","created_at":"2024-05-30 18:52:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":21803,"visible":true,"origin":"","legend":"\u003cp\u003ePooled odds ratios of major congenital anomalies in newborns of women who used dipyrone during pregnancy\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/332d16ff3c421def9a5f9b9c.png"},{"id":57444630,"identity":"3abf3668-e5a0-425e-bc7b-de893d0c414b","added_by":"auto","created_at":"2024-05-30 19:00:24","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":25923,"visible":true,"origin":"","legend":"\u003cp\u003ePooled odds ratio of fetal death with dipyrone exposure during pregnancy\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/8ef74197a3a75394361cfb8a.png"},{"id":57443782,"identity":"51a08b02-6bb6-48e5-b3f1-879c50926353","added_by":"auto","created_at":"2024-05-30 18:52:24","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":26045,"visible":true,"origin":"","legend":"\u003cp\u003ePooled odds ratio of prematurity with dipyrone exposure during pregnancy\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/59d072eb1cf8d103b664d3af.png"},{"id":57443785,"identity":"5cc7cd3c-1d0e-4944-b96b-e5e48139430d","added_by":"auto","created_at":"2024-05-30 18:52:24","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":26985,"visible":true,"origin":"","legend":"\u003cp\u003ePooled odds ratios of leukemia in infants of women who used dipyrone during pregnancy\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/e64de408f9c590601f254d9f.png"},{"id":57443789,"identity":"2e1ee0b0-9471-44f3-bd4b-84bd3f8a8939","added_by":"auto","created_at":"2024-05-30 18:52:25","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":21799,"visible":true,"origin":"","legend":"\u003cp\u003ePooled adjusted odds ratios of leukemia in newborns of women who used dipyrone during pregnancy\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/b14e59e7fb42f6d2b6f045fe.png"},{"id":86699522,"identity":"f58bb234-7c8e-4ca5-814a-f09694c7dbec","added_by":"auto","created_at":"2025-07-14 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18:52:24","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":12840,"visible":true,"origin":"","legend":"","description":"","filename":"APPENDIXS1Searchstrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4421640/v1/5ebd390faaba460107b54da1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adverse Effects of Dipyrone (Metamizole) Use During Pregnancy on Offspring Health: A Systematic Review and Meta-Analysis","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003eDipyrone (metamizole) is a nonopioid drug with significant antipyretic and analgesic properties. It is commonly used to manage pain in Spain, Brazil, and Germany in outpatient and inpatient care\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e. Dipyrone is a well-tolerated medication\u003csup\u003e1,2,4\u003c/sup\u003e, although drug-induced agranulocytosis reactions have led to its prohibition in some countries, including the UK and the US\u003csup\u003e5\u003c/sup\u003e. Currently, there is still uncertainty over its use during pregnancy. Studies have investigated potential myelotoxic, teratogenic, and endocrine-disruptive effects on fetuses in recent decades, but no conclusions have been reached\u003csup\u003e6,7\u003c/sup\u003e. Therefore, this systematic review and meta-analysis were conducted to investigate the safety and risk of dipyrone use during pregnancy to the health of offspring.\u003c/p\u003e"},{"header":"2 METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Protocol and registration\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines\u003csup\u003e8\u003c/sup\u003e. The protocol was previously registered in PROSPERO (CRD42023453817).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Search strategy and eligibility criteria\u003c/h2\u003e \u003cp\u003eA systematic literature search (up to 22 March 2024) was conducted in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, and the Cochrane Library for articles reporting adverse effects from maternal exposure to dipyrone without language or date restrictions. The final search query is presented in Appendix S1. The study\u0026rsquo;s investigators designed the search.\u003c/p\u003e \u003cp\u003ePublications that met the following predefined inclusion criteria were considered: clinical trials or observational studies (cohorts and case-controls) that studied women who had used dipyrone during pregnancy and assessed offspring health. When only some of the patients in a study fulfilled the mentioned criteria, only those patients were included in the review. Studies were excluded if there were no disaggregated data on the exposed group. Contact with the study\u0026rsquo;s authors by email was made in the case of exclusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Study selection and data extraction\u003c/h2\u003e \u003cp\u003eAll found reports were registered in a prestructured formulary containing data about authorship, year, and journal of publication. Two reviewers (GML, FSI) independently accessed titles and abstracts and excluded duplicates, redundant publications, and reports that did not meet the inclusion criteria. Thus, the same two reviewers (GML, FSI) performed the full-text reading to exclude articles for which at least one exclusion criterion was met. Whenever disagreement was found between the reviewers in the abstract or full-text reading, a third reviewer (GAMC) was consulted.\u003c/p\u003e \u003cp\u003eThe data from the selected studies were searched and extracted independently by two reviewers (GML, FSI) for adverse outcomes related to the health of the offspring. Data on the study (design, country and period of enrollment, sample size, comparison groups, participant selection, allocation, certainty of outcome, confounding variables), exposure to dipyrone during pregnancy (mother\u0026rsquo;s age, daily dose, duration of therapy, trimester of pregnancy, over-the-counter or prescription use) and adverse outcomes related to the health of the offspring were collected. The following outcomes were found: spontaneous abortions, intrauterine death, stillbirths, birth weight, prematurity, oligohydramnios, patent ductus arteriosus, congenital anomalies, infant leukemia and nephroblastoma (including leukemia cases associated with MLL rearrangements and the NAT2 phenotype). Spontaneous abortions, intrauterine deaths, and stillbirths were analyzed conjunctly as fetal deaths.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Risk of bias assessment in included studies\u003c/h2\u003e \u003cp\u003eTwo independent reviewers (GML, GAMC) used the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies. This tool was designed to analyze the quality of observational studies (cohort and case-control) based on study group selection, comparability, exposure (case-control), or outcome (cohort). A score above 6 on the NOS indicated high quality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eQuantitative data were analyzed using R software, version 4.2.2, with the packages meta, metafor, bayesmeta, and tidyverse\u003csup\u003e9\u0026ndash;12\u003c/sup\u003e. The outcomes are reported as dichotomous data and were compared using odds ratios (ORs) with 95% confidence intervals (CIs). The adjusted ORs (aORs) were extracted from studies to minimize confounding factors\u003csup\u003e13\u003c/sup\u003e. Heterogeneity was evaluated with tau and I\u003csup\u003e2\u003c/sup\u003e statistics; p values less than 0.10 and I\u003csup\u003e2\u003c/sup\u003e values\u0026thinsp;\u0026gt;\u0026thinsp;25% were considered significant for heterogeneity. A random-effects restricted maximum likelihood (REML) model on the log-odds scale was used. Publication bias was analyzed using funnel plots. Sensitivity analyses were performed for significant outcomes in a Bayesian framework with Markov chain Monte Carlo (MCMC) methods utilizing weakly informative and noninformative priors.\u003c/p\u003e \u003cp\u003eZanrosso 2010\u003csup\u003e14\u003c/sup\u003e was not included in the statistical synthesis because the data reported were from the same population as one of the included studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Certainty of the evidence assessment\u003c/h2\u003e \u003cp\u003eThe Grading of Recommendations, Assessment, Development and Evaluation (GRADE)\u003csup\u003e15\u003c/sup\u003e was used to determine the quality of evidence of the analyses. In this evaluation, evidence can be divided into four grades based on how certain the outcomes are: high (we are very confident that the true effect lies close to that of the estimate of the effect), moderate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different), low (the true effect may be substantially different from the estimate of the effect) and very low (the true effect is likely to be substantially different from the estimate of effect). The tables were generated with GRADEpro GDT software\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 RESULTS","content":"\u003cp\u003eFrom the 375 records initially identified, 41 duplicates were removed. Three hundred thirty-four abstracts were screened, and fifty-nine reports were selected for full-text reading. Ten studies were included in the systematic review, and seven were included in the meta-analysis (Fig. \u003cspan\u003e1\u003c/span\u003e). The reasons for exclusion are described in the flowchart.\u003c/p\u003e\n\u003cp\u003eThe characteristics of the studies, exposure to dipyrone, and adverse outcomes related to the health of the offspring are summarized in Table \u003cspan\u003e1\u003c/span\u003e. There were six case-control studies\u003csup\u003e6,14,17\u0026ndash;19,24\u003c/sup\u003e and four prospective cohorts\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e. Five studies were conducted in Brazil\u003csup\u003e6,14,18,21,24\u003c/sup\u003e, two in Germany\u003csup\u003e22\u003c/sup\u003e, one in Hungary\u003csup\u003e19,\u003c/sup\u003e and two in multiple other countries (Italy, Israel, Greece, Egypt, Brazil, Chile, China, Hong Kong, and Japan)\u003csup\u003e17,20\u003c/sup\u003e. Only five studies reported the gestational age of exposure; among three, the exposure occurred during the first trimester. The health outcomes reported for the offspring were congenital anomalies (n\u0026thinsp;=\u0026thinsp;4)\u003csup\u003e19\u0026ndash;22\u003c/sup\u003e, infant leukemia (n\u0026thinsp;=\u0026thinsp;4)\u003csup\u003e6,14,17,18\u003c/sup\u003e, fetal death (n\u0026thinsp;=\u0026thinsp;3)\u003csup\u003e20\u0026ndash;23\u003c/sup\u003e, prematurity (n\u0026thinsp;=\u0026thinsp;3)\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e, birth weight (n\u0026thinsp;=\u0026thinsp;3)\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e, oligohydramnios (n\u0026thinsp;=\u0026thinsp;2)\u003csup\u003e19,23\u003c/sup\u003e, patent ductus arteriosus (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e23\u003c/sup\u003e, constriction or closure of ductus arteriosus (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e23\u003c/sup\u003e, renal disorders (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e23\u003c/sup\u003e, cardiac disorders (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e23\u003c/sup\u003e, and nephroblastoma (n\u0026thinsp;=\u0026thinsp;1)\u003csup\u003e24\u003c/sup\u003e. Drug therapy was based almost exclusively on self-reported information.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003e\u0026ndash; Characteristics of the included studies\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"10\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor (Year)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePeriod\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample size: exposed/\u003c/p\u003e\n \u003cp\u003enot exposed\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003cp\u003e(child age)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePregnancy trimester of dipyrone use\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDrug therapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSource of information\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNOS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlexander et al. (2001)\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple countries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1996-ND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e136:266\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALL and AML\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026thinsp;18 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCouto et al. (2015)\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1999\u0026ndash;2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e231:411\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALL and AML\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026thinsp;23 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePombo-de-Oliveira et al. (2006)\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1999\u0026ndash;2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e202:440\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALL and AML\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026thinsp;21 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZanrosso et al. (2010)\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2000\u0026ndash;2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e132:131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALL\u003c/p\u003e\n \u003cp\u003e(\u0026lt;\u0026thinsp;21 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBanhidy et al. (2007)\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHungary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePopulation-based case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1980\u0026ndash;1996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,843:38,151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA, OLIGO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 g (0.5\u0026ndash;4.0mg)/ day of oral dipyrone for 2.5 weeks for cases and 2.8 weeks for controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported by women retrospectively identified in a dataset (81.1%) and medical records (18.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBar-Oz et al. (2005)\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIsrael and Italy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter prospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e108:108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA, FD, PREM and BW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u0026ndash;2 g/ day of oral dipyrone for 1\u0026ndash;4 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported by women calling teratogen information services at the time of exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eda Silva Dal Pizzol et al. (2009)\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter prospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1991\u0026ndash;1995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e555:4,276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA, FD, PREM and BW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond trimester\u003c/p\u003e\n \u003cp\u003e(21st \u0026minus;\u0026thinsp;28th week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported in interviews\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDathe et al. (2017)\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProspective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2000\u0026ndash;2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e446:887\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA, FD,\u0026nbsp;PREM and BW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMost therapies were short-term, further information not provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported by women who contacted the Embryotox institute\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDathe et al. (2022)\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProspective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2008\u0026ndash;2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1092:1154\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFD, OLIGO, PDA, constriction or closure of ductus arteriosus, renal and cardiac disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond and third trimesters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTherapy was reported individually for all cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported by women who contacted the Embryotox institute\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSharpe et al. (1996)\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMulticenter case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1987\u0026ndash;1989\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e109:218\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephroblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelf-reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003c/table\u003e\n\u003cp\u003eALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BW: Birth weight; CA: congenital anomaly; FD: fetal death; ND: not determined; NOS: newcastle-ottawa scale; OLIG: oligohydramnios; PDA: patent ductus arteriosus; PREM: prematurity.\u003csup\u003ea\u003c/sup\u003eIn these studies, exposures other than dipyrone were included in the total sample size.\u003c/p\u003e\n\u003cp\u003eFive studies had a low risk of bias. The confounding variables and adjustment methods differed across studies (Table \u003cspan\u003eS1\u003c/span\u003e). The evaluation of the risk of bias in each study is presented in the supplementary file (Table \u003cspan\u003eS2\u003c/span\u003e). Regarding publication bias, funnel plots showed some visual asymmetry (Figures \u003cspan\u003eS1\u003c/span\u003e and S2).\u003c/p\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e3.1 Congenital anomalies\u003c/h2\u003e\n \u003cp\u003eFour studies, including a total of 67,374 newborns, investigated the occurrence of congenital anomalies. There was an increased chance of congenital anomalies in the exposed group (OR 1.21, 95% CI 1.13\u0026ndash;1.30, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 cohorts and 1 case-control, n\u0026thinsp;=\u0026thinsp;67,374, very low certainty evidence) (Fig. \u003cspan\u003e2\u003c/span\u003e). The pooled ORs with adjusted data were similar (aOR 1.19, 95% CI 1.10\u0026ndash;1.29, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 2 cohorts and 1 case-control, very low certainty evidence) (Fig. \u003cspan\u003e3\u003c/span\u003e). A total of 95% of the weight of these estimates can be attributed to the study of Banhidy et al., which revealed a statistically significant correlation between dipyrone exposure and diaphragmatic and cardiovascular congenital anomalies. Sensitivity analysis with MCMC revealed no evidence of an association for congenital anomalies (OR 1.18, 95% CI 0.80\u0026ndash;1.63; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;33.73%).\u003c/p\u003e\n \u003cp\u003eThere was no evidence of risk in the subgroup analysis of major congenital anomalies (OR 1.06, 95% CI 0.47\u0026ndash;2.37, p\u0026thinsp;=\u0026thinsp;0.89; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 2 cohorts, n\u0026thinsp;=\u0026thinsp;1,356, very low certainty evidence) (Fig. \u003cspan\u003e4\u003c/span\u003e). Adjusted data on major congenital anomalies were not available.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e3.2 Perinatal outcomes (fetal death, prematurity, low birth weight, oligohydramnios, patent ductus arteriosus, constriction of ductus arteriosus, renal and cardiac disorders)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eFour studies investigated fetal death\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e and did not observe an increase in risk with dipyrone exposure during pregnancy (OR 0.81, 95% CI 0.57\u0026ndash;1.14, p\u0026thinsp;=\u0026thinsp;0.22; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 cohorts, n\u0026thinsp;=\u0026thinsp;6,380, very low certainty evidence) (Fig. \u003cspan\u003e5\u003c/span\u003e). One study not included in the meta-analysis reported two cases of fetal death, from 72 exposed pregnancies that were unlikely to have been caused by dipyrone exposure, based on the World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality assessment\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThree studies investigated prematurity. There was no evidence of a risk of prenatal exposure to dipyrone for prematurity (OR 0.99, 95% CI 0.80\u0026ndash;1.21, p\u0026thinsp;=\u0026thinsp;0.90; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 cohorts, n\u0026thinsp;=\u0026thinsp;6,194, very low certainty evidence) (Fig. \u003cspan\u003e6\u003c/span\u003e). One study provided adjusted data, corroborating previous observations (aOR 0.77, 95% CI 0.58\u0026ndash;1.02)\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThree studies reported birth weight. Only one study compared the chance of low birth weight between exposed and unexposed groups without significant findings (aOR 0.77, 95% CI 0.51\u0026ndash;1.17; 1 cohort, n\u0026thinsp;=\u0026thinsp;4,755, very low certainty evidence)\u003csup\u003e21\u003c/sup\u003e. The other two studies reported only the mean (3320\u0026thinsp;\u0026plusmn;\u0026thinsp;540 g)\u003csup\u003e20\u003c/sup\u003e and median (3330, IQR 2995\u0026ndash;3652.5 g)\u003csup\u003e22\u003c/sup\u003e birth weight in cohorts of pregnant women using dipyrone.\u003c/p\u003e\n \u003cp\u003eTwo studies investigated oligohydramnios. In Dathe 2022, which assessed 72 pregnancies exposed to dipyrone in the second and third trimesters, only two cases of oligohydramnios were possibly caused by dipyrone, based on the WHO-UMC causality assessment\u003csup\u003e23\u003c/sup\u003e. In comparison, there were 29/1154 patients in the comparison cohort. The second study found no evidence of an association with first-trimester exposures (RR 1.4, 95% CI 0.3\u0026ndash;6.9)\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eDathe 2022 also investigated the outcomes of patent ductus arteriosus, constriction of ductus arteriosus, and renal and cardiac disorders following second- and third-trimester exposures. One study reported two cases of patent ductus arteriosus in premature infants and one in a full-term infant\u003csup\u003e23\u003c/sup\u003e. Comparatively, there were 10/1133 patients in the comparison cohort, including 5/117 in premature infants and 5/1010 in full-term infants. For the other outcomes, no patients were included in the exposed group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e3.3 Infant cancer (leukemia and nephroblastoma)\u003c/h2\u003e\n \u003cp\u003eFour case-control studies, including 1,949 patients, investigated infant leukemia patients. There was an increased chance of infant leukemia (OR 1.48, 95% CI 1.18\u0026ndash;1.86, p\u0026thinsp;=\u0026thinsp;0.0007; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;6%; 3 case-controls, n\u0026thinsp;=\u0026thinsp;1,686, very low certainty evidence) (Fig. \u003cspan\u003e7\u003c/span\u003e). The pooled ORs with adjusted data were similar (aOR 1.63, 95% CI 1.23\u0026ndash;2.17, p\u0026thinsp;=\u0026thinsp;0.0009; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 case‒controls, very low certainty evidence) (Fig. \u003cspan\u003e8\u003c/span\u003e). The frequency of mixed lineage leukemia (MLL) gene rearrangements was greater in the exposed group (aOR of 2.69, 95% CI 1.23\u0026ndash;5.88, p\u0026thinsp;=\u0026thinsp;0.01; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;62%; 3 case-controls, very low certainty evidence). Sensitivity analysis with MCMC revealed no evidence of an association for infant leukemia (OR 1.25, 95% CI 0.86\u0026ndash;2.22; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72.82%) and a positive association for MLL gene rearrangements (OR 2.86, 95% CI 1.14\u0026ndash;7.12; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;78.12%).\u003c/p\u003e\n \u003cp\u003eOne study analyzed the interaction of prenatal exposure to dipyrone with the NAT2 acetylation phenotype in mothers/children. The NAT2 slow-acetylation haplotype was associated with an increased chance of acute lymphoblastic leukemia without dipyrone exposure (OR 8.90; 95% CI, 1.71\u0026ndash;86.7)\u003csup\u003e14\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eIn a case-control study with 109 patients and 218 controls, nephroblastoma was associated with dipyrone use in low-income pregnant women (aOR 10.9, 95% CI 2.40\u0026ndash;49.90) but not in middle-income (aOR 0.66, 95% CI 0.17\u0026ndash;2.60) or high-income women (aOR 2.56, 95% CI 0.72\u0026ndash;9.12).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003e3.4 Quality of evidence\u003c/h2\u003e\n \u003cp\u003eThe summary of the evidence following the GRADE approach indicated a very low certainty grade of evidence for all the analyses conducted (Table \u003cspan\u003eS3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 DISCUSSION","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1 Main findings\u003c/h2\u003e\n \u003cp\u003eThe findings of this study, summarized according to the GRADE recommendations (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), indicate that there is no evidence of an association between maternal dipyrone exposure and congenital anomalies or major congenital anomalies in first- and second-trimester exposures or between maternal dipyrone exposure and infant leukemia, fetal death, prematurity, low birth weight, constriction of the ductus arteriosus, or renal and cardiac disorders in newborns. However, there is insufficient evidence to exclude patent ductus arteriosus and oligohydramnios in second- and third-trimester exposures, even though substantial risk is improbable based on the available information. Hence, there is currently no evidence that dipyrone during pregnancy is harmful to offspring. \u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of findings\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eDipyrone compared to no dipyrone in pregnancy\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient or population\u003c/strong\u003e: Pregnancy\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSetting: -\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e: Dipyrone\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eComparison\u003c/strong\u003e: No dipyrone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnticipated absolute effects\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e*\u003c/strong\u003e\u003c/sup\u003e (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eRelative effect\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e№ of participants\u003c/p\u003e\n \u003cp\u003e(studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCertainty of the evidence\u003c/p\u003e\n \u003cp\u003e(GRADE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eComments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk with no dipyrone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk with dipyrone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCongenital anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(3 to 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR 1.18\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0.80 to 1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66850\u003c/p\u003e\n \u003cp\u003e(3 non-randomised studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may increase/have little to no effect on congenital anomaly but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMajor congenital anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e20 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(9 to 45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR 1.06\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0.47 to 2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1356\u003c/p\u003e\n \u003cp\u003e(2 non-randomised studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may increase/have little to no effect on major congenital anomaly but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfant leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e361 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e414 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(327 to 556)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR 1.25\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0.86 to 2.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e569 cases 1117 controls\u003c/p\u003e\n \u003cp\u003e(3 non-randomised studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003eb,c,d\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may increase/have little to no effect on infant leukemia but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatent ductus arteriosus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0 to 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enot estimable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1205\u003c/p\u003e\n \u003cp\u003e(1 non-randomised study)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003eb,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may increase/have little to no effect on patent ductus arteriosus but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOligohydramnios\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0 to 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enot estimable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1226\u003c/p\u003e\n \u003cp\u003e(1 non-randomised study)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003eb,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may increase/have little to no effect on oligohydramnios but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFetal death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(19 to 38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR 0.81\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0.57 to 1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6380\u003c/p\u003e\n \u003cp\u003e(3 non-randomised studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003eb,c,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may reduce/have little to no effect on spontaneous gestational loss but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrematurity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e147 per 1 000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e145 per 1 000\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(121 to 172)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR 0.99\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(0.80 to 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6194\u003c/p\u003e\n \u003cp\u003e(3 non-randomised studies)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e⨁◯◯◯\u003c/p\u003e\n \u003cp\u003eVery low\u003csup\u003eb,c,e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDipyrone may reduce/have little to no effect on prematurity but the evidence is very uncertain.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003e*\u003cstrong\u003eThe risk in the intervention group\u003c/strong\u003e (and its 95% confidence interval) is based on the assumed risk in the comparison group and the \u003cstrong\u003erelative effect\u003c/strong\u003e of the intervention (and its 95% CI).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e: confidence interval; \u003cstrong\u003eOR\u003c/strong\u003e: odds ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cstrong\u003eGRADE Working Group grades of evidence\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHigh certainty\u003c/strong\u003e: we are very confident that the true effect lies close to that of the estimate of the effect.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModerate certainty\u003c/strong\u003e: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLow certainty\u003c/strong\u003e: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eVery low certainty\u003c/strong\u003e: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eExplanations\u003c/p\u003e\n \u003cp\u003e\u003cspan\u003ea. Most evidence comes from studies not at serious risk of bias. Two studies had a high quality NOS score (above 6) and one study had a score of six.\u003cbr\u003e\u003c/span\u003e \u003cspan\u003eb. Differences in interventions across participants cannot be assessed, once it relies on reported information. Lack of data on dose and length of therapy in most studies.\u003cbr\u003e\u003c/span\u003e \u003cspan\u003ec. 95% CI suggests both benefit and harm\u003cbr\u003e\u003c/span\u003e \u003cspan\u003ed. Evidence comes from studies at serious risk of bias. Only one study had a NOS score above six.\u003cbr\u003e\u003c/span\u003e \u003cspan\u003ee. All studies had a high Newcastle-Ottawa scale score (above 6)\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2 Strengths and limitations\u003c/h2\u003e\n \u003cp\u003eTo our knowledge, this is the first systematic review and meta-analysis to investigate the adverse effects of prenatal dipyrone exposure on offspring health. We included four prospective cohorts and six case-control studies, resulting in the analysis of more than 68,000 patients. There were no restrictions in terms of intervention, exposure, or outcome reported. Exposures were analyzed according to pregnancy trimester, and both adjusted and unadjusted data are presented. The quality of the evidence was summarized according to GRADE, which allows a better understanding of the clinical significance and generalizability of our results. Ultimately, the significant results presented were subjected to a sensitivity analysis with a random-effects Bayesian hierarchical model (Markov chain Monte Carlo), which estimates heterogeneity more adequately when few studies are included.\u003c/p\u003e\n \u003cp\u003eThere are limitations to the evidence discussed in this review. Only one study assessed the causality of suspected adverse drug reactions based on the WHO-UMC criteria. This implies that there could be a significant overestimation of the adverse events attributed to dipyrone in our review. Additionally, only four studies provided information about the dose or length of therapy, and only five studies reported the trimester of exposure.\u003c/p\u003e\n \u003cp\u003eThere are few published studies on these thematics in the literature, which was the principal challenge in the development of this review. Consequently, the small number of studies included was a substantial limitation in our review. Additionally, none of the included studies adjusted for possible teratogenic maternal infections, which could be the reason why the mother sought the medication.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003e4.3 Interpretation\u003c/h2\u003e\n \u003cp\u003eWe estimated an increase of 20% in the chance of congenital anomalies with exposure to dipyrone in the first trimester, an estimate heavily influenced by a single study that did not address important sources of bias. No association was observed with major congenital anomalies. Thus, substantial harm is improbable in first-trimester exposure. We estimated a 25% increase in the likelihood of infant leukemia derived from retrospective studies at a high risk of bias. The evidence is very uncertain regarding any association between maternal dipyrone exposure and infant leukemia. Some patients were observed to have oligohydramnios and patent ductus arteriosus during second- and third-trimester exposures, but none were classified as certain or probable according to the WHO-UMC. In that sense, dipyrone use in late pregnancy may increase the risk for these outcomes, but not substantially. It may be prudent to avoid extended exposures in late pregnancy. For the other outcomes, there is no evidence that dipyrone could be a potential cause.\u003c/p\u003e\n \u003cp\u003eConcerns about exposure to dipyrone during pregnancy have been discussed in the literature. Based on previous reports, the European Medicines Agency recommended against third-trimester use of dipyrone\u003csup\u003e25\u003c/sup\u003e. This recommendation was based on case reports that revealed acute renal failure, oligohydramnios, pulmonary hypertension, and ductus arteriosus constriction or closure after dipyrone therapy. In the cohort included in our review that investigated these outcomes during second- and third-trimester exposures, acute renal failure, pulmonary hypertension, and ductus arteriosus constriction or closure were not observed following dipyrone therapy. However, two cases of oligohydramnios were reported, which were classified as possibly caused by dipyrone.\u003c/p\u003e\n \u003cp\u003eOn the other hand, short-term therapies were considered acceptable in the first and second trimesters\u003csup\u003e25\u003c/sup\u003e. Our findings are mostly congruent with the assessment from the European Medicines Agency, as we did not observe certain substantial harm for any particular outcome during pregnancy. However, we did not find significant indications of fetotoxicity in the second- or third-trimester exposures.\u003c/p\u003e\n \u003cp\u003eHistorically, dipyrone has been considered a dangerous analgesic. However, contemporary understanding indicates that toxic effects, as in the case of agranulocytosis reactions, are not as frequent as presumed\u003csup\u003e5\u003c/sup\u003e. Moreover, our study revealed that the available evidence does not indicate substantial harm from prenatal exposure during pregnancy. Analgesia is a common necessity in pregnancy, and mothers in need of medications should be correctly informed about the evidence of harm from pharmacological interventions. This ensures that important interventions are not unnecessarily withheld.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"5 CONCLUSION","content":"\u003cp\u003eAccording to this systematic review and meta-analysis of observational studies, exposure to dipyrone during pregnancy does not seem to pose substantial risks to offspring. However, it may be ideal to avoid extended exposure regardless of the trimester of pregnancy. Postmarketing clinical trials of pharmacovigilance are recommended for investigating the use of dipyrone in reproductive-aged women and identifying possible adverse effects of prenatal dipyrone use on the health of offspring.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The data of this study can be shared upon formal and reasonable request.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or nonfinancial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eContribution to Authorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGM Lino was responsible for the study search, selection, data extraction, data analysis, data synthesis, risk of bias and grade of evidence assessment, and writing of the manuscript; FS Ishibashi was responsible for the study search, selection, and data extraction; GAM Conrado was responsible for reviewing the study search, selection, data extraction, data synthesis, and risk of bias assessment; CC Bresani was responsible for reviewing the final manuscript; and PVM Galv\u0026atilde;o was responsible for the data analysis and reviewing the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoffmann F, Bantel C, von Rosen FT, Jobski K. Regional Differences in Prescribing Patterns of Metamizole in Germany Based on Data from 70 Million Persons. Int J Environ Res Public Health. Multidisciplinary Digital Publishing Institute; 2020 Jan;17(11):3892.\u003c/li\u003e\n\u003cli\u003eSznejder H, Amand C, Stewart A, Salazar R, Scala WAR. Real world evidence of the use of metamizole (dipyrone) by the Brazilian population. A retrospective cohort with over 380,000 patients. Einstein. 20:eAO6353. PMCID: PMC9060643\u003c/li\u003e\n\u003cli\u003eLutz M. Metamizole (Dipyrone) and the Liver: A Review of the Literature. J Clin Pharmacol. 2019;59(11):1433\u0026ndash;1442.\u003c/li\u003e\n\u003cli\u003eHearn L, Derry S, Moore RA. Single dose dipyrone (metamizole) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2016 Apr 20;2016(4):CD011421. PMCID: PMC6540653\u003c/li\u003e\n\u003cli\u003eAndrade S, Bartels DB, Lange R, Sandford L, Gurwitz J. Safety of metamizole: a systematic review of the literature. J Clin Pharm Ther. 2016 Oct;41(5):459\u0026ndash;477.\u003c/li\u003e\n\u003cli\u003ePombo-de-Oliveira MS, Koifman S. Infant acute leukemia and maternal exposures during pregnancy. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. United States; 2006 Dec;15(12):2336\u0026ndash;2341. PMID: 17164354\u003c/li\u003e\n\u003cli\u003eWinters AC, Bernt KM. MLL-Rearranged Leukemias\u0026mdash;An Update on Science and Clinical Approaches. Front Pediatr [Internet]. 2017 [cited 2023 Dec 23];5. Available from: https://www.frontiersin.org/articles/10.3389/fped.2017.00004\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hr\u0026oacute;bjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. British Medical Journal Publishing Group; 2021 Mar 29;372:n71. PMID: 33782057\u003c/li\u003e\n\u003cli\u003eR Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2022. Available from: https://www.R-project.org/\u003c/li\u003e\n\u003cli\u003eWickham H, Averick M, Bryan J, Chang W, McGowan LD, Fran\u0026ccedil;ois R, Grolemund G, Hayes A, Henry L, Hester J, Kuhn M, Pedersen TL, Miller E, Bache SM, M\u0026uuml;ller K, Ooms J, Robinson D, Seidel DP, Spinu V, Takahashi K, Vaughan D, Wilke C, Woo K, Yutani H. Welcome to the Tidyverse. J Open Source Softw. 2019 Nov 21;4(43):1686.\u003c/li\u003e\n\u003cli\u003eViechtbauer W. Conducting meta-analyses in {R} with the {metafor} package. J Stat Softw. 2010;36(3).\u003c/li\u003e\n\u003cli\u003eBalduzzi S, R\u0026uuml;cker G, Schwarzer G. How to perform a meta-analysis with {R}: a practical tutorial. Evid Based Ment Health. 2019;(22):153\u0026ndash;160.\u003c/li\u003e\n\u003cli\u003ePaul M, Leeflang MM. Reporting of systematic reviews and meta-analysis of observational studies. Clin Microbiol Infect. 2021 Mar;27(3):311\u0026ndash;314. PMCID: PMC8885144\u003c/li\u003e\n\u003cli\u003eZanrosso CW, Emerenciano M, de Aguiar Goncalves BA, Faro A, Koifman S, Pombo-de-Oliveira MS. N-Acetyltransferase 2 Polymorphisms and Susceptibility to Infant Leukemia with Maternal Exposure to Dipyrone during Pregnancy. Cancer Epidemiol Biomarkers Prev. 2010 Dec;19(12):3037\u0026ndash;3043.\u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;nemann H, Brożek J, Guyatt G, Oxman A, editor(s). Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach (updated October 2013). [Internet]. GRADE Working Group; 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html\u003c/li\u003e\n\u003cli\u003eGRADEpro GDT: GRADEpro Guideline Development Tool [Software] [Internet]. Hamilton (ON): McMaster University and Evidence Prime; 2024. Available from: gradepro.org\u003c/li\u003e\n\u003cli\u003eAlexander F, Patheal S, Biondi A, Brandalise S, Cabrera M, Chan L, Chen Z, Cimino G, Cordoba J, Gu L, Hussein H, Ishii E, Kamel A, Labra S, Magalhaes I, Mizutani S, Petridou E, de Oliveira M, Yuen P, Wiemels J, Greaves M. Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer Res. 2001 Mar 15;61(6):2542\u0026ndash;2546.\u003c/li\u003e\n\u003cli\u003eCouto AC, Ferreira JD, Pombo-de-Oliveira MS, Koifman S. Pregnancy, maternal exposure to analgesic medicines, and leukemia in Brazilian children below 2 years of age. Eur J Cancer Prev. 2015 May;24(3):245\u0026ndash;252.\u003c/li\u003e\n\u003cli\u003eBanhidy F, Acs N, Puho E, Czeizel AE. A population-based case-control teratologic study of oral dipyrone treatment during pregnancy. DRUG Saf. 2007;30(1):59\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eBar-Oz B, Clementi M, Di Giantonio E, Greenberg R, Beer M, Merlob P, Arnon J, Ornoy A, Zimmerman D, Berkovitch M. Metamizol (dipyrone, optalgin) in pregnancy, is it safe? - A prospective comparative study. Eur J Obstet Gynecol Reprod Biol. 2005 Apr 1;119(2):176\u0026ndash;179.\u003c/li\u003e\n\u003cli\u003eda Silva Dal Pizzol T, Schueler-Faccini L, Mengue SS, Fischer MI. Dipyrone use during pregnancy and adverse perinatal events. Arch Gynecol Obstet. 2009 Mar;279(3):293\u0026ndash;297.\u003c/li\u003e\n\u003cli\u003eDathe K, Padberg S, Hultzsch S, Meixner K, Tissen-Diabate T, Meister R, Beck E, Schaefer C. Metamizole use during first trimesterA prospective observational cohort study on pregnancy outcome. Pharmacoepidemiol Drug Saf. 2017 Oct;26(10):1197\u0026ndash;1204.\u003c/li\u003e\n\u003cli\u003eDathe K, Frank J, Padberg S, Hultzsch S, Beck E, Schaefer C. Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort. BMC Pregnancy Childbirth. 2022 Aug 26;22(1).\u003c/li\u003e\n\u003cli\u003eSharpe C, Franco E. Use of dipyrone during pregnancy and risk of Wilms\u0026rsquo; tumor. Epidemiology. 1996 Sep;7(5):533\u0026ndash;535.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Metamizole containing medicinal products - referral [Internet]. Metamizole containing medicinal products - referral | European Medicines Agency. 2019 [cited 2024 Mar 9]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dipyrone, Pregnancy, Congenital anomalies, Patent ductus arteriosus, Infant leukemia","lastPublishedDoi":"10.21203/rs.3.rs-4421640/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4421640/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis meta-analysis and systematic review aimed to review the health outcomes of offspring following dipyrone use during pregnancy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA systematic literature search was conducted in MEDLINE, Embase, and the Cochrane Library to identify clinical trials or observational studies investigating women who used dipyrone during pregnancy published up to 22 March 2024. Two independent reviewers were responsible for the data extraction. The data were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) and a random effects model. Sensitivity analyses were performed using Bayesian Markov Chain Monte Carlo methods.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSix case-control studies and four prospective cohort studies met the inclusion criteria. There was no evidence of associations with congenital anomalies (OR 1.18, 95% CI 0.80\u0026ndash;1.63; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;33.73%; 3 cohorts and 1 case-control, n\u0026thinsp;=\u0026thinsp;67,374), major congenital anomalies (OR 1.06, 95% CI 0.47\u0026ndash;2.37; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 2 cohorts, n\u0026thinsp;=\u0026thinsp;1,356), infant leukemia (OR 1.25, 95% CI 0.86\u0026ndash;2.22; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72.82%; 3 case-controls, n\u0026thinsp;=\u0026thinsp;1,686), fetal death (OR 0.81, 95% CI 0.57\u0026ndash;1.14; 3 cohorts, n\u0026thinsp;=\u0026thinsp;6,380), prematurity (OR 0.99, 95% CI 0.80\u0026ndash;1.21; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; 3 cohorts, n\u0026thinsp;=\u0026thinsp;6,194), low birth weight, constriction of the ductus arteriosus, or renal and cardiac disorders. There is insufficient evidence to exclude oligohydramnios and patent ductus arteriosus in second- and third-trimester exposures. All analyses were of very low certainty.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThere is no evidence indicating that maternal use of dipyrone causes substantial harm to offspring. According to the sensitivity analyses, exposure during the first and second trimesters was not associated with any negative outcomes. Some observed outcomes, particularly in the third trimester of pregnancy, merit further research.\u003c/p\u003e","manuscriptTitle":"Adverse Effects of Dipyrone (Metamizole) Use During Pregnancy on Offspring Health: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 18:52:19","doi":"10.21203/rs.3.rs-4421640/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-08T04:37:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-19T12:19:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-01T06:17:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23084891077307346682975045864024254784","date":"2024-06-27T07:42:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"142141086751649887341087415115729947707","date":"2024-06-20T04:31:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-18T03:58:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-20T07:02:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-16T05:33:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-16T05:33:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-05-14T23:12:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"149d1f04-c9f1-460e-ad08-2ac2d4f8cc75","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:07:42+00:00","versionOfRecord":{"articleIdentity":"rs-4421640","link":"https://doi.org/10.1186/s12884-025-07872-x","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2025-07-12 15:57:13","publishedOnDateReadable":"July 12th, 2025"},"versionCreatedAt":"2024-05-30 18:52:19","video":"","vorDoi":"10.1186/s12884-025-07872-x","vorDoiUrl":"https://doi.org/10.1186/s12884-025-07872-x","workflowStages":[]},"version":"v1","identity":"rs-4421640","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4421640","identity":"rs-4421640","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}