Safety of Cotrimoxazole in Pregnancy: a Systematic Review and Meta-Analysis

CLINICAL SCIENCE

Safety of Cotrimoxazole in Pregnancy: A Systematic Review and Meta-Analysis

Nathan Ford, MPH, PhD,* Zara Shubber, MBBCH, MSc,† Jennifer Jao, MD, MPH,‡ Elaine J. Abrams, MD,§ Lisa Frigati, MBCHB, MSc, MMED,k and Lynne Mofenson, MD¶

defects) coming from a single study. The majority of adverse drug Introduction: Cotrimoxazole is widely prescribed to treat a range reactions were mild. The quality of the evidence was very low. of infections, and for HIV-infected individuals it is administered as prophylaxis to protect against opportunistic infections. Some reports Conclusions: The findings of this review support continued suggest that fetuses exposed to cotrimoxazole during early preg- recommendations for cotrimoxazole as a priority intervention for nancy may have an increased risk of congenital anomalies. We HIV-infected pregnant women. It is critical to improve data carried out this systematic review to update the evidence of collection on maternal and infant outcomes. cotrimoxazole safety in pregnancy. Key Words: birth defects, congenital anomalies, cotrimoxazole, Methods: Three databases and 1 conference abstract site were HIV/AIDS, pregnancy searched in duplicate up to October 31, 2013, for studies reporting (J Acquir Immune Defic Syndr 2014;66:512–521) adverse maternal and infant outcomes among women receiving cotrimoxazole during pregnancy. This search was updated in MEDLINE via PubMed to April 28, 2014. Studies were included irrespective of HIV infection status or the presence of other coinfections. Our primary INTRODUCTION outcome was birth defects of any kind. Secondary outcomes included Cotrimoxazole (trimethoprim–sulfamethoxazole) is a safe, spontaneous abortions, terminations of pregnancy, stillbirths, preterm effective, and low-cost combination antibiotic that is widely pre- deliveries, and drug-associated toxicity. scribed to treat a range of bacterial, parasitic, and fungal infections. For HIV-infected individuals, cotrimoxazole administered Results: Twenty-four studies were included for review. There were as prophylaxis provides protection against the opportunistic infec- 232 infants with congenital anomalies among 4196 women receiving tion pathogens Pneumocystis jirovecii and Toxoplasma gondii.It cotrimoxazole during pregnancy, giving an overall pooled prevalence of has also been shown to be protective against malaria, bacterial 3.5% (95% confidence interval: 1.8% to 5.1%; t2 = 0.03). Three studies fi pneumonia, and diarrheal disease in resource-limited countries, reported 31 infants with neural tube defects associated with rst trimes- resultinginareducedriskofdeath in clinical trials in these ter exposure to cotrimoxazole, giving a crude prevalence of 0.7% (95% 1,2 fi settings. For HIV-infected pregnant women, the use of pro- con dence interval: 0.5% to 1.0%) with most data (29 neural tube phylactic cotrimoxazole is associated with a reduction in preterm delivery and neonatal mortality in their HIV-exposed infants.3 Received for publication January 13, 2014; accepted May 5, 2014. From the *Department of HIV/AIDS, World Health Organization, Geneva, Since 2006, the World Health Organization (WHO) has recom- Switzerland; †Department of Infectious Disease Epidemiology, Faculty of mended that cotrimoxazole prophylaxis should be provided to all Medicine, Imperial College, London, United Kingdom; ‡Department of HIV-infected individuals with a CD4 cell count ,350 per cubic Medicine, Divisions of Infectious Diseases and General Internal Medicine, millimeter, particularly in resource-limited settings where bacte- Icahn School of Medicine at Mount Sinai, New York, NY; §ICAP, Mailman rial infections and malaria are prevalent.4 School of Public Health, and College of Physicians and Surgeons, Columbia University, New York, NY; kDepartment of Paediatrics and Child Cotrimoxazole provides sequential and synergistic inhi- Health, Tygerberg Hospital, University of Stellenbosch, Cape Town bition of bacterial folate metabolism through its action on South Africa; and ¶Maternal and Pediatric Infectious Disease Branch, Eu- dihydropteroate synthase and dihydrofolate reductase enzymes, nice Kennedy Shriver National Institute of Child Health and Human Devel- inhibiting the biosynthesis of nucleic acids. Although more opment, National Institutes of Health, Rockville, MD. Supplemental digital content is available for this article. Direct URL citations selective for the bacterial than the human dihydrofolate appear in the printed text and are provided in the HTML and PDF reductase isoenzyme, the drug can nevertheless interfere with versions of this article on the journal’s Web site (www.jaids.com). human folate metabolism.5 Pregnancyisassociatedwithrapid Partially funded by a grant from the Bill and Melinda Gates Foundation. J.J. cell division in the unborn child, and folate is essential for fetal received salary support from National Institute of Child Health and development because of its critical role in DNA synthesis.6 Human Development K23HD070760 during the preparation of the fi manuscript. Folate de ciency in early pregnancy is associated with adverse The conclusions and views expressed in this article are those of the authors pregnancy outcomes, including an increased risk of neural tube and do not necessarily reflect those of their respective organizations. The defects and other congenital defects.7 Both trimethoprim and authors have no conflicts of interest to disclose. sulfamethoxazole cross the placental barrier, reaching peak Correspondence to: Nathan Ford, MPH, PhD, Department of HIV/AIDS, World Health Organization, Avenue Appia 20, Geneva 1211, Switzerland fetal levels within 3 hours of administration; fetal levels of (e-mail: [email protected]). sulfamethoxazole average 70%–90% of maternal levels, Copyright © 2014 by Lippincott Williams & Wilkins whereas those of trimethoprim are comparable with maternal

512 | www.jaids.com J Acquir Immune Defic Syndr Volume 66, Number 5, August 15, 2014 J Acquir Immune Defic Syndr Volume 66, Number 5, August 15, 2014 Safety of Cotrimoxazole in Pregnancy levels.8,9 Pregnancy exposure studies carried out in rats and METHODS rabbits10 and small retrospective studies in humans have reported some evidence of congenital anomalies with first-trimester co- Search Strategy and Study Selection trimoxazole exposure.11 Cotrimoxazole is listed as a class D Using a predefined protocol incorporating a compound drug by the Food and Drug Administration12,13 meaning that search strategy (see Appendix 1, Supplemental Digital Content, there is positive evidence of human fetal risk based on adverse http://links.lww.com/QAI/A531), we searched EMBASE, reaction data from investigational or marketing experience or MEDLINE via PubMed, and The Cochrane Library up to Octo- from studies in humans, but the potential benefits of the drug ber 31, 2013, for studies reporting adverse maternal and infant may warrant its use in pregnancy despite the potential risks. outcomes among women exposed to cotrimoxazole during In the United States, guidelines for the management of pregnancy. The search was updated in MEDLINE via HIV-infected adults and adolescents acknowledge a possible PubMed up to April 28, 2014. We also reviewed online association between first-trimester exposure to trimethoprim abstracts of all conferences of the International AIDS Soci- and an increased risk of congenital anomalies; cotrimoxazole ety using single terms for cotrimoxazole (up to Kuala Lum- use in the first trimester of pregnancy is still recommended for pur, June 2013) and hand searched bibliographies of the treatment of Pneumocystis pneumonia because of its con- previously published systematic and nonsystematic reviews siderable benefit, whereas for prophylaxis, the guidelines state and other relevant articles. No language or geographical that health-care providers may consider using alternative reg- restrictions were applied. imens.14 WHO’s 2006 guidelines recommend that women Two reviewers (N.F., Z.S.), working independently, who fulfill the criteria for cotrimoxazole prophylaxis should scanned all the titles for eligibility according to predefined continue cotrimoxazole throughout their pregnancy because inclusion criteria. Once all potentially relevant full-text the risk of life-threatening infections outweighs the potential articles and abstracts were identified, we consulted clinical risk of congenital abnormalities.4 experts (L.M., E.A., J.J.) to achieve consensus regarding We carried out this systematic review to update the eligibility criteria. Studies were included irrespective of HIV evidence of cotrimoxazole safety in pregnancy to inform infection status or the presence of other coinfections. Where a revision of WHO’s guidelines for cotrimoxazole prophy- infections were associated with outcomes under assessment laxis in the context of HIV infection. (eg, brucellosis and stillbirth), however, we did not pool data

FIGURE 1. Identiﬁcation process for eligible studies.

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TABLE 1. Study Characteristics Overall Numbers Study Design; Setting Reporting Period Study Size Receiving CTX Indication HIV+ Anderson et al22 Hospital registry cohort and Danish 1997–2007 931,504 265 UTI 0 Fertility Registry; Denmark Anderson et al23 Danish Fertility Registry; Denmark 1997–2005 521,267 402 UTI (assumed) 0 Angelakis et al24 Retrospective cohort; France 2006–2011 46 17 Brucellosis NR Bailey et al25 RCT; New Zealand 1980–1982 44 44 Asymptomatic bacteriuria NR Brumﬁtt and Pursell26 RCT; United Kingdom 1973 155 120 + 35 referrals Bacteriuria 0 Carcopino et al27 Retrospective cohort; France 1991–2005 53 22 Q fever NR Colley et al28 Retrospective cohort; Australia 1978–1981 7371 209* Unclear 0 Czeizel et al29 Case–control study; Hungary 1980–1996 61,016 794 Respiratory and UTI 0 Denoeud-Ndam et al43 RCT; Benin 2009–2011 432 364 HIV (malaria prophylaxis) 432 Dow et al44 RCT; Malawi 2004–2009 1236 768 HIV (malaria prophylaxis) 1236 Hernández-Díaz et al30 Case–control study; United States 1976–1998 15,319 66† UTI 0 and Canada Hill et al31 Case–control study; United Kingdom 1983 791‡ 42 NR NR Jungman et al32 Retrospective cohort; United 1994–1999 195 29 HIV (prophylaxis) 29 Kingdom Khan et al33 Retrospective cohort; Saudi Arabia 1983–1995 92 40 Brucellosis 0 Klement et al45 RCT; Togo 2009–2012 264 126 (number HIV (malaria prophylaxis) 264 analyzed) Matok et al34,§ Retrospective cohort‡; Israel 1998–2007 84,823 346 “Primarily” UTI NR Meijer et al35 Case–control study; The Netherlands 1997–2002 2217 15 Unclear NR Michigan Medicaid Surveillance; United States Unclear 2296 2296 Unclear NR surveillance study36 Roushan et al37 Retrospective case series; Iran 2000–2010 19 14 Brucellosis NR Santos et al38 Case–control (prospectively collected 1998–2003 63,338 214 Unclear NR data); Canada Valentini et al39 Retrospective hospital case review; 2009 (published) 76 76 Toxoplasmosis NR Italy Walter et al3 Cohort nested within an RCT; 2001–2004 255 67 HIV (prophylaxis) 67 Zambia Wen et al40 Retrospective cohort; Canada 1980–2000 74,807 DHRI: 11,386 NR (any exposure but NR TMP–SMX: mostly UTI) 12,546 Yaris et al41 Toxicology Information and Follow-up 1999–2004 511 11 UTI NR Service; Turkey

Main Drug Study Dose Timing Duration Provided Other Drugs Folate Anderson et al22 NR First trimester NR TMP or TMP + Sulfamethizole given to NR SMX 34/265 Anderson et al23 NR 12 wk before NR TMP or TMP + NR 9 pregnancy SMX Angelakis et al24 NR Throughout Variable (range TMP + SMX No NR pregnancy 2wk–6 mo) Bailey et al25 Either single dose CTX ,30 wk gestation Single dose or TMP + SMX No No at 1.92 g or 0.96 g 5d CTX BD (160 mg TMP + 800 mg SMX) for 5 d Brumﬁtt and NR Only 10 ,16 wk Unclear TMP + SMX NR NR Pursell26 pregnant; 35 referrals exposed at time of conception Carcopino et al27 320 mg TMP and 1600 Throughout Variable; mainly TMP + SMX No No mg SMX pregnancy long-term, .5wk Colley et al28 NR (most given “normal Throughout NR TMP + SMX NR NR dose”) pregnancy

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TABLE 1. (Continued) Study Characteristics Main Drug Study Dose Timing Duration Provided Other Drugs Folate Czeizel et al29 80 mg TMP + 400 mg Throughout 4 d TMP + SMX Various Cases 50% SMX, 2 tablets · 2/3 pregnancy daily on day 1, then 1 tablet · 2/d Denoeud-Ndam 160 mg TMP + 800 mg Second and third Throughout TMP + SMX Mefloquine (one arm, 5 mg folic acid (all) et al43 SMX trimesters pregnancy n = 146); mefloquine, quinine, or arthemeter– lumefantrine in case of malaria, depending on symptoms and levels of parasitemia; ART (32.7% AZT/ 3TC/EFV, 23.6% AZT/3TC/NVP, 18.1% D4T/3TC/ NVP, 15.7% D4T/ 3TC/EFV) Dow et al44 160 mg TMP + 800 mg Second and third Throughout TMP + SMX ART (225/768) NR SMX BD trimesters pregnancy Hernández-Díaz NR 21 to +3 lunar NR TMP + SMX Unclear 11% used daily et al30 months periconceptional folic acid supplements Hill et al31 NR 3 mo preconception NR TMP + sulfa drugs NR Unclear and first trimester Jungman et al32 NR First Trimester NR TMP + SMX No NR Khan et al33 160 mg TMP + 800 mg Throughout $4 wk TMP + SMX (23); 17 also received NR SMX BD pregnancy TMP + SMX + rifampicin rifampicin (17) Klement et al45 160 mg TMP + 800 mg Second and third Throughout TMP + SMX 300 mg AZT or d4T, Yes (all) SMX BD trimesters pregnancy 3TC and NVP (depending on WHO stage); malaria treatment where indicated Matok et al34,§ NR First trimester Mean 7.4 d for TMP + SMX 2 women methotrexate NR all DHRI only, 1 sulfasalazine only Meijer et al35 NR First Trimester Unclear TMP 7 TMP only, 2 TMP + ;24% all cases and sulfoxamide, 3 controls sulfasalazine Michigan Medicaid NR NR NR TMP + SMX NR NR surveillance study36 Roushan et al37 NR Throughout 2 mo TMP + SMX Rifampicin (all women) NR pregnancy Santos et al38 NR Throughout Variable TMP + SMX NR NR pregnancy Valentini et al39 160 mg TMP + 800 mg Second and third Variable—up to TMP + SMX Spiramycin (all Yes (all) SMX BD trimesters (start at 24 wk women) least after week 14, and stop 2 wk before delivery) Walter et al3 80 mg TMP + 400 mg Delayed until second Ongoing; TMP + SMX Chloroquine (2002) 800 mg (all women) SMX BD trimester dependent on then sulfadoxine– CD4 pyrimethamine (2003); ART

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TABLE 1. (Continued) Study Characteristics Main Drug Study Dose Timing Duration Provided Other Drugs Folate Wen et al40 NR Preconception period NR TMP + SMX No NR and throughout pregnancy Yaris et al41 TMP–SMX 160–800 mg First trimester 7–10 d TMP + SMX Gentamicin in 2 cases NR (unlikely) for 7–10d(2cases with gentamicin)

*Sulfamethizole alone was given in 127 additional patients. †Trimethoprim, triamterene, and sulfasalazine. Exact numbers not given. ‡Cases only. §Includes fetal anomalies diagnosed via prenatal ultrasound. 3TC, lamivudine; ART, antiretroviral therapy; AZT, zidovudine; BD, twice daily; CTX, cotrimoxazole; DHRI, dihydrofolate reductase inhibitors; EFV, efavirenz; NR, not reported; NVP, nevirapine; RCT, randomized control trial; TMP + SMX, cotrimoxazole (TMP trimethoprim; SMX sulfamethoxazole); UTI, urinary tract infection. because of confounding by indication. We made no distinc- tion to the original scale.18 Data derived from randomized tion regarding whether cotrimoxazole was provided for trials were pooled together with data from observational prophylaxis or treatment. Studies assessing sulfonamide studies using random effects analysis, consistent with rec- drugs alone were excluded. ommended approaches for systematic reviews of adverse events.19 The following preplanned subgroup analyses were conducted for the pooled prevalence estimate of con- Data Extraction genital anomalies: trimester of cotrimoxazole exposure Data extraction was conducted independently and (first trimester versus second or third trimester), study in duplicate using a prepiloted data extraction form (Z.S., design, and provision of folate supplementation ($50% N.F.) and subsequently verified by 2 other reviewers versus ,50% of the cohort). For outlier studies, we under- (J.J., L.M.). Information was extracted on study size, took a leave-one-out meta-analysis in which each study setting, and population; coinfection status; period and was dropped in turn to assess its influence on the overall duration of exposure; and birth outcomes. Our primary pooled prevalence.20 Odds ratios (OR) and corresponding outcome was birth defects of any kind. Secondary out- 95% CIs were calculated for data derived from case–control comes included spontaneous abortions, terminations of studies, and where appropriate, the data were pooled, also using pregnancy, stillbirths, preterm deliveries, and drug- random effects models. Data for secondary outcomes were not associated toxicity. pooled because background prevalence rates are known to vary considerably between study settings. Heterogeneity was assessed using both the I2 and t2 statistics.21 All analyses were conducted Assessment of Methodological Quality using STATA (version 12, www.stata.com) and GRADE Pro Risk of bias was assessed according to 6 criteria: (www.gradeworkinggroup.org). direct ascertainment of cotrimoxazole use, adjustment for confounders, prospective study design, outcomes reported by trimester, outcomes reported by folate supplement use, RESULTS and potential for confounding by indication. This risk of bias assessment was used to inform the overall assessment Characteristics of Included Studies of the quality of the evidence, which followed the From a total of 2344 publications initially screened, GRADE approach.15 24 met the inclusion criteria and were taken through for full review (Fig. 1).3,22–41 One paper reported the results of several studies in a single paper,26 one study reported data Data Analysis in 2 separate publications,30–42 and data from another, Point estimates and 95% confidence intervals (95% unpublished study, were reported in a review article.36 CI) were calculated for the proportion of congenital Two studies reported data from the Danish national preg- anomalies reported among live births for each study. nancy registry during overlapping periods: one reported Where possible, we excluded spontaneous and induced the risk of miscarriage among all births22 and the other abortions and stillbirths from the numerator and denomi- reported the risk of congenital anomalies among live nator for the estimate of congenital anomalies, consistent births.23 Four studies were carried out in sub-Saharan Africa with current reporting conventions. Because of heteroge- (Benin,43 Malawi,44 Togo,45 and Zambia3), whereas the rest neity between studies, the overall prevalence of congenital were carried out in high-income settings. Five studies reported anomalies was estimated by pooling data from each study outcomes among HIV-infected women.3,32,43–45 There were 4 using a DerSimonian–Laird random effects model16 after surveillance studies, 6 randomized controlled trials, 5 case– arcsine square root transformation to stabilize the variance control studies, and 9 cohort studies. The reporting period of the raw proportions17 and subsequent back transforma- ranged from 197326 to 2012,45 with over half of the studies

516 | www.jaids.com 2014 Lippincott Williams & Wilkins J Acquir Immune Defic Syndr Volume 66, Number 5, August 15, 2014 Safety of Cotrimoxazole in Pregnancy reporting data collected from 2002 onward. Study character- Odds of Congenital Anomalies istics are summarized in Table 1. Four case–control studies, reported in 5 articles,29–31,35,42 provided data on the OR of congenital anomalies comparing cotrimoxazole exposure among cases and controls. There was fi Congenital Anomalies no statistically signi cant difference in the risk of overall congenital anomalies (2 studies; OR: 0.6, 95% CI: 0.1 to 3.4), with Prevalence of Congenital Anomalies high heterogeneity between studies (I2 =84%,t2 =1.2).An Sixteen studies reported 232 infants with congenital increased risk was reported for neural tube defects (1 study; anomalies among 4196 women receiving cotrimoxazole during OR: 3.4, 95% CI: 1.1 to 10.3;), cardiovascular defects (1 study; – – pregnancy,3,23 28,32 34,36,37,39,41,43,45 summarized in Table 2. The OR: 2.9, 95% CI: 1.6 to 5.5), and oral clefts (2 studies; OR: remaining 8 studies were not included in this analysis for the 2.0, 95% CI: 1.2 to 3.4; I2 =0%,t2 = 0), but not urinary tract following reasons: 5 were case–control studies,29–31,35,38 defects (1 study; OR: 0.9, 95% CI: 0.2 to 3.9). whereas the remaining 3 studies reported only data regarding secondary outcomes.22,40,44 The prevalence of congenital anom- Secondary Outcomes alies ranged from 0.3% (95% CI: 0.3% to 2.8%) to 16.3% 26,27,39,43,45 (95% CI: 0.8% to 45.7%), with an overall pooled prevalence Five studies provided data on maternal toxicity. Of 714 women exposed to cotrimoxazole during pregnancy in of 3.5% (95% CI: 1.8% to 5.1%; I2 =84.9%,t2 =0.03).34 The these studies (490 with HIV infection), 31 (4.3%) experienced pooled prevalence was higher for studies that included pregnant fi an adverse drug reaction; the majority of events were mild with women receiving cotrimoxazole during the rst trimester of only 4 events (0.6%) resulting in treatment discontinuation. One pregnancy (4.8%, 95% CI: 0.6% to 8.9%) compared with stud- study provided data on neonatal jaundice, reporting one case ies in which there were no first-trimester exposures (1.4%, 95% out of 67 exposures.3 Other reported birth outcomes included CI: 0.3% to 2.4%). These differences were, however, not found stillbirths (6 studies), spontaneous abortions (6 studies), to be statistically significant (P = 0.1). These data are summa- small for gestational age (7 studies), and preterm birth (6 stud- rized in Figure 2. When comparing the reported prevalence of ies). Data were not pooled because of the limited data congenital anomalies by study design, the pooled prevalence reported for these outcomes, differing background population was higher for population surveillance studies (7.8%, 95% CI: rates, and risk of confounding by indication. No cases of 3.6% to 11.9%) compared with randomized controlled trials kernicterus were reported. These outcomes are summarized (1.4%, 95% CI: 0.5% to 2.4%), prospective cohort studies in Tables S2 and S3 (see Supplemental Digital Content, http://links.lww.com/QAI/A531). (2.1%, 95% CI: 0% to 5.6%), or retrospective cohorts (2.0%, 95% CI: 0.1% to 3.6%). The pooled prevalence of birth defects in infants in studies that included HIV-infected pregnant Assessment of Methodological Quality 3,32,43,45 women (1.7%, 95% CI: 0.6% to 2.7%) was lower com- Risk of bias was considered to be moderate to high. pared with the overall prevalence in all women. Seven studies did not directly ascertain cotrimoxazole use, 15 We conducted a sensitivity analysis in which the pooled studies did not assess the potential influence of confounders, 14 prevalence was assessed after dropping each study in turn to studies used retrospective designs, 9 studies did not disaggre- determine the degree of influence of any single study on gate outcomes by trimester of exposure, 17 studies did not the overall pooled prevalence estimate of congenital report on folate use, and 7 studies were at risk of confounding anomalies. In this analysis, the pooled prevalence was by indication for secondary outcomes (see Table S4, Supple- reduced from 3.5% (95% CI: 1.8% to 5.1%) to 2.6% (95% mental Digital Content, http://links.lww.com/QAI/A531). The CI: 1.2% to 4.0%) when one study34 was dropped from the risk of publication bias was considered to be high, considering analysis (see Table S1, Supplemental Digital Content, that cohorts among whom adverse outcomes occurred are more http://links.lww.com/QAI/A531). This study differed from likely to be documented and published. This was not formally the other studies in 2 notable ways: first, fetal anomalies assessed because of the small number of identified studies. were diagnosed in utero; second, around half of the cohort were Overall, the GRADE assessment determined that the quality Bedouins in Israel, a community in which there is increased of the evidence contributing to the assessment of prevalence consanguinity.46 Incidence of birth defects was reported to be and odds of congenital anomalies was very low. This informa- higher among the Bedouin community during the reporting tion is summarized in Tables S5 and S6 (see Supplemental period of this study.47 These factors may have led to both Digital Content, http://links.lww.com/QAI/A531). a higher ascertainment of congenital anomalies and a higher background prevalence of anomalies in this cohort. Among the 16 studies reporting on the prevalence of CONCLUSIONS congenital anomalies, 3 studies reported 31 infants with Cotrimoxazole has been commonly prescribed for over neural tube defects associated with cotrimoxazole exposure 40 years for the treatment of a wide range of infections and during the first trimester of pregnancy, giving a crude has been recommended as life-saving prophylaxis by the prevalence of 0.7% (95% CI: 0.5% to 1.0%). These data WHO for all HIV-infected individuals with low CD4 cell were also dominated by the study described above,34 which count, including pregnant women. Despite its long history of contributed 29 of 31 neural tube defects. widespread use, this review found very limited evaluable data

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TABLE 2. Congenital Anomalies (Case–Control Studies not Included) Number of Live Births to Number of Infants With Number of Infants With Women Receiving CTX Congenital Anomaly Neural Tube Congenital Type of Anomaly (all Study Trimester (N = 4196) (N = 232) Anomaly (N = 32) Reported) Anderson et al23 T1 402 25* 1 Limb defects UTD Orofacial defects CVD NTD Angelakis et al24 T1 5 0 0 — Angelakis et al24 T2/3 8 1 0 Bilateral renal agenesis Bailey et al25 T1/T2 43 0 0 — Brumfitt and Pursell26 T1 10 0 0 — Brumfitt and Pursell26 T1 35 0 0 — Brumfitt and Pursell26 T2/3 110 4† Cleft lip, hypospadias, Robin syndrome, extra digits All cases at T2 Carcopino et al27 NS 19 1 0 Potter’s syndrome Colley et al28 T1/2/3 209 8‡ 1 Patent ductus arteriosis Atrial septal defect Hypospadias Dislocated hip Metatarsus varus Cavernous hemangioma Other Denoeud-Ndam et al43 T2/3 325 5§ 0k Clubfoot Umbilical hernia Hydrocephaly Jungman et al32 T1 29 1 1 NTD, hydrocephalus Khan et al33 NS 40 0 0 — Klement et al45 T2/3 117 1 0 Polydactyly Matok et al34 T1 385 59 29 29 NTD 13 CVD 4 UTD Michigan Medicaid NS 2296 126 — 37 CVD surveillance study36 Roushan et al37 T1–39 0 0 — Valentini et al39 T2/3 76 0 0 — Walter et al3 T2/3 67 1 NR NR Yaris et al41 T1 11 0 0 NR

*Only major malformations included. †All events were associated with T2 exposure. ‡All events were associated with T2/3 exposure. §An additional malformation was reported among stillborn infants. kThere was one intrauterine fetal death diagnosed with encephalocele and ventral hernia. CTX, cotrimoxazole; CVD, cardiovascular defects; NR, not reported; NS, not signiﬁcant; NTD, neural tube defects; T, trimester; UTD, urinary tract defects.

on maternal and infant outcomes associated with cotrimox- tube defects was 0.7%, which is higher than that reported azole exposure during pregnancy. Although some studies among the general population in the United States (0.04%– included in this review suggested that cotrimoxazole exposure 0.06% before regular folic acid fortification),51 United in pregnancy was associated with congenital abnormalities, the Kingdom (0.14%),52 and South Africa (0.36%)53; however, overall pooled prevalence was not significantly higher than the most of the defects were reported by one study in which pre- reported rates in the general population.48 In the United States, natal ultrasound screening was standard and that included the prevalence of congenital anomalies is 2.7%,49 whereas in a population with increased consanguinity.34 Thus, the poor sub-Saharan Africa, the reported prevalence ranges from 0.4% quality of the data prevents any definitive conclusions from to 3.7%.50 Evidence from case–control studies suggests a poten- being drawn. Nevertheless, this review found some reassuring tial increased risk of certain specific congenital anomalies, evidence of cotrimoxazole safety. Although the data were including neural tube defects. The crude prevalence of neural limited, maternal treatment limiting adverse events were rare.

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FIGURE 2. Pooled prevalence of infant congenital anomalies by trimester.

There was no evidence of excessive rates of infant jaundice CIs were calculated for outcomes of individual studies and for associated with cotrimoxazole exposure in pregnancy, pooled estimates to reflect the level of uncertainty around the although only 1 study reported on neonatal jaundice. prevalence estimates. To compensate for the limited number of A previous systematic assessment of cotrimoxazole studies reporting outcomes specifically for cotrimoxazole pro- safety in pregnancy, carried out in 2006, took a broad approach phylaxis, we included studies in which pregnant women that considered any sulfonamide exposure, concluding that received cotrimoxazole for the treatment of various infections. there was mixed evidence about safety in pregnancy; overall The duration of drug exposure and the indication for its use— estimates of risk were not calculated.9 We limited our review to including for infections known to be associated with some of cotrimoxazole but did include HIV-uninfected cohorts and the secondary outcomes under assessment—differed consider- exposure to cotrimoxazole for both treatment and prophylaxis ably between these studies. Although the primary outcome of of various infectious diseases. Our search strategy and inclusion birth defects was not found to be influenced by infection status criteria allowed for the identification of over 4000 exposures in in sensitivity analyses, secondary outcomes should nevertheless randomized trials and observational cohort studies that could be interpreted with particular caution given the risk of con- contribute to estimating prevalence of congenital anomalies, founding by indication. Other methodological issues of concern with additional information provided by case–control studies. included the retrospective nature of many studies, the

2014 Lippincott Williams & Wilkins www.jaids.com | 519 Ford et al J Acquir Immune Defic Syndr Volume 66, Number 5, August 15, 2014 inadequate reporting of timing and duration of cotrimoxazole In conclusion, the findings of this review support exposure, the limited reporting of folate use and other potential continued recommendations to provide cotrimoxazole pro- confounders, and the likelihood of publication bias favoring the phylaxis to HIV-infected pregnant women. As with the use of documentation and reporting of adverse outcomes. These lim- any drug in pregnancy, the benefits of the drug need to be itations resulted in the quality of the evidence being rated as weighed against its potential risks. It is crucial that data very low. Further studies are needed to improve judgment collection on maternal and infant outcomes is improved to about the safety of cotrimoxazole in pregnancy. better assess the safety of cotrimoxazole use during preg- Despite the widespread use of cotrimoxazole prophylaxis nancy. Because of the substantial mortality reduction benefits in HIV-infected individuals, including pregnant women, an associated with cotrimoxazole use in HIV-infected individu- important limitation of our review is the limited data found on als with low immunity1,2 and the particular vulnerability birth outcomes in HIV-infected pregnant women receiving of HIV-infected pregnant women to diseases potentially long-term cotrimoxazole prophylaxis. The majority of studies preventable by cotrimoxazole, such as malaria, continued rec- included in this review reported on short-term cotrimoxazole ommendations for cotrimoxazole as a priority intervention for use for the treatment of various infectious diseases, such as HIV-infected pregnant women are warranted. urinary tract infections, brucellosis, toxoplasmosis, or Q fever. Less than a quarter of data contributing to the prevalence assessment came from HIV-infected women, and only one of ACKNOWLEDGMENTS these studies (29 exposures) reported on first-trimester cotri- The authors would like to thank Marco Vitoria for moxazole use; this study suggested that exposure to the comment on an earlier draft. combination of antiretroviral drugs and folate antagonists was associated with an increased risk of congenital abnormalities. In this study, of 32 women receiving folate antagonists in the first REFERENCES trimester, 3 were not exposed to cotrimoxazole but to other 1. 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