We conducted a sensitivity analysis in which the pooled prevalence was assessed after dropping each study in turn to determine the degree of influence of any single study on the overall pooled prevalence estimate of congenital anomalies. In this analysis, the pooled prevalence was reduced from 3.5% (95% CI: 1.8% to 5.1%) to 2.6% (95% CI: 1.2% to 4.0%) when one study34 was dropped from the analysis (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A531). This study differed from the other studies in 2 notable ways: first, fetal anomalies were diagnosed in utero; second, around half of the cohort were Bedouins in Israel, a community in which there is increased consanguinity.46 Incidence of birth defects was reported to be higher among the Bedouin community during the reporting period of this study.47 These factors may have led to both 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 congenital anomalies, 3 studies reported 31 infants with neural tube defects associated with cotrimoxazole exposure during the first trimester of pregnancy, giving a crude prevalence of 0.7% (95% CI: 0.5% to 1.0%). These data were also dominated by the study described above,34 which contributed 29 of 31 neural tube defects.
Risk of bias was considered to be moderate to high. Seven studies did not directly ascertain cotrimoxazole use, 15 studies did not assess the potential influence of confounders, 14 studies used retrospective designs, 9 studies did not disaggregate outcomes by trimester of exposure, 17 studies did not report on folate use, and 7 studies were at risk of confounding by indication for secondary outcomes (see Table S4, Supplemental Digital Content, http://links.lww.com/QAI/A531). The risk of publication bias was considered to be high, considering that cohorts among whom adverse outcomes occurred are more likely to be documented and published. This was not formally assessed because of the small number of identified studies. Overall, the GRADE assessment determined that the quality of the evidence contributing to the assessment of prevalence and odds of congenital anomalies was very low. This information is summarized in Tables S5 and S6 (see Supplemental Digital Content, http://links.lww.com/QAI/A531).
Cotrimoxazole has been commonly prescribed for over 40 years for the treatment of a wide range of infections and has been recommended as life-saving prophylaxis by the WHO for all HIV-infected individuals with low CD4 cell count, including pregnant women. Despite its long history of widespread use, this review found very limited evaluable data on maternal and infant outcomes associated with cotrimoxazole exposure during pregnancy. Although some studies included in this review suggested that cotrimoxazole exposure in pregnancy was associated with congenital abnormalities, the overall pooled prevalence was not significantly higher than the reported rates in the general population.48 In the United States, the prevalence of congenital anomalies is 2.7%,49 whereas in sub-Saharan Africa, the reported prevalence ranges from 0.4% to 3.7%.50 Evidence from case–control studies suggests a potential increased risk of certain specific congenital anomalies, including neural tube defects. The crude prevalence of neural tube defects was 0.7%, which is higher than that reported among the general population in the United States (0.04%–0.06% before regular folic acid fortification),51 United Kingdom (0.14%),52 and South Africa (0.36%)53; however, most of the defects were reported by one study in which prenatal ultrasound screening was standard and that included a population with increased consanguinity.34 Thus, the poor quality of the data prevents any definitive conclusions from being drawn. Nevertheless, this review found some reassuring evidence of cotrimoxazole safety. Although the data were limited, maternal treatment limiting adverse events were rare. There was no evidence of excessive rates of infant jaundice associated with cotrimoxazole exposure in pregnancy, although only 1 study reported on neonatal jaundice.
A previous systematic assessment of cotrimoxazole safety in pregnancy, carried out in 2006, took a broad approach that considered any sulfonamide exposure, concluding that there was mixed evidence about safety in pregnancy; overall estimates of risk were not calculated.9 We limited our review to cotrimoxazole but did include HIV-uninfected cohorts and exposure to cotrimoxazole for both treatment and prophylaxis of various infectious diseases. Our search strategy and inclusion criteria allowed for the identification of over 4000 exposures in randomized trials and observational cohort studies that could contribute to estimating prevalence of congenital anomalies, with additional information provided by case–control studies. CIs were calculated for outcomes of individual studies and for pooled estimates to reflect the level of uncertainty around the prevalence estimates. To compensate for the limited number of studies reporting outcomes specifically for cotrimoxazole prophylaxis, we included studies in which pregnant women received cotrimoxazole for the treatment of various infections. The duration of drug exposure and the indication for its use—including for infections known to be associated with some of the secondary outcomes under assessment—differed considerably between these studies. Although the primary outcome of birth defects was not found to be influenced by infection status in sensitivity analyses, secondary outcomes should nevertheless be interpreted with particular caution given the risk of confounding by indication. Other methodological issues of concern included the retrospective nature of many studies, the inadequate reporting of timing and duration of cotrimoxazole exposure, the limited reporting of folate use and other potential confounders, and the likelihood of publication bias favoring the documentation and reporting of adverse outcomes. These limitations resulted in the quality of the evidence being rated as very low. Further studies are needed to improve judgment about the safety of cotrimoxazole in pregnancy.
Despite the widespread use of cotrimoxazole prophylaxis in HIV-infected individuals, including pregnant women, an important limitation of our review is the limited data found on birth outcomes in HIV-infected pregnant women receiving long-term cotrimoxazole prophylaxis. The majority of studies included in this review reported on short-term cotrimoxazole use for the treatment of various infectious diseases, such as 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 these studies (29 exposures) reported on first-trimester cotrimoxazole use; this study suggested that exposure to the 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 trimester, 3 were not exposed to cotrimoxazole but to other antifolates (pyrimethamine, carbamazepine) and only 13 women received both antiretroviral and antifolate drugs (and the study did not delineate whether all 13 were exposed to cotrimoxazole or to the other antifolates).27 Almost all data on birth defects for HIV-infected women were from Africa, where concomitant nutritional deficiencies may be more common than in resource-rich countries.
This review highlights several areas for future research. First, improved surveillance is critical to gather data on cotrimoxazole exposure during pregnancy, as is the case for a number of drugs commonly used in the management of HIV/AIDS, notably efavirenz. This review found few reports from high HIV-burden resource-limited settings, where cotrimoxazole prophylaxis is likely to be of most benefit. The lack of screening for congenital abnormalities and the high rate of unattended deliveries in these settings may change the programmatic implications of the results reported by this review. It will be critical for pregnancy outcome surveillance to include an evaluation of exposure to cotrimoxazole and antiretroviral drugs. Pregnancy outcome surveillance is being reinforced in several countries with the support of WHO and major donors, and the findings from this work will help inform future guidance. More data are needed for all important maternal and infant outcomes when using cotrimoxazole for prophylaxis in HIV-infected pregnant women, in particular in settings of high malaria prevalence, with outcomes disaggregated by trimester and duration of cotrimoxazole exposure, and, where possible, reporting of relevant concomitant exposures (eg, smoking, folate and other nutritional supplementation, use of other drugs). Finally, cotrimoxazole inhibits folic acid synthesis, and 2 studies included in this review suggested that periconceptional daily folic acid supplementation may reduce cotrimoxazole's potential teratogenic effect.29,42 However, concomitant folate use may reduce the antibacterial effect of cotrimoxazole, which warrants further study.
In conclusion, the findings of this review support continued recommendations to provide cotrimoxazole prophylaxis to HIV-infected pregnant women. As with the use of any drug in pregnancy, the benefits of the drug need to be weighed against its potential risks. It is crucial that data collection on maternal and infant outcomes is improved to better assess the safety of cotrimoxazole use during pregnancy. Because of the substantial mortality reduction benefits associated with cotrimoxazole use in HIV-infected individuals with low immunity1,2 and the particular vulnerability of HIV-infected pregnant women to diseases potentially preventable by cotrimoxazole, such as malaria, continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women are warranted.
The authors would like to thank Marco Vitoria for comment on an earlier draft.
1. Anglaret X, Chene G, Attia A, et al.. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet. 1999;353:1463–1468.
2. Suthar AB, Granich R, Mermin J, et al.. Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. Bull World Health Organ. 2012;90:128C–138C.
3. Walter J, Mwiya M, Scott N, et al.. Reduction in preterm delivery and neonatal mortality after the introduction of antenatal cotrimoxazole prophylaxis among HIV-infected women with low CD4 cell counts. J Infect Dis. 2006;194:1510–1518.
4. . Guidelines on Co-trimoxazole Prophylaxis for HIV-related Infections Among Children, Adolescents and Adults. Recommendations for a Public Health Approach. Geneva, Switzerland: WHO; 2006.
5. Mandell GLSM. Antimicrobial Agents. In: Gilman AG, Rall TW, Nies AS, et al., eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York, NY: Pergamon Press; 1990:1047–1064.
6. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71(5 suppl l):1295S–1303S.
7. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the medical research council vitamin study. Lancet. 1991;338:131–137.
8. Reid DW, Caille G, Kaufmann NR. Maternal and transplacental kinetics of trimethoprim and sulfamethoxazole, separately and in combination. Can Med Assoc J. 1975;112(13 Spec No):67–72.
9. Forna F, McConnell M, Kitabire FN, et al.. Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. AIDS Rev. 2006;8:24–36.
10. Briggs G, eds. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams and Wilkens; 1988.
11. Townsend CL, Willey BA, Cortina-Borja M, et al.. Antiretroviral therapy and congenital abnormalities in infants born to HIV-infected women in the UK and Ireland, 1990-2007. AIDS. 2009;23:519–524.
15. Guyatt GH, Oxman AD, Vist GE, et al.. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–926.
16. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.
17. Freeman MF. Transformations related to the angular and the square root. Ann Inst Stat Mathematics. 1950;21:607–611.
18. Miller J. The inverse of the Freeman-Tukey double arcsine transformation. Am Stat. 1978;32:138.
19. Golder S, Loke YK, Bland M. Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview. Plos Med. 2011;8:e1001026.
20. Viechtbauer WCM. Outlier and influence diagnostics for meta-analysis. Res Synthesis Methods. 2010;1:112–125.
21. Higgins JP, Thompson SG, Deeks JJ, et al.. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560.
22. Andersen JT, Petersen M, Jimenez-Solem E, et al.. Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study. Epidemiol Infect. 2013;141:1749–1755.
23. Andersen JT, Petersen M, Jimenez-Solem E, et al.. Trimethoprim use prior to pregnancy and the risk of congenital malformation: a register-based nationwide cohort study. Obstet Gynecol Int. 2013;2013:364526.
24. Angelakis E, Million M, D'Amato F, et al.. Q fever and pregnancy: disease, prevention, and strain specificity. Eur J Clin Microbiol Infect Dis. 2013;32:361–368.
25. Bailey RR, Bishop V, Peddie BA. Comparison of single dose with a 5-day course of co-trimoxazole for asymptomatic (covert) bacteriuria of pregnancy. Aust N Z J Obstet Gynaecol. 1983;23:139–141.
26. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973;128(suppl 6):57–65.
27. Carcopino X, Raoult D, Bretelle F, et al.. Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy. Clin Infect Dis. 2007;45:548–555.
28. Colley DKJ, Gibson G. A study on the use in pregnancy of co-trimoxazole and sulphamethizole. Aust J Pharm. 1982;570–575.
29. Czeizel AE, Rockenbauer M, Sorensen HT, et al.. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol. 2001;15:637–646.
30. Hernandez-Diaz S, Werler MM, Walker AM, et al.. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343:1608–1614.
31. Hill L, Murphy M, McDowall M, et al.. Maternal drug histories and congenital malformations: limb reduction defects and oral clefts. J Epidemiol Community Health. 1988;42:1–7.
32. Jungmann EM, Mercey D, DeRuiter A, et al.. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect. 2001;77:441–443.
33. Khan MY, Mah MW, Memish ZA. Brucellosis in pregnant women. Clin Infect Dis. 2001;32:1172–1177.
34. Matok I, Gorodischer R, Koren G, et al.. Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations. Br J Clin Pharmacol. 2009;68:956–962.
35. Meijer WM, de Walle HE, Kerstjens-Frederikse WS, et al.. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists. Reprod Toxicol. 2005;20:203–207.
36. Sivojelezova A, Einarson A, Shuhaiber S, et al.. Trimethoprim-sulfonamide combination therapy in early pregnancy. Can Fam Physician. 2003;49:1085–1086.
37. Roushan MR, Baiani M, Asnafi N, et al.. Outcomes of 19 pregnant women with brucellosis in Babol, northern Iran. Trans R Soc Trop Med Hyg. 2011;105:540–542.
38. Santos F, Sheehy O, Perreault S, et al.. Exposure to anti-infective drugs during pregnancy and the risk of small-for-gestational-age newborns: a case-control study. BJOG. 2011;118:1374–1382.
39. Valentini P, Annunziata ML, Angelone DF, et al.. Role of spiramycin/cotrimoxazole association in the mother-to-child transmission of toxoplasmosis infection in pregnancy. Eur J Clin Microbiol Infect Dis. 2009;28:297–300.
40. Wen SW, Zhou J, Yang Q, et al.. Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes. CMAJ. 2008;179:1263–1268.
41. Yaris F, Kadioglu M, Kesim M, et al.. Urinary tract infections in unplanned pregnancies and fetal outcome. Eur J Contracept Reprod Health Care. 2004;9:141–146.
42. Hernandez-Diaz S, Werler MM, Walker AM, et al.. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153:961–968.
43. Denoeud-Ndam L, Zannou DM, Fourcade C, et al.. Cotrimoxazole prophylaxis versus mefloquine intermittent preventive treatment to prevent malaria in HIV-infected pregnant women: two randomized controlled trials. J Acquir Immune Defic Syndr. 2014;65:198–206.
44. Dow A, Kayira D, Hudgens MG, et al.. The effect of cotrimoxazole prophylactic treatment on malaria, birth outcomes, and postpartum CD4 count in HIV-infected women. Infect Dis Obstet Gynecol. 2013;2013:340702.
45. Klement E, Pitche P, Kendjo E, et al.. Effectiveness of co-trimoxazole to prevent plasmodium falciparum malaria in HIV-positive pregnant women in sub-Saharan Africa: an open-label, randomized controlled trial. Clin Infect Dis. 2014;58:651–659.
46. Vardi-Saliternik R, Friedlander Y, Cohen T. Consanguinity in a population sample of Israeli Muslim Arabs, Christian Arabs and Druze. Ann Human Biology. 2002;29:422–431.
47. Silberstein E, Silberstein T, Elhanan E, et al.. Epidemiology of cleft lip and palate among Jews and Bedouins in the Negev. Isr Med Assoc J. 2012;14:378–381.
49. Correa A, Cragan JD, Kucik JE, et al.. Reporting birth defects surveillance data 1968-2003. Birth Defects Res A Clin Mol Teratol. 2007;79:65–186.
50. Orenstein LA, Orenstein EW, Teguete I, et al.. Background rates of adverse pregnancy outcomes for assessing the safety of maternal vaccine trials in sub-Saharan Africa. PloS One. 2012;7:e46638.
51. Centers for Disease Control Prevention. Spina bifida and anencephaly before and after folic acid mandate–United States, 1995-1996 and 1999-2000. MMWR Morb Mortal Wkly Rep. 2004;53:362–365.
52. Rankin J, Pattenden S, Abramsky L, et al.. Prevalence of congenital anomalies in five British regions, 1991-99. Arch Dis Child Fetal Neonatal Ed. 2005;90:F374–F379.
53. Venter PA, Christianson AL, Hutamo CM, et al.. Congenital anomalies in rural black South African neonates—a silent epidemic? S Afr Med J. 1995;85:15–20.