Libro aids 1 06.indb

Systematic Review of the Safety of Trimethoprim-
Sulfamethoxazole for Prophylaxis in HIV-Infected Pregnant
Women: Implications for Resource-Limited Settings
Fatu Forna1,2, Michel e McConnel 3,4, Florence N. Kitabire5, Jaco Homsy5, John T. Brooks2, Jonathan
Mermin4,5 and Paul J. Weidle2
1Epidemic Intel igence Service, Division of Applied Public Health Training, Epidemiology Program Office, CDC, Atlanta, GA, USA; 2Division
of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), CDC, Atlanta, GA, USA; 3Thailand Ministry of Public
Health, US CDC Col aboration, Nonthaburi, Thailand; 4Global AIDS Program, NCHSTP, CDC, Atlanta, GA, USA; 5Global AIDS Program,
CDC-Uganda, Uganda Virus Research Institute, Entebbe, Uganda
Abstract
Daily prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) significantly decreases morbidity
and mortality among people living with HIV. Some clinicians are reluctant to use TMP-SMZ in pregnant
and breastfeeding HIV-infected women because of concerns about the possible teratogenicity when
used in the first trimester and about its potential to induce hyperbilirubinemia near term and during
early breastfeeding.
We systematically reviewed evidence regarding the toxicity of TMP-SMZ prophylaxis in pregnant and
breastfeeding women to help guide practice in resource-limited settings. We identified relevant lit-
erature by searching PubMed and MEDLINE via OVID, Embase, and Science Citation Index for data
on hyperbilirubinemia, kernicterus, and teratogenicity associated with administration of sulfonamides
and TMP-SMZ through July 2005. We also reviewed the reference lists of identified articles.
Most studies demonstrated that TMP-SMZ was not associated with hyperbilirubinemia when admin-
istered to mothers during pregnancy and breastfeeding. No cases of kernicterus were reported in
neonates after maternal ingestion of sulfonamides. There is mixed evidence linking ingestion of TMP-
SMZ and other sulfonamides in early pregnancy to elevated risks of oral clefts, neural tube defects,
and cardiovascular and urinary tract abnormalities, although some sources found that supplementa-
tion with folic acid might ameliorate this potential risk. Existing guidelines recommend that HIV-in-
fected pregnant women receive prophylaxis, but they differ with regards to stage of disease at which
to initiate treatment, need for CD4+ T-lymphocyte testing, and prophylaxis during the first trimester.
Existing data indicate that the risk of serious injury to neonates from maternal use of daily TMP-SMZ
prophylaxis during pregnancy and breastfeeding is small. Given the substantial benefits of TMP-SMZ
prophylaxis for HIV-infected women living in resource-limited settings, this review indicates that it is
safe to abide by the WHO guidelines recommending daily TMP-SMZ prophylaxis for HIV-infected
pregnant women. (AIDS Reviews 2006;8:24-36)
Key words
Hyperbilirubinemia. Kernicterus. Trimethoprim. Sulfamethoxazole. Sulfonamide. Pregnancy. HIV.
Correspondence to:
Fatu Forna
Centers for Disease Control & Prevention1600 Clifton Road, MS-E45Atlanta, GA 30333, USAE-mail: [email protected] Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
Introduction
ries, and case reports. Data are presented in the form of a structured summary describing the studies’ char-acteristics and findings and are presented in the ta- Studies of HIV-infected persons in sub-Saharan Af- bles13. A quantitative meta-analysis was not performed rica have demonstrated that daily trimethoprim-sulfa- because of the heterogeneity of the studies evaluated, methoxazole (TMP-SMZ) prophylaxis reduces mortality the treatments used, and the outcomes examined13-14. by 20-46%, and decreases incidence of malaria, bac-
terial pneumonia, and diarrheal il ness as wel as hos- Characteristics
pitalizations1-7. Over half of al persons living with HIV of trimethoprim-sulfamethoxazole
in the world are female. In developing countries, young women 15-24 years of age comprise 64% of people TMP-SMZ is a synthetic antibacterial combination living with HIV or AIDS8. Prior to the widespread use of product that blocks two consecutive steps of folate TMP-SMZ prophylaxis in developed countries, Pneu- metabolism involved in the biosynthesis of nucleic ac- mocystis jiroveci pneumonia (PCP) was a major cause ids and proteins essential to many bacteria and some of morbidity and mortality among HIV-infected patients. parasites12. The recommended dose of TMP-SMZ for Among HIV-infected pregnant women in the USA, mor- prophylaxis in HIV-infected adults, including pregnant tality from PCP was 50% and it accounted for 80% of women, is one double-strength tablet a day (160 mg trimethoprim, 800 mg sulfamethoxazole)15-16. TMP-SMZ TMP-SMZ is classified for use in pregnancy as a can be produced generical y and is available widely in category C drug, indicating that it should be used only resource-limited settings for about US $10 per year17. when the potential benefit exceeds the potential risk11- Both drugs are excreted in low concentrations in hu- 12. Concerns about possible teratogenicity when used man milk and cross the placental barrier reaching peak in the first trimester and induction of hyperbilirubinemia fetal levels within three hours after administration11-12,18. near term and during early breastfeeding have made Fetal levels of sulfamethoxazole and other sulfonamides some clinicians reluctant to prescribe daily TMP-SMZ average 70-90% of maternal levels, and significant levels prophylaxis for HIV-infected pregnant and breastfeed- may persist in the newborn for several days after birth ing women, despite multiple guideline documents rec- when given near term12. Sulfamethoxazole is classified ommending its use in this population. This paper is a as an intermediate-acting sulfonamide with regard to its systematic review of the evidence regarding the toxic- rate of absorption and elimination19. Labeling information ity of TMP-SMZ with regards to its use as prophylaxis for Septra® (trimethoprim-sulfamethoxazole) states that in pregnant and breastfeeding HIV-infected women. “Septra® is contraindicated in pregnant and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus”, and that “Because trimethoprim and sulfamethoxazole may We identified relevant literature by searching PubMed interfere with folic acid metabolism, Septra® should be and MEDLINE via OVID from 1950 to 2005, Embase from used during pregnancy only if the potential benefit justi-1980 to 2005, and Science Citation Index from 1980 to fies the potential risk to the fetus”11. 2005. We used the subject headings “trimethoprim-sul- Reported incidence of adverse reactions to TMP- famethoxazole and pregnancy”, trimethoprim and preg- SMZ in adults and children may be lower among Afri-nancy”, “sulfonamide and pregnancy”, “sulfonamide and cans than among persons living in industrialized na-kernicterus”, and “sulfonamide and hyperbilirubinemia” tions and consist mostly of No part of this publication may be skin eruptions1,2,11,17,20. to perform the computerized literature search. To ensure Severe adverse reactions can include Stevens-John-completeness, we also reviewed the reference lists of al son syndrome, neutropenia, thrombocytopenia, and identified articles. We included only reports that docu- renal or hepatic insufficiency11,15,17,21. TMP-SMZ is con-mented the use of TMP-SMZ, trimethoprim, or any sul- traindicated in patients who have had a severe adverse fonamide in humans during pregnancy, and that report- reaction to the drug or other sulfonamides11,15. It is ed the clinical outcomes of hyperbilirubinemia, kernicterus, recommended that HIV-infected patients with a non- or congenital abnormalities in the infant. life-threatening adverse reaction continue the drug for Forty-six reports fit the criteria and were included in prophylaxis, or have desensitization or reintroduction the systematic review. Reports included randomized at a reduced dose or frequency if the drug has been studies, cohort studies, case-control studies, case se- discontinued22,23. Individuals with glucose-6-phosphate AIDS Reviews 2006;8
Table 1: Altered bilirubin metabolism – Evidence for increased risk
Number of Infants:
Year Author
Report type Exposure period
Treatment
hyperbilirubinemia kernicterus indication / Notes
1941 Heckel33 Sulfanilamide Case series Month 3-8 1942 Ginzler34 Sulfanilamide Case report Case 1: during labor 1956 Silverman35 Sulfisoxazole Randomized Drug given directly Sulfamethoxy- Case report Case 1: 2 weeks before 2 1971 Perkins38 Sulfisoxazole Case report 2 weeks before dehydrogenase (G6PD) deficiency are also suscepti- Neonatal hyperbilirubinemia or jaundice, defined as ble to sulfonamide-induced hemolysis, and there is an total serum bilirubin exceeding 5 mg/dl, occurs in most increased incidence of neonatal hyperbilirubinemia infants and is usual y benign, but may require treat-among infants with G6PD deficiency24,25. ment with phototherapy or exchange transfusion to prevent kernicterus30,31. Hyperbilirubinemia is observed Hyperbilirubinemia and kernicterus
typical y in 60% of ful term and 80% of preterm infants during the first week of life28. Bilirubin concentrations Bilirubin is the end product of heme catabolism, and < 20 mg/dl are general y considered safe for ful term it is bound mostly to albumin with only a smal quan- newborns26,28. Most kernicterus occurs in infants with tity existing freely in plasma. Sulfonamides have an a bilirubin level ≥ 25 mg/dl, although premature infants affinity for albumin and can displace bilirubin, increas- may develop kernicterus at lower levels26,28,29. A 1999 ing the amount of free bilirubin in the plasma26. The review of laboratory records of more than 50,000 Cali-glucuronyl transferase system that conjugates most fornia newborns found that 2% had total serum bilirubin bilirubin for excretion is immature in neonates, espe- levels > 20 mg/dl; 0.15% > 25 mg/dl; and only 0.01% cial y premature neonates, thus predisposing them to > 30 mg/dl32. As many as a No part of this publication may be third of infants with un- hyperbilirubinemia27,28. Kernicterus is a neurologic syn- treated hemolytic disease and serum bilirubin levels > drome that results from deposition of free bilirubin in 20 mg/dl may develop kernicterus24.
neuronal tissues of the central nervous system26,28,29.
Clinical manifestations include loss of the Moro reflex, Altered bilirubin metabolism –
a weak suck, poor feeding, lethargy, vomiting, a high- Evidence for increased risk
pitched cry, fever, seizures, and muscle rigidity26-28.
Mortality rates of up to 70% have been reported in The first case reports describing neonatal hyperbiliru- symptomatic infants, and those who survive usual y binemia after maternal ingestion of sulfonamides ap-have serious neurologic sequelae including hearing peared in 1941 and 194233,34 (Table 1). A 1956 random-loss, seizures, and mental deficiency26-29.
ized trial of two prophylactic antibacterial regimens Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
administered to premature infants demonstrated higher fant), and blood group incompatibility (one infant); again rates of kernicterus and mortality among 95 infants treat- no evidence of kernicterus was observed46.
ed with a combination of penicil in and subcutaneous A 1979 study of five patients with ulcerative colitis who sulfisoxazole compared to 97 infants treated with oxytet- became pregnant during treatment with oral sulfasala-racycline35. Further concern was raised in 1964 by a zine and who were maintained on therapy throughout report of jaundice in the newborns of nine women who their pregnancies noted that sulfasalazine was present had received daily oral doses of sulphamethoxypyrida- in cord blood and breast milk, but that the use of the zine as antibiotic prophylaxis after premature rupture of drug did not adversely affect their infants47. A 1981 membranes36. The authors noted that sulfonamides, es- study on the placental transfer of sulfasalazine among pecial y long-acting sulfonamides such as sulphame- 11 pregnant women with inflammatory bowel disease thoxypyridazine, may be dangerous to the newborn and who were administered the drug daily reported no ad-should not be administered to women during pregnancy verse events in their infants48. In 1981 the same author or to infants during the first week of life. In 1965 maternal reported on an additional 12 pregnant women with in-ingestion of sulfamethoxypyridazine near term was also flammatory bowel disease who were treated with daily reported to cause jaundice in two infants with G6PD sulfasalazine and noted that their newborn infants were deficiency37. Final y, a case report in 1971 described the “al healthy”49. A 1981 survey of American gastroenter-stil birth of a male fetus born to a G6PD-deficient mother, ologists evaluating the experience of 174 women who possibly related to maternal sulfisoxazole ingestion for a received sulfasalazine and corticosteroids for inflamma-urinary tract infection two weeks before delivery38.
tory bowel disease throughout their pregnancies, found that none of their infants developed jaundice50. A 1981 Altered bilirubin metabolism –
case series of eight pregnant women treated with sul- Evidence for safety
fasalazine for ulcerative colitis also found that none of their infants developed jaundice51. In 1938 two studies reported the cases of 34 women In 1987 a study of 15 infants born to mothers with in- given sulfanilamide during labor and noted no adverse flammatory bowel disease who received sulfasalazine events in their infants39,40 (Table 2). Another 1938 study during pregnancy and lactation reported no cases of of 19 pregnant women treated with a five-day course of kernicterus and two cases of hyperbilirubinemia, neither sulfanilamide for gonorrhea reported that there were of which required treatment52. In 1989 a report on the no “harmful effects” on the baby41. A 1959 study of treatment of 43 cases of Toxoplasma infection throughout 17 women treated with sulfadimethoxine reported no pregnancy with spiramycin, pyrimethamine, and sulfon-adverse events in their infants42. In 1961 a study of amides found that “no neonatal complications could be 44 mothers given oral sulfisoxazole during labor re- at ributed to prenatal treatment with sulfonamides”53. In ported no episodes of hyperbilirubinemia or kernic- 2003 a Danish report found no association between the terus43. A 1976 study of 46 women given sulfadimidine use of sulfamethizole late in pregnancy in 40 women and during labor also found that bilirubin levels were not risk of neonatal jaundice54. Final y, case-reports have de-significantly altered in their infants44. scribed treatment of PCP in two pregnant women with A 1965 review of the clinical records of 100 infants TMP-SMZ, and treatment of toxoplasmosis in two preg- born to mothers with a history of rheumatic fever receiv- nant women with sulfadiazine55-58. The women delivered ing sulfadiazine prophylaxis throughout their pregnan- viable infants who were discharged home within one cies, identified seven infants with jaundice that was at- week of delivery, but no specific information was given tributed to “physiologic” reasons (four infants), and blood about the presence or absenc No part of this publication may be e of hyperbilirubinemia. group incompatibility (three infants); they observed no
evidence of kernicterus45. The authors concluded that Congenital abnorm
reproduced or photocopying alities -
antenatal sulfadiazine prophylaxis was not associated Evidence for increased risk
with an increased incidence of prematurity, hyperbiliru-
binemia, or kernicterus. A later investigation by the same A 1971 case-control study of 458 mothers of infants authors in 1980 of an additional 94 infants born to moth- with congenital abnormalities found an increased risk of ers with a history of rheumatic fever receiving sulfadia- congenital anomalies associated with maternal ingestion zine prophylaxis during pregnancy identified nine cases of sulfonamides throughout pregnancy59 (Table 3). This of neonatal jaundice that they attributed to “physiologic” study also found an increased risk of congenital ab-reasons (seven infants), Rhesus incompatibility (one in- normalities associated with maternal ingestion of aspi- AIDS Reviews 2006;8
Table 2: Altered bilirubin metabolism – Evidence for safety
Number of infants:
Report type
Exposure period
Treatment
hyperbiliru- kernicterus indication /
Sulfadi-methoxine Pharmaco-kinetic study During labor rin, antacids, nicotinamide, iron, and other common of Congenital Abnormalities Study, found an increased drugs. A 1975 case-control study of 599 Finnish chil- risk of cardiovascular and urinary tract malformations dren with cleft lip reported an association between oral among infants whose mothers ingested TMP-SMZ in the clefts with “additional malformations” and maternal in- second and third month of pregnancy, and cardiovascu-gestion of sulfonamides in the first and second trimes- lar malformations among infants whose mothers ingested ter of pregnancy60. Other agents associated with oral trimethoprim-sulfamethazine in the second and third clefts in this study included iron, vitamins, salicylates, months of pregnancy63. A protective ef ect against the penicil in, and anticonvulsants. malformations was associated with taking high doses of A 2000 case-control study that included 6932 infants folic acid (6 mg/d) with TMP-SMZ. An evaluation of 22,843 with congenital abnormalities found that consumption of infants with congenital abnormalities from the same data-dihydrofolate reductase inhibitors (trimethoprim, triam- base in 2004 found a higher r No part of this publication may be ate of cardiovascular mal- terene, and sulfasalazine) in the second or third month of formation and clubfoot in infants born to mothers who in-pregnancy was associated with increased risk of oral gested dif erent sulfonamides in the second and third clefts and cardiovascular defects, and that folic acid months of pregnancy64. In 2001 a report on a study of 195 supplementation might reduce these risks61. A 2001 case- HIV-infected women with first trimester exposure to the control study by the same authors of 1242 infants with combination of antiretroviral therapy and folate antago-neural-tube defects found that trimethoprim was also as- nists also found that exposure to both agents was associ- sociated with increased risk of neural-tube defects when ated with an increased risk of congenital abnormalities65.
taken in the first trimester62. In 2001 an evaluation of A 1966 report described limb defects and multiple 22,865 women with newborns or fetuses with congenital other abnormalities in an infant whose mother ingested abnormalities in the Hungarian Case-Control Surveil ance sulfaguanidine during the seventh week of pregnan- Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
Table 3: Congenital abnormalities – Evidence for increased risk
Year Author
Report type
Exposure Participants
Main findings
“limb defects”, “heart defects”, Case-control Throughout 458 mothers of infants with major pregnancy and minor congenital abnormalities; of infants with major abnormalities took sulfonamides ( p < 0.05) – “additional malformations” and their “additional malformations” took sulfonamides (p < 0.05) – Throughout Mother with ulcerative colitis receiving Infant died 10 minutes after birth; Throughout Three infants born to two mothers pregnancy with inflammatory bowel disease receiving daily sulfasalazine therapy died at 10 days of age and had Throughout Mother received daily sulfasalazine pregnancy therapy for ulcerative colitis 2000 Richardson70 Case 1: TMP-SMZ, Case report Throughout Two mothers receiving antiretrovirals Case 1: Infant born with lumbar spine Case-control Trimester 1 1242 infants with neural-tube defects Higher proportion of mothers of No part of this publication may be others versus 8/6660 (0.1%) reproduced or photocopying of infants with cardiovascular and AIDS Reviews 2006;8
Table 3: Congenital abnormalities – Evidence for increased risk (continued)
Year Author
Report type
Exposure Participants
Main findings
Folate antagonists Cohort study Trimester 1 195 HIV-infected mothers RR: relative risk; OR: odds ratio; CI: Confidence interval; POR: Prevalence odds ratio.
cy66. From 1980 to 1988, three case reports described ed with placebo during al trimesters of pregnancy five cases of multiple congenital abnormalities in the found four cases of congenital abnormalities in the offspring of women who received daily sulfasalazine TMP-SMZ group and three cases in the placebo therapy for inflammatory bowel disease throughout group72,73 (Table 4). A 1969 case-control study of 833 their pregnancies67-69. Reported abnormalities included mothers of infants with congenital abnormalities in an infant with cleft lip, cleft palate, and hydrocepha- Wales found no association between maternal inges-lus67; stil born twins, both with urinary tract abnormali- tion of sulfonamides throughout pregnancy and any ties and one with coarctation of the aorta and a ven- type of congenital abnormalities74. A 1971 case report tricular septal defect68; and an infant with coarctation described a pregnant woman with actinomycosis treat-of the aorta, a ventricular septal defect, and macro- ed daily with TMP-SMZ through eight months gestation, cephaly69. In 2000 a report described two cases of who gave birth to a normal, healthy infant75.
HIV-positive women treated with daily TMP-SMZ and A 1983 study of 44 women comparing single-dose to antiretrovirals who had offspring with abnormalities that five-day treatment with TMP-SMZ for bacteriuria during the included lumbar hemivertebra, ventriculomegal y, and first trimester of pregnancy described no congenital ab-spina bifida70. Final y, a 2002 report described caudal normalities in their infants, but No part of this publication may be reported one stilbirth in a regression syndrome in a fetus whose mother had woman treated for five days76,77. In 1990 evaluation of data been treated in the first trimester with TMP-SMZ and from 6228 mothers of infants with abnormalities in the erythromycin, and who had also been treated with Hungarian Case-Control Surveil ance of Congenital Anom-topical minoxidil before and throughout pregnancy71.
alies Study found no evidence of teratogenicity associated with maternal TMP-SMZ use78. An evaluation of the 22,865 Congenital abnormalities -
infants or fetuses with congenital abnormalities from the Evidence for safety
same database in 2001 also found no evidence of in-creased prevalence of congenital abnormalities associ- A 1969 report comparing infants of 120 women treat- ated with maternal sulfasalazine use79. In 1996 a study of ed for bacteriuria with TMP-SMZ and 66 women treat- 110 infants with gastroschisis from the California Birth Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
Table 4: Congenital Abnormalities – Evidence for safety
Report type
Exposure
Participants
Main findings
First trimester: 4/833 (0.5%) case-mothers No statistical measure of association noted 44 women randomly assigned One stil birth in group treated with 5-day to treatment with either single course, no congenital abnormalities 6228 mothers of infants with Higher proportion of mothers of infants TMP-SMZ (p < 0.01), but authors 110 infants with gastroschisis No association between maternal ingestion ingestion of sulfasalazine and congenital Ratanajmit54 Sulfamethizole Cohort Study 30 days before conception to end prescription in first trimester or prescription for sulfamethizole and congenital abnormalities found (OR 1.17, 60,175 mothers who did not 95% CI 0.95-1.43) – 101/2173 (4.6%) Defects Monitoring Program found no association be- congenital abnormality54. Final y, reports have provided tween maternal ingestion of sulfonamides and gastroschi- evidence of the safety of sulfadoxine-pyrimethamine use sis80. In 2003 a cohort study in Denmark found no asso- during the second and third trimesters of pregnancy for ciation between maternal sulfamethizole ingestion and intermit ent preventive treatment of malaria81-85.
AIDS Reviews 2006;8
Table 5 – Guidelines providing recommendations for use of trimethoprim-sulfamethoxazole as prophylaxis against opportu-
nistic infections for HIV-infected women during pregnancy
Trimester
Use During CD4 Count Criteria
Clinical Criteria
Drug regimen
Comment on risk/benefit
Breastfeeding
of TMP-SMZ
Al asymptomatic HIV-positive Al adults with adults (age > 13years) with symptomatic HIV (i) Al adults and adolescents (i) History of strength tablets three associated with drug (b) persons with CD4+ cel with history of an strength tablet daily may choose to withhold count < 250/µl in set ings AIDS-defining il ness Immunocompromised women “Immunocompromised” “According to usual “TMP-SMZ is relatively One double-strength “There is a very smal Presence of clinical Two single-strength None No specific clinical One double-strength None TMP-SMZ: Trimethoprim/sulfamethoxazole; PCP – Pneumocystis jiroveci pneumonia* Same study reported in 2 articles Existing guidelines
They differ, however, with regards to stage of disease at initiation of prophylaxis, need for CD4+ T-lympho- Existing guidelines recommend that HIV-infected preg- cyte testing, and administration during the first trimes- nant women receive TMP-SMZ prophylaxis (Table 5). ter. For persons living with HIV/AIDS in Africa, pro- Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
visional recommendations from the World Health not in utero, exposure to the drug among premature Organization (WHO) are that TMP-SMZ prophylaxis be infants who are highly susceptible to hyperbilirubine-offered as primary prophylaxis to al HIV-positive adults mia35. Multiple other studies have shown that the use with symptomatic HIV disease (WHO stage 2, 3, or 4), of sulfonamides is not associated with hyperbilirubine-asymptomatic individuals who have a CD4+ T-lympho- mia when taken by mothers during pregnancy and cyte count ≤ 500, and pregnant women after the first when breastfeeding39-53. We found no reports of neo-trimester15. natal kernicterus attributable to maternal ingestion of The United States Public Health Service (USPHS) sulfonamides. and Infectious Diseases Society of America (IDSA) rec- There is mixed evidence linking ingestion of TMP- ommend that HIV-infected pregnant women with a SMZ and other sulfonamides in early pregnancy to CD4+ T-lymphocyte count of < 200/µl or a history of elevated risks of oral clefts, neural tube defects, and oropharyngeal candidiasis receive PCP prophylaxis. cardiovascular and urinary tract abnormalities. Limited However, USPHS/IDSA guidelines for pregnant women data suggest that supplementation with folic acid may note that providers may choose to withhold prophy- ameliorate this risk. The available information is com-laxis during the first trimester, in which case aerosol- plicated by inability of some large studies to differenti-ized pentamidine may be considered22. USPHS/IDSA ate between women who took TMP-SMZ or other sul-further recommends that children born to HIV-infected fonamides early in pregnancy during organogenesis mothers begin primary prophylaxis with TMP-SMZ at and those who took the drugs later in pregnancy after about 4-6 weeks of age. Canadian consensus guide- completion of organogenesis. Additional y, smal er lines for the management of HIV-positive pregnant studies may have insufficient sample sizes to detect women recommend PCP prophylaxis for women with rare events. As several large-scale studies have found CD4+ T-lymphocyte count ≤ 200/µl86. differing results, the potential teratogenicity of TMP- For resource-limited communities, the Columbia SMZ is stil uncertain, but the drug likely poses at least Clinical Manual recommends giving TMP-SMZ to al a minimal risk. pregnant women with i) WHO stage 3 or 4 disease, It is unlikely that a definitive trial wil be performed in irrespective of CD4+ T-lymphocyte count; i ) a CD4+ sub-Saharan Africa evaluating the safety of daily TMP-T-lymphocyte count ≤ 200/µl irrespective of WHO SMZ prophylaxis during pregnancy or during breast-stage; or i i) al patients with previously diagnosed feeding. It would be operational y chal enging in re-PCP16. The South African Department of Health policy source-limited settings to establish capacity to perform guidelines recommend PCP prophylaxis with TMP-SMZ serial bilirubin determinations, to provide phototherapy for pregnant women with CD4+ T-lymphocyte counts and exchange transfusions when needed, to train and < 200/µl or with clinical signs of advanced immune outfit pathologists to diagnose kernicterus postmortem, deficiency87. Uganda’s national policy guidelines rec- and to maintain registries to detect rare outcomes such ommend prophylaxis be given to al HIV-positive preg- as congenital abnormalities potential y related to first nant women after the first trimester, regardless of CD4+ trimester in utero exposure to a teratogen. We must T-lymphocyte count, noting that HIV-positive pregnant rely therefore on the existing evidence to make deci-women should not be given concurrent sulfadoxine- sions about TMP-SMZ use for prophylaxis in HIV-in-pyrimethamine therapy for malaria since TMP-SMZ is fected pregnant women.
effective for malaria prophylaxis17.
Some guidelines recommend TMP-SMZ use for pro- phylaxis in HIV-infected pregnant women only after the Discussion
No part of this publication may be tinued concern about its potential teratogenicity15,17. Others, however, do not Reports documenting the association of hyperbiliru- address first trimester use86,87, leave it up to the clinical binemia and kernicterus with sulfonamide use during judgment of the provider22, or recommend use through-pregnancy are derived mostly from smal studies and out pregnancy including the first trimester16. The deci- retrospective case series that examined sulfonamides sion to use TMP-SMZ in the first trimester for prophy-other than sulfamethoxazole, or that did not differenti- laxis should weigh the potential risk for teratogenicity ate the effects of sulfonamides from other causes of against the potential morbidity associated with PCP hyperbilirubinemia33-38. The often-cited study by Silver- and other infections in pregnancy. Given the mixed man that found increased risk of mortality and kernic- evidence linking ingestion of TMP-SMZ to congenital terus associated with sulfisoxazole involved postnatal, abnormalities, use in the first trimester should target AIDS Reviews 2006;8
women at highest risk for HIV-related il ness (such as efits of TMP-SMZ prophylaxis for HIV-infected women
those with CD4+ cel counts < 200, those with clinical living in resource-limited settings, this review indicates
evidence of advanced disease, or those who have that it is safe to abide by the WHO guidelines recom-
been previously diagnosed with PCP). The benefit of mending daily TMP-SMZ prophylaxis for HIV-infected
improved morbidity and mortality with TMP-SMZ pro- pregnant women.
phylaxis among these high-risk women may outweigh
the smal risk to the fetus. Women who become preg- Acknowledgements
nant while taking TMP-SMZ at prophylactic dosages
should be counseled that the potential risk of teratoge-
We are grateful to Dr. Monica Parise, Dr. Philip Pe- nicity is smal . Given that trimethoprim and sulfa- ters, and Dr. Kwame Asamoa for reviewing the manu-
methoxazole are known antagonists of folic acid, the script and offering very useful comments and advice.
usual recommendation of periconceptional folic acid
supplementation should be especial y emphasized for Disclaimer
women on TMP-SMZ prophylaxis.
Few guidelines recommending TMP-SMZ use for The findings and conclusions from this review are prophylaxis in HIV-infected pregnant women specifi- those of the authors and do not necessarily represent
cal y address use during the third trimester and during the views of the Centers for Disease Control and Pre-
breastfeeding16. Multiple studies have shown that the vention.
risk of hyperbilirubinemia and kernicterus secondary to
TMP-SMZ prophylaxis is very low, and that the benefits References
of use greatly outweigh the risks in HIV-infected preg-nant women. For HIV-infected women in developing 1. Mermin J, Lule J, Ekwaru J, et al. Effect of co-trimoxazole prophy-countries who may elect to breastfeed when no safe, laxis on morbidity, mortality, CD4-cel count, and viral load in HIV infection in rural Uganda. Lancet 2004;364:1428-34.
affordable alternatives are available, daily TMP-SMZ 2. Chintu C, Bhat G, Walker A, et al. Co-trimoxazole as prophylaxis prophylaxis should be at least as safe as in utero ex- against opportunistic infections in HIV-infected Zambian children posure and likely safer, since both trimethoprim and (CHAP): a double-blind randomized placebo-control ed trial. Lancet 2004;364:1865-71.
sulfamethoxazole are excreted only in low concentra- 3. Zachariah R, Spielmann M, Chinji C, et al. Voluntary counseling, tions in breast milk. Guidelines should therefore dispel HIV testing and adjunctive co-trimoxazole reduces mortality in tu-berculosis patients in Thyolo, Malawi. AIDS 2003;17:1053-61.
ambiguity by clearly encouraging continued prophy- 4. Badri M, Ehrlich R, Wood R, Maartens G. Initiating co-trimoxazole lactic use of TMP-SMZ by HIV-infected women in the prophylaxis in HIV-infected patients in Africa: an evaluation of the third trimester and during breastfeeding.
provisional WHO/UNAIDS recommendations. AIDS 2001;15:1143-8.
5. Anglaret X, Chene G, Attia A, et al. Early chemoprophylaxis with TMP-SMZ for HIV-1-infected adults in Abidjan, Cote d’Ivoire: a ran- Conclusion
domized trial. Lancet 1999;353:1463-8.
6. Wiktor S, Sassan-Morokro M, Grant A, Maurice C, et al. Efficacy of TMP-SMZ prophylaxis to decrease morbidity and mortality in HIV- TMP-SMZ prophylaxis can provide substantial ben- 1-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a efits for HIV-infected pregnant women; recent data randomized control ed trial. Lancet 1999;353:1469-75.
7. Kaplan J, Hu D, Holmes K, Jaffe H, Masur H, De Cock K. Prevent- from Zambia indicate significantly improved birth out- ing opportunistic infections in HIV-infected persons: implications for comes among HIV-infected pregnant women with the developing world. Am J Trop Med Hyg 1996;55:1-11.
CD4+ cel counts < 200 who receive routine TMP-SMZ 8. UNAIDS. Women, Girls, HIV and AIDS – World AIDS Campaign 2004. Available at: http:/www.unaids.org/ prophylaxis88. Pregnancy poses a special chal enge 9. Ahmad H, Mehta N, Manikal V, et al. Pneumocystis carini pneumo-for HIV-infected women, as clinicians must weigh the No part of this publication may be 0:666-71.
benefits of drugs used to treat HIV disease against 10. Koonin L, El erbrock T, Atrash H, et al. Pregnancy-associated deaths due to AIDS in the United States. JAMA 1989;261:1306-9.
the potential harm their use poses to the fetus. Prophy- 11. Anonymous. Product information: Septra brand of TMP-SMZ. King laxis against PCP and other opportunistic infections is Pharmaceuticals, Inc., Bristol, TN, Rev 2/00.
12. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation: an important component of HIV/AIDS care that should a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Wil- be made available to al eligible HIV-infected individu- liams and Wilkins, 1998:986-90,1061-3.
als, including pregnant women. For HIV-infected preg- 13. Higgins J, Green S, editors. Analysing and presenting results. Co- chrane Handbook for Systematic Reviews of Interventions 4.2.5 nant women, the substantial benefits of TMP-SMZ pro- [updated May 2005]; Section 8. http://www.cochrane.org/resources/ phylaxis should be considered in conjunction with handbook/hbook.htm (accessed November 2005).
the operational limitations of interrupting prophylaxis 14. O’Rourke K, Detsky A. Meta-analysis in medical research: strong encouragement for higher quality in individual research efforts. J around term. Given the comparatively substantial ben- Fatu Forna, et al.: Trimethoprim-Sulfamethoxazole Prophylaxis in HIV-Infected Pregnant Women
15. UNAIDS/WHO. Provisional WHO/UNAIDS Secretariat recommenda- 39. Speert H. The passage of sulfanilamide through the human pla- tions on the use of co-trimoxazole prophylaxis in adults and children centa. Bul Johns Hopkins Hosp 1938;63:337-9.
living with HIV/AIDS in Africa. Available at: http://www.unaids.org/ 40. Barker R. The placental transfer of sulfanilamide. New Engl J Med 16. International Center for AIDS Care and Treatment Programs at Co- lumbia University. The Columbia Clinical Manual: Care and Treat- 41. Bomze E, Fuerstner P, Fal s F. Use of a sulfanilamide derivative in ment of HIV during Pregnancy. Available at: http://www.mtctplus.
the treatment of gonorrhea in pregnant and non-pregnant women. 17. Ministry of Health, Republic of Uganda. National policy guidelines for 42. Lucey J, Driscol T. Hazard to newborn infants of administration of co-trimoxazole prophylaxis for people with HIV/AIDS. March 2005. long-acting sulfonamides to pregnant women. Pediatrics 1959; 18. Reid D, Cail e G, Kaufmann N. Maternal and transplacental kinetics of trimethoprim and sulfamethoxazole, separately and in combina- 43. Kantor H, Sutherland D, Leonard J, Kamholz J, Fry N, White W. Effect on bilirubin metabolism in the newborn of sulfisoxazole ad- 19. American Society of Health-System Pharmacists. AHFS Drug infor- ministered to the mother. Obstet Gynecol 1961;17:494-500.
44. Drew J, Kitchen W. The effect of maternal y administered drugs 20. Maynart M, Lievre L, Sow P, et al. Primary prevention with co-tri- on bilirubin concentrations in the newborn infant. J Pediatr 1976; moxazole for HIV-1-infected adults: Results of the pilot study in Dakar, Senegal. J Acquir Immune Defic Syndr Hum Retrovirol 45. Morgan A, Wenger N. Sulfadiazine prophylaxis against rheumatic fever during pregnancy: its safety as regards the infant. JMA Geor- 21. Fisk D, Meshnick S, Kazanjian P, et al. Pneumocystis carini pneu- monia in patients in the developing world who have AIDS. Clin Infect 46. Baskin C, Law S, Wenger N. Sulfadiazine rheumatic fever prophy- laxis during pregnancy: does it increase the risk of kernicterus in 22. US Public Health Service and the Infectious Diseases Society of the newborn? Cardiology 1980;65:222-5.
America. 2001 USPHS/IDSA guidelines for preventing opportunistic 47. Khan A, Truelove S. Placental and mammary transfer of sulphasala- infections in persons infected with HIV. Available at: http://aidsinfo.
48. Jarnerot G, Andersen S, Esbjorner E, Sandstrom B, Brodersen R. 23. Para M, Finkelstein D, Becker S, et al. Reduced toxicity with grad- Albumin reserve for binding of bilirubin in maternal and cord serum ual initiation of TMP-SMZ as primary prophylaxis for Pneumocystis under treatment with sulphasalazine. Scand J Gastroenterol carini pneumonia: AIDS Clinical Trials Group 268. J Acquir Immune Defic Syndr Hum Retrovirol 2000;24:337-43.
49. Jarnerot G, Into-Malmberg M, Esbjorner E. Placental transfer of 24. Beutler E. G6PD Deficiency. Blood 1994;84:3613-36.
sulphasalazine and sulphapyridine and some of its metabolites. 25. Beutler E. G6PD: Population genetics and clinical manifestations: Scand J Gastroenterol 1981;16:693-7.
50. Mogadam M, Dobbins W, Korelitz B, Ahmed S. Pregnancy in inflam- 26. Walker P. Neonatal bilirubin toxicity: A review of kernicterus and the matory bowel disease: effect of sulfasalazine and corticosteroids implications of drug-induced bilirubin displacement. Clin Pharma- on fetal outcome. Gastroenterology 1981;80:72-6.
51. Levy N, Roisman I, Teodor I. Ulcerative colitis in pregnancy in Is- 27. Morgan A, Wenger N. Sulfadiazine prophylaxis against rheumatic rael. Dis Col & Rect 1981;24:351-4.
fever during pregnancy: its safety as regards the infant. JMA Geor- 52. Esbjorner E, Jarnerot G, Wranne L. Sulphasalazine and sulpha- pyridine serum levels in children to mothers treated with sulphasala- 28. Behrman R, Kliegman R, Jenson H, eds. Nelson Textbook of Pedi- zine during pregnancy and lactation. Acta Paediatr Scand atrics. 17th ed. Philadelphia: Saunders, 2004:592-9.
29. Ip S, Chung M, Kulig J, et al. An evidence-based review of impor- 53. Hohlfeld P, Daffos F, Thul iez P, et al. Fetal toxoplasmosis: outcome tant issues concerning neonatal hyperbilirubinemia. Pediatrics of pregnancy and infant fol ow-up after in utero treatment. J Pediatr 30. American Academy of Pediatrics, subcommittee on hyperbilirubine- 54. Ratanajamit C, Skriver M, Norgaard M, Jepsen P, Schoenheyder H, mia. Management of hyperbilirubinemia in the newborn infant 35 or Sorensen H. Adverse pregnancy outcome in users of sulfamethizole more weeks of gestation. Pediatrics 2004;114:297-316.
during pregnancy: a population-based observational study. J Anti- 31. Porter M, Dennis B. Hyperbilirubinemia in the term newborn. Am 55. Hedriana H, Mitchel J, Brown G, Wil iams S. Normal fetal outcome 32. Newman T, Escobar G, Gonzalez V, et al. Frequency of neonatal in a pregnancy with central nervous system toxoplasmosis and HIV bilirubin testing and hyperbilirubinemia in a large health mainte- infection. J Reprod Med 1993;38:747-50.
nance organization. Pediatrics 1999;104:1198-203.
56. Albino J, Shapiro J. Respiratory failure in pregnancy due to Pneu- 33. Heckel G. Chemotherapy during pregnancy. Danger of fetal injury mocystis carini : Report of a successful outcome. Obstet Gynecol from sulfanilamide and its derivatives. JAMA 1941;117:1314-6.
34. Ginzler A, Cherner C. Toxic manifestations in the newborn infant 57. Hicks M, Nolan G, Maxwel S, Mickle C. AIDS and Pneumocystis fol owing placental transmission of sulfanilamide. With a report of 2 carini infection in a pregnant woman. Obstet Gynecol 1990; cases simulating erythroblastosis fetalis. Am J Obstet Gynecol 58. Pajor A. Pancytopenia in a patient given pyrimethamine and sul- 35. Silverman W, Andersen D, Blanc W, Crozier D. A difference in phamethoxidiazine during pregnancy. Arch Gynecol Obstet 1990; mortality rate and incidence of kernicterus among premature infants al otted to two prophylactic antibacterial regimens. Pediatrics 59. Nelson M, Forfar J. Associations between drugs administered dur- ing pregnancy and congenital abnormalities of the fetus. Brit Med 36. Dunn P. The possible relationship between the maternal administra- tion of sulphamethoxypyridazine and hyperbilirubinaemia in the 60. Saxen I. Associations between oral clefts and drugs taken during newborn. J Obstet Gynaecol Br Comm 1964;71:128-31.
37. Brown A, Cevik N. Hemolysis and jaundice in the newborn fol owing 61. Hernandez-Diaz S, Werler M, Walker A, Mitchel A. Folic acid an- maternal treatment with sulfamethoxypyridazine. Pediatrics tagonists during pregnancy and the risk of birth defects. New Engl 38. Perkins R. Hydrops fetalis and stil birth in a male glucose-6-phos- 62. Hernandez-Diaz S, Werler M, Walker A, Mitchel A. Neural tube phate dehydrogenase-deficient fetus possibly due to maternal in- defects in relation to use of folic acid antagonists during preg- gestion of sulfisoxazole. Am J Obstet Gynecol 1971;111:379-81.
AIDS Reviews 2006;8
63. Czeizel A, Rockenbauer M, Sorensen H, Olsen J. The teratogenic 78. Czeizel A. A case-control analysis of the teratogenic effects of co- risk of trimethoprim-sulfonamides: A population based case-control trimoxazole. Reproduct Toxicol 1990;4:305-13.
study. Reproduct Toxicol 2001;15:637-46.
79. Torfs C, Katz E, Bateson T, Lam P, Curry C. Maternal medications 64. Czeizel A, Puho E, Sorensen H, Olsen J. Possible association and environmental exposures as risk factors for gastroschisis. between different congenital abnormalities and use of different sulfonamides during pregnancy. Congenital Anomalies 2004; 80. Norgard B, Czeizel A, Rockenbauer M, Olsen J, Sorensen H. Pop- ulation-based case control study of the safety of sulfasalazine use 65. Jungmann E, Mercey D, DeRuiter A, et al. Is first trimester expo- during pregnancy. Aliment Pharmacol and Ther 2001;15:483-6.
sure to the combination of antiretroviral therapy and folate an- 81. Schultz L, Steketee R, Macheso A, Kazembe P, Chitsulo L, Wirima tagonists a risk factor for congenital abnormalities? Sex Transm J. The efficacy of antimalarial regimens containing sulfadoxine-py- rimethamine and/or chloroquine in preventing peripheral and pla- 66. Pogorzelska E. A case of multiple congenital anomalies in a child of a cental Plasmodium falciparum infection among pregnant women in mother treated with sulfaguanidine. Patologia Polska 1966;17:383-6.
Malawi. Am J Trop Med Hyg 1994;51:515-22.
67. Craxi A, Pagliarel o F. Possible embryotoxicity of sulfasalazine. Ar- 82. Parise M, Ayisi J, Nahlen B, et al. Efficacy of sulfadoxine-pyrimeth- chives of Internal Medicine 1980;140:1674.
amine for prevention of placental malaria in an area of Kenya with 68. Newman N, Correy J. Possible teratogenicity of sulphasalazine. a high prevalence of malaria and HIV infection. Am J Trop Med Hyg 69. Hoo J, Hadro T. Possible teratogenicity of sulfasalazine. New Engl 83. Newman R, Parise M, Slutsker L, Nahlen B, Steketee R. Safety, efficacy and determinants of effectiveness of antimalarial drugs 70. Richardson M, Osrin D, Donaghy S, Brown N, Hay P, Sharland M. during pregnancy: implications for prevention programs in Plasmo- Spinal malformations in the fetuses of HIV-infected women receiving dium falciparum-endemic sub-Saharan Africa. Trop Med Int Health combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reproduct Biol 2000;93:215-7.
84. Sowunmi A, Akindele J, Omitowoju G, Omigbodun O, Oduola A, 71. Rojansky N, Fasouliotis S, Ariel I, Nadjari M. Extreme caudal agenesis: Salako L. Intramuscular sulfadoxine-pyrimethamine in uncompli- possible drug-related etiology? J Reproduct Med 2002;47:241-5.
cated chloroquine-resistant falciparum malaria during pregnancy. 72. Wil iams J, Condie A, Brumfitt W, Reeves D. The treatment of bac- Trans Roy Soc Trop Med Hyg 1993;87:472.
teriuria in pregnant women with sulphamethoxazole and trime- 85. Shulman C, Dorman E, Cut s F, et al. Intermit ent sulphadoxine-pyri- thoprim. Postgrad Med J 1969;45(Suppl):71-6.
methamine to prevent severe anemia secondary to malaria in preg- 73. Brumfitt W, Pursel R. TMP-SMZin the treatment of urinary infection. nancy: a randomized placebo control ed trial. Lancet 1999;353:632-6.
86. Burdge D, Money D, Forbes J, et al. Canadian consensus guide- 74. Richards I. Congenital malformations and environmental influences lines for the management of pregnancy, labor and delivery and for in pregnancy. Brit J Prev Soc Med 1969;23:218-25.
postpartum care in HIV-positive pregnant women and their offspring 75. Ochoa A. Trimethoprim and sulfamethoxazole in pregnancy. JAMA (summary of 2002 guidelines). CMAJ 2003;168:1671-4.
87. South African Department of Health. Strategies to reduce mother to 76. Bailey R, Bishop V, Peddie B. Comparison of single dose with a child HIV transmission during pregnancy and childbirth. Available 5-day course of co-trimoxazole for asymptomatic (covert) bacteri- at: http://www.doh.gov.za/aids/docs.html.
uria of pregnancy. Austr NZ J Obstet Gynaecol 1983;23:139-41.
88. Walter J, Mwiya M, Scott N, et al. Cotrimoxazole prophylaxis and 77. Bailey R. Single-dose antibacterial treatment for bacteriuria in preg- adverse birth outcomes among HIV-infected women in Lusaka, Zambia [abstract 126]. Presented at: 13th CROI, 2006; Denver.

Source: http://www.aidsreviews.com/files/2006_08_1_024-036.pdf