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Home > Topics > Emerging Issues > ARV Exposure & Birth Defects
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In Utero Exposure to Antiretroviral Drugs and Birth Defects: A Brief Review of the Evidence

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As worldwide access to antiretroviral treatment (ART) and prophylaxis for the prevention of mother-to-child transmission (PMTCT) of HIV increases, so does concern that the use of antiretroviral (ARV) drugs during pregnancy could result in congenital anomalies and long-term malignancies in children who are exposed in utero.

The precise number of HIV-infected pregnant women who have received one or more ARV drugs during pregnancy is not known, but it is estimated that <10% of such women worldwide receive ART or ARV prophylaxis.( 1 ) If this figure is correct, then approximately 1.2 million infants are exposed to ARV drugs annually. At a minimum, such exposure would consist of a single dose of nevirapine given to the mother at the onset of labor and a single dose given to the infant within 72 hours of delivery. Maximum exposure would occur when a mother conceives while receiving combination ART and remains on treatment throughout her pregnancy. In such cases, her infant would most likely receive prophylaxis in the postnatal period and, if the infant were breast-fed, he or she would be exposed to ARV drugs though breast milk as well.

For mothers who are severely ill, the benefits of ART far outweigh any potential risk to the infant. For those infants whose infection is prevented by ARV prophylaxis interventions, the benefits of ARV exposure are also clearly greater than the risks. However, since most infants (55-80%) born to HIV-infected women would never have been infected as a result of HIV transmission even in the absence of PMTCT interventions, careful monitoring of the ARV exposure risks to infants remains ethically necessary.

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Historical Overview

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There was considerable debate about the potentially harmful effects of fetal exposure to zidovudine (ZDV) before the first PMTCT clinical trial of the drug, which was known to induce clastogenic effects (microscopically visible damage or changes to whole chromosomes) in vitro and had been shown to be carcinogenic in animals.( 2 , 3 , 4 , 5 , 6 , 7 ) With these concerns in mind, the National Institutes of Health (NIH) AIDS Clinical Trials Group 076 study was designed to administer ZDV beginning at 14 to 34 weeks to minimize the potential of teratogenicity during early fetal development.( 2 ) The study was halted early when researchers observed a dramatic decrease in vertical HIV transmission rates. The study's immediate short-term results did not reveal any ZDV-related adverse effects.( 2 )

The fact that a majority of infants born to HIV-infected mothers do not become infected but are nevertheless exposed to ARV drugs has been a concern for researchers and has led to many long-term studies looking at the prevalence of birth defects and adverse birth outcomes in ARV-exposed infants. These studies are designed to follow cohorts of HIV-infected women and their infants and to extend the follow-up period of study subjects for as long as possible. The major risks of ARV exposure to noninfected infants fall into the following categories:

  • Mitochondrial and metabolic toxicities
  • Congenital anomalies and impairment of growth and development
  • Induction of malignancies

This paper provides a brief review of research on these risks.

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Mitochondrial Toxicity

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In 1999, Blanche et al reported on 8 uninfected infants who were exposed to ZDV in utero and later developed severe mitochondrial toxicity. Five of these infants died.( 8 ) Mitochondrial toxicity and metabolic duty disorders secondary to ART are known to be associated with several ARV drugs and are observed in both children and adults. However, these occurrences in uninfected infants exposed to ZDV were of great concern.( 9 , 10 , 11 , 12 , 56 ) The significance of the report was immediately recognized. Both the NIH and the U.S. Centers for Disease Control and Prevention (CDC) retrospectively analyzed medical records from more than 10,000 infants and children to determine whether mitochondrial toxicity had occurred in their large cohort studies. No definitive cases of mitochondrial toxicity or death were uncovered, and ZDV has continued to be recommended for PMTCT.( 13 , 14 )

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Congenital Anomalies

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There have long been sporadic reports of a possible association between ART and congenital anomalies. In 1998, reports cited evidence that efavirenz was associated with the occurrence of central nervous system abnormalities when given to pregnant monkeys.( 15 , 16 , 17 ) As a result of this finding, the drug is not recommended for use during pregnancy, although there are reports of pregnant women who receive efavirenz during pregnancy and give birth to infants without abnormalities.( 18 , 19 ) Several individual cases of central nervous system abnormalities have been reported in infants exposed to efavirenz in utero but, because such evidence has not been found in large clinical studies, no definitive conclusion can be made regarding an association between these congenital abnormalities and efavirenz.( 19 , 20 ) However, until the relationship can be ruled out, efavirenz remains contraindicated for pregnant women and women of childbearing potential who lack access to reliable contraception.

Other clinical trials on the occurrence of congenital anomalies following in utero exposure to ARV drugs, with larger numbers of study subjects, have been reassuring.

Early studies of ZDV suggested that its use during pregnancy did not increase the risk of congenital anomalies.( 21 , 22 , 23 , 24 ) Similarly, large clinical studies from the United States, the United Kingdom, Ireland, and other countries in Europe, have reported no increased risk of congenital anomalies following ARV exposure.( 25 , 26 , 27 ) One study reported the occurrence of an increased risk of birth defects in infants born to HIV-infected pregnant women who had received both ART and folate antagonists. However, the risk of birth defects was not associated with the use of folate antagonists alone or ART alone.( 28 )

A study in the state of New York on the prevalence of congenital abnormalities in infants with intrauterine exposure to ZDV reported an adjusted prevalence of any anomaly that was 2.8 times greater than in the general population. However, detailed evaluation of the data indicated that the increased risk of major anomalies was not associated with exposure to ZDV during the first trimester , when adverse effects would be most likely to occur.( 29 )

A recent clinical evaluation of 2,527 live births by Watts et al also provides reassurance that infants exposed to ARVs in utero do not have higher risk of severe congenital anomalies than those who are not exposed.( 30 ) The exception to this general finding is a significant increase in the occurrence of hypospadias in infants whose mothers received ARVs during the first trimester of pregnancy. It is worth keeping in mind that hypospadias occurred in only 3.3 per 1,000 live births reported in the evaluation and that, although it is a definite developmental abnormality, it is not a life-threatening problem and can be corrected surgically. There also have been two reports of an increase in septal cardiac defects following ARV exposure in the first trimester.( 31 ) However such an increase in septal cardiac defects was not observed in the evaluation by Watts et al or in other large-scale reviews of ARV-exposed infants.

Low birth weight and preterm delivery has been reported in the United States and Europe in association with the use of combination ART, particularly regimens containing protease inhibitors.( 32 , 33 ) However, this association was not confirmed by other studies.( 34 , 35 , 36 ) Evaluation of the impact of ARVs on low birth weight in resource-poor countries is difficult as there are many factors, such as malaria, that contribute to low birth weight and preterm delivery. However, low birth weight is significantly associated with an increase in infant mortality in resource-poor countries, and it would be useful to know whether the association between ART during pregnancy and low birth weight is seen in these settings.

Follow-up studies evaluating height and weight in uninfected ARV-exposed infants have been performed in both resource-poor and resource-rich countries. A study from Thailand found that the initial growth in these children was delayed, but the children subsequently grew at normal rates.( 37 ) Studies from the United States and Europe have not shown any impact of intrauterine exposure to ARVs on subsequent growth of uninfected infants.( 22 , 38 , 39 ) A Pediatric AIDS Clinical Trials Group long-term follow-up study of children who received either ZDV or placebo found no significant differences between the two groups in relation to Z scores for height, weight, and head circumference.( 22 ) The study, which followed children for as long as 5.6 years, also found that cognitive development and function was similar in the two groups. No differences in malignancy or echocardiogram results were observed. The lack of impact of ARV exposure on the growth of uninfected children is confirmed by more recent studies.( 16 , 38 )

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An increased risk of malignancy is a feature of HIV infection in adults and children. However, there is no evidence of an increased rate of malignancy in uninfected, ARV-exposed children, even in studies that have followed children for as long as 16 years.( 40 , 41 , 42 , 43 ) How then to interpret the results of two recent studies ( 44 , 45 ) that found laboratory evidence of DNA damage in the blood cells of ARV-exposed infants? These and other in vitro and in vivo studies have found elevated rates of ARV-associated genetic mutations, malignancies in animals, and damage to DNA and chromosomes, along with in vitro evidence that ZDV can be incorporated into the DNA of cells obtained from ARV-exposed animals and humans.( 6 , 7 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ) Cautious interpretation of these results is warranted. In most of the studies, the dosage of ARVs administered to animals to obtain the reported abnormalities was a daily administration 50- to 100-fold higher than drug dosages administered to pregnant women or infants for PMTCT or ART.( 47 , 49 , 51 , 52 )

Although some of the recent studies use newer methods of cell analysis, they mostly affirm previously known effects of nucleoside drugs in vitro and in vivo. The study reported by Witt and associates found a higher rate of occurrence of cellular DNA damage, as determined by the measurement of micronucleated red blood cells, in the blood of infants exposed to ZDV maternally compared with cellular damage in infants who had not been exposed.( 44 ) It is difficult to ascertain the significance of this result because the control sample consisted of only 3 infants and abnormalities were no longer present at 6 months of age. Moreover, there have been no studies correlating the association of micronucleated red blood cells in humans with the subsequent occurrence of malignancy.

Another recent study that has aroused concern, performed by Escobar et al,( 45 ) also should be interpreted cautiously. Researchers in this study used two assays (a "Comet" assay and a glycophorin A somatic cell mutation assay) to measure the genetic damage of cells obtained from the blood of infants exposed to ZDV in utero. The Comet assay failed to show any evidence of genetic damage, whereas the glycophorin A somatic cell mutation assay yielded a positive result. After 12 months, abnormalities were no longer detectable.

The significance of these studies in relation to clinical outcomes for uninfected HIV-exposed infants is not certain. Neither positive nor negative in vitro or in vivo animal studies are consistently predictive of the occurrence of abnormalities in humans.( 53 ) Nevertheless, safety studies that show potential toxic effects in humans always must be taken seriously, and long-term follow-up studies on ARV-exposed infants who are HIV infected and those who are HIV uninfected are essential. Often, such long-term follow-up clinical trials are not popular with funders because they are costly and present major difficulties for clinical investigators working in regions with inadequate infrastructure.

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  • Increasing access to ARV prophylaxis for PMTCT and long-term combination ART for HIV-infected pregnant women provided throughout pregnancy and lactation means that increasing numbers of infants, most of whom are born uninfected, are being exposed to ARVs in utero and postpartum.( 54 )
  • As it cannot be determined in advance which infants will be uninfected, it is not possible to selectively treat HIV-infected pregnant women. Even with a potential risk of adverse consequences to the fetus, it would be unethical to withhold ART from HIV-infected women who require it to manage their infection.
  • This situation demands renewed vigilance in the monitoring of possible adverse effects of ARV exposure in infants. Long-term follow-up studies are necessary to evaluate possible associations of in utero exposure to ARVs and the subsequent occurrence of malignancy and developmental abnormalities in light of findings such as those reported by Witt et al and Escobar et al.
  • It is obvious that the best means of reducing infants' exposure to the potential toxic effects of ARVs is to prevent HIV infection in women. The continued increase in the number of uninfected, ARV-exposed infants is a measure of the success of PMTCT programs but it also highlights the larger failure of health systems to prevent HIV infection and unintended pregnancies in women.
  • Current evidence from large clinical trials does not show that in utero exposure to ARVs poses a significant risk of severe congenital abnormalities, increased malignancy, or impaired growth and development.
  • Whereas these findings are reassuring, larger studies with more extensive follow-up of exposed children are necessary as the use of ART expands in resource-poor countries and ARVs are used in conjunction with other antimicrobial drugs.
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  1. UNAIDS, WHO. 2006 Report on the Global AIDS Epidemic . May 2006.
  2. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group . N Engl J Med.
  3. Agur Z, Arnon R, Sandak B, et al. Zidovudine toxicity to murine bone marrow may be affected by the exact frequency of drug administration . Exp Hematol. 1991;19(5):364-8.
  4. Calabresi P, Falcone A, St Clair MH, et al. Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity . Blood. 1990;76(11):2210-5.
  5. Shirae H, Kobayashi K, Shiragami H, et al. Production of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine from 2',3'-dideoxyuridine and the corresponding purine bases by resting cells of Escherichia coli AJ 2595 . Appl Environ Microbiol. 1989;55(2):419-24.
  6. Ayers KM. Preclinical toxicology of zidovudine. An overview . Am J Med. 1988;85(2A):186-8.
  7. Olivero OA, Shearer GM, Chougnet CA, et al. Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero . Aids. 1999;13(8):919-25.
  8. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues . Lancet. 1999;354(9184):1084-9.
  9. McComsey GA, Leonard E. Metabolic complications of HIV therapy in children . Aids. 2004;18(13):1753-68.
  10. Sweet DE. Metabolic complications of antiretroviral therapy . Top HIV Med. 2005;13(2):70-4.
  11. McGuire S. Metabolic toxicities and HIV. Posit Aware . 2002;13(6):23-5.
  12. Bartlett JG. Toxicity of antiretroviral agents . Hopkins HIV Rep. 1999;11(6):2, 12.
  13. Bulterys M, Nesheim S, Abrams EJ, et al. Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study . Ann N Y Acad Sci. 2000;918:212-21.
  14. Lindegren ML, Rhodes P, Gordon L, et al. Drug safety during pregnancy and in infants. Lack of mortality related to mitochondrial dysfunction among perinatally HIV-exposed children in pediatric HIV surveillance . Ann N Y Acad Sci. 2000;918:222-35.
  15. Mofenson LM. Efavirenz reclassified as FDA pregnancy category D . AIDS Clin Care. 2005;17(2):17.
  16. Thorne C, Newell ML. Antenatal and neonatal antiretroviral therapy in HIV-infected women and their infants: a review of safety issues . Med Wieku Rozwoj. 2003;7(4 Pt 1):425-36.
  17. Baker R. Safety alert issued on efavirenz (Sustiva) . Beta. 1998:6-7.
  18. Centers for Disease Control and Prevention. Recommendations for the use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce periantal HIV-1 transmission in the United States . 2006.
  19. Jeantils V, Khuong MA, Delassus JL, et al. [Efavirenz (Sustiva) in pregnancy: a study about 12 HIV patients] . Gynecol Obstet Fertil. 2006;34(7-8):593-6.
  20. Saitoh A, Hull AD, Franklin P, et al. Myelomeningocele in an infant with intrauterine exposure to efavirenz . J Perinatol. 2005;25(8):555-6.
  21. Sperling RS, Shapiro DE, McSherry GD, et al. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study . Aids. 1998;12(14):1805-13.
  22. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams . Jama. 1999;281(2):151-7.
  23. Bakshi SS, Britto P, Capparelli E, et al. Evaluation of pharmacokinetics, safety, tolerance, and activity of combination of zalcitabine and zidovudine in stable, zidovudine-treated pediatric patients with human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 190 Team . J Infect Dis. 1997;175(5):1039-50.
  24. McSherry GD, Shapiro DE, Coombs RW, et al. The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076) . J Pediatr. 1999;134(6):717-24.
  25. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women . J Acquir Immune Defic Syndr. 2003;32(4):380-7.
  26. Townsend CL, Tookey PA, Cortina-Borja M, et al. Antiretroviral therapy and congenital abnormalities in infants born to HIV-1-infected women in the United Kingdom and Ireland, 1990 to 2003 . J Acquir Immune Defic Syndr. 2006;42(1):91-4.
  27. Watts DH, Covington DL, Beckerman K, et al. Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy . Am J Obstet Gynecol. 2004;191(3):985-92.
  28. 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(6):441-3.
  29. Newschaffer CJ, Cocroft J, Anderson CE, et al. Prenatal zidovudine use and congenital anomalies in a medicaid population . J Acquir Immune Defic Syndr. 2000;24(3):249-56.
  30. Watts DH, Li D, Handelsman E, et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study . J Acquir Immune Defic Syndr. 2007;44(3):299-305.
  31. Antiretroviral Pregnancy Registry. International Interim Report for 1 January 1989 to 31 July 2006 .
  32. Cotter AM, Garcia AG, Duthely ML, et al. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. 2006;193(9):1195-201.
  33. Goldstein PJ, Smit R, Stevens M, et al. Association between HIV in pregnancy and antiretroviral therapy, including protease inhibitors and low birth weight infants . Infect Dis Obstet Gynecol. 2000;8(2):94-8.
  34. Schulte J, Dominguez K, Sukalac T, et al. Schulte J, Dominguez K, Sukalac T, et al. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs: Pediatric Spectrum of HIV Disease, 1989-2004 . Pediatrics. 2007;119(4):e900-6. Pediatrics. 2007;119(4):e900-6.
  35. Szyld EG, Warley EM, Freimanis L, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth . Aids. 2006;20(18):2345-53
  36. Lambert JS, Watts DH, Mofenson L, et al. Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team . Aids. 2000;14(10):1389-99.
  37. Briand N, Le Coeur S, Traisathit P, et al. Growth of human immunodeficiency virus-uninfected children exposed to perinatal zidovudine for the prevention of mother-to-child human immunodeficiency virus transmission . Pediatr Infect Dis J. 2006;25(4):325-32.
  38. Newell ML, Borja MC, Peckham C. Height, weight, and growth in children born to mothers with HIV-1 infection in Europe . Pediatrics. 2003;111(1):e52-60.
  39. Agostoni C, Zuccotti GV, Giovannini M, et al. Growth in the first two years of uninfected children born to HIV-1 seropositive mothers . Arch Dis Child. 1998;79(2):175-8.
  40. Mueller BU. Cancers in children infected with the human immunodeficiency virus . Oncologist. 1999;4(4):309-17.
  41. Chitsike I, Siziya S. Seroprevalence of human immunodeficiency virus type 1 infection in childhood malignancy in Zimbabwe . Cent Afr J Med. 1998;44(10):242-5.
  42. Mbulaiteye SM, Biggar RJ, Goedert JJ, et al. Immune deficiency and risk for malignancy among persons with AIDS . J Acquir Immune Defic Syndr. 2003;32(5):527-33.
  43. Pollock BH, Jenson HB, Leach CT, et al. Risk factors for pediatric human immunodeficiency virus-related malignancy . Jama. 2003;289(18):2393-9.
  44. Witt KL, Cunningham CK, Patterson KB, et al. Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother-to-child transmission of HIV . Environ Mol Mutagen. 2007;48(3-4):322-9.
  45. Escobar PA, Olivero OA, Wade NA, et al. Genotoxicity assessed by the comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother-child pairs to AZT or AZT-3TC . Environ Mol Mutagen. 2007;48(3-4):330-43.
  46. Hong HH, Dunnick J, Herbert R, et al. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT . Environ Mol Mutagen. 2007;48(3-4):299-306.
  47. Torres SM, Walker DM, Carter MM, et al. Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations . Environ Mol Mutagen. 2007;48(3-4):224-38.
  48. Olivero OA, Parikka R, Poirier MC, et al. 3'-azido-3'-deoxythymidine (AZT) transplacental perfusion kinetics and DNA incorporation in normal human placentas perfused with AZT . Mutat Res. 1999;428(1-2):41-7.
  49. Poirier MC, Olivero OA, Walker DM, et al. Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drugs . Toxicol Appl Pharmacol. 2004;199(2):151-61.
  50. Ayers KM, Clive D, Tucker WE Jr., et al. Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats . Fundam Appl Toxicol. 1996;32(2):148-58.
  51. Walker DM, Malarkey DE, Seilkop SK, et al. Transplacental carcinogenicity of 3'-azido-3'-deoxythymidine in B6C3F1 mice and F344 rats . Environ Mol Mutagen. 2007;48(3-4):283-98.
  52. Walker DM, Poirier MC, Campen MJ, et al. Persistence of mitochondrial toxicity in hearts of female B6C3F1 mice exposed in utero to 3'-azido-3'-deoxythymidine. Cardiovasc Toxicol . 2004;4(2):133-53.
  53. Fleming TR. Evaluating the safety of interventions for prevention of perinatal transmission of HIV . Ann N Y Acad Sci. 2000;918:201-11.
  54. Little K, Newell ML, Luo C, et al. Estimating the number of vertically HIV-infected children eligible for antiretroviral treatment in resource-limited settings . Int J Epidemiol. 2007.
  55. ter Hofstede HJ, Burger DM, Koopmans PP. Antiretroviral therapy in HIV patients: aspects of metabolic complications and mitochondrial toxicity . Neth J Med. 2003;61(12):393-403.
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