Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes
Shapiro, Roger L.a; Ribaudo, Heatherb; Powis, Kathleenc; Chen, Jenniferd; Parekh, Natashae
aDivision of Infectious Diseases, Beth Israel Deaconess, Medical Center, Boston, MA, USA
bHarvard School of Public Health, Department of Biostatistics, Boston, MA, USA
cDepartments of Medicine and Pediatrics, Massachusetts, General Hospital, Boston, MA, USA
dDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA
eDepartment of Medicine, University of Pittsburgh,Pittsburgh, PA, USA.
Correspondence to Roger L. Shapiro, MD, MPH, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel: +1 617 771 0040; fax: +1 617 632 0766; e-mail: email@example.com
Received 27 September, 2011
Accepted 28 September, 2011
We read the article entitled ‘Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes’ by Marazzi et al. with great interest. Although data are mixed from previous studies [2–10], broad protection against several categories of adverse pregnancy outcomes has not been previously reported with the use of highly active antiretroviral therapy (HAART) in pregnancy. We are concerned that this novel finding may stem from important differences in the comparator groups. First, the lack of receipt of any antiretrovirals during pregnancy (e.g. in contrast with the receipt of short-course zidovudine) may be a marker for poor access to antenatal care or first presentation in labor. A second inherent problem with this comparator group is that all women are categorized as untreated prior to antiretroviral initiation. This time-dependent classification creates more opportunity for adverse events that occur early in pregnancy to affect ‘untreated’ women.
Of these concerns, it appears that the former is most problematic in the authors’ analysis. Only 68 women did not receive HAART (only 10 women were available for the prematurity comparison), making the comparator group small relative to the 3205 women who received HAART. No information is directly provided about why these women did not access HAART, their gestational age upon accessing antenatal care, or other potential differences from treated women. Because women had to access program centers prior to 37 weeks to be considered for the preterm delivery analysis, we can use the number of women missing from the denominators of this analysis (shown in Table 1 of the original article) to infer the proportion of women in each category who presented to a treatment site before 37 weeks. As shown in Table 1, the comparator groups were dissimilar.
Over 85% of the women who did not receive HAART were first seen in a study site after 37 weeks’ gestation, whereas only 3% of the women who received HAART for greater than 90 days presented at greater than 37 weeks. We do not know the reasons why women who did not receive HAART presented so late in pregnancy, nor whether they may have received antenatal care elsewhere, but lack of antenatal care has been associated with higher risk for adverse birth outcomes [11–15].
We have additional concerns regarding the analyses that associate improved outcomes with longer duration of HAART. This finding may be a marker for the lack of uniformity of birth outcomes in pregnancy. In-utero stillbirths often occur in complicated pregnancies that end earlier in gestation, thereby limiting the total number of days on HAART during pregnancy. Maternal illnesses or obstetric events that precipitated both early delivery and maternal mortality would also be associated with shorter HAART duration. Duration of HAART before delivery and prematurity are linked variables that cannot be meaningfully compared; reverse causality would best explain the strong association between less than 30 days of HAART and prematurity. Finally, we are concerned that only 15% of infants had a birth weight recorded, as data from such a small subset are unlikely to be generalizable.
In summary, we believe these data may compare very different groups of women in which the effect of HAART cannot be isolated, and that temporal biases may further limit the conclusions that can be drawn from these comparisons.
1. Marazzi MC, Palombi L, Nielsen-Saines K, Haswell J, Zimba I, Magid NA, et al. Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes
2. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe
3. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland
4. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis
5. Parekh N, Ribaudo H, Souda S, Chen J, Mmalane M, Powis K, et al.Risk factors for very preterm delivery and delivery of very-small-for-gestational-age infants among HIV-exposed and HIV-unexposed infants in Botswana.Int J Gynaecol Obstet
6. Chen J, Ribaudo H, Ogwu A, Lockman S, Svab P, Wester C, et al.Risk factors for adverse pregnancy outcomes among HIV-infected women in Gaborone, Botswana
[abstract 949]. In: Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections
; 2009; Montreal, Quebec, Canada. Alexandria, Virginia, USA: Foundation for Retrovirology and Human Health.
7. Tuomala R, Shapiro D, Mofenson L, Bryson Y, Culnane M, Hughes M, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome
. N Engl J Med
8. Tuomala RE, Watts DH, Li D, Vajaranant M, Pitt J, Hammill H, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy
. J Acquir Immune Defic Syndr
9. Ekouevi DK, Coffie PA, Becquet R, Tonwe-Gold B, Horo A, Thiebaut R, et al. Antiretroviral therapy in pregnant women with advanced HIV disease and pregnancy outcomes in Abidjan, Cote d’Ivoire
10. Cotter AM, Garcia AG, Duthely ML, Luke B, O'Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth?
. J Infect Dis
11. Coria-soto IL, Bobadilla JL, Notzon F. The effectiveness of antenatal care in preventing intrauterine growth retardation and low birth weight due to preterm delivery
. Int J Qual Health Care
12. Yakoob MY, Menezes EV, Soomro T, Haws RA, Darmstadt GL, Bhutta ZA. Reducing stillbirths: behavioural and nutritional interventions before and during pregnancy
. BMC Pregnancy Childbirth
2009; 9 (Suppl 1):S3.
13. Lawn JE, Yakoob MY, Haws RA, Soomro T, Darmstadt GL, Bhutta ZA. 3.2 million stillbirths: epidemiology and overview of the evidence review
. BMC Pregnancy Childbirth
2009; 9 (Suppl 1):S2.
14. Di Mario S, Say L, Lincetto O. Risk factors for stillbirth in developing countries: a systematic review of the literature
. Sex Transm Dis
2007; 34 (7 Suppl):S11–S21.
15. Feresu SA, Harlow SD, Welch K, Gillespie BW. Incidence of stillbirth and perinatal mortality and their associated factors among women delivering at Harare Maternity Hospital, Zimbabwe: a cross-sectional retrospective analysis
. BMC Pregnancy Childbirth
© 2012 Lippincott Williams & Wilkins, Inc.