Dryden-Peterson S, Shapiro RL, Hughes MD, Powis K, Ogwu A, Moffat C, Moyo S, Makhema J, Essex M, Lockman S. Increased Risk of Severe Infant Anemia Following Exposure to Maternal HAART, Botswana. J Acquir Immune Defic Syndr. 2011 January 24. [Epub ahead of print]
To determine the effect of maternal HAART started in pregnancy on the incidence of anemia among HIV-exposed, uninfected infants.
One town, one city, and two villages in Botswana; HIV-infected pregnant women and their exposed but HIV-uninfected infants.
Analysis was performed on data from two trials, the Mashi study (2001 to 2003), and the Mma Bana study (2006 to 2008). HIV-infected, highly active antiretroviral therapy (HAART)-naïve pregnant women presenting for antenatal care were enrolled. In the Mashi study, mothers (with any CD4 count) were given zidovudine (ZDV) monotherapy at 34 weeks gestation, and infants received single-dose nevirapine (sdNVP) or placebo and then were randomized to breastfeeding plus six months of ZDV (ZDV-BF group), or to formula feeding plus one month of ZDV (ZDV-FF group). In the Mma Bana study, women were started on HAART at 18-34 wks of gestation. Those with CD4 count <200 cells/µl received NVP/ZDV/lamiduvine (3TC); those with CD4 ≥ 200 cells/µl received either ABC/ZDV/3TC or Lopinavir/ritonivir/ZDV/3TC. All infants of these mothers received sdNVP, were breastfed and received one month of ZDV (HAART-BF group). Only data from infants who remained HIV uninfected through seven months of follow-up were included.
The main outcome measures were hemoglobin measurements on infants at birth, one month, three or four months, and six or seven months were used to compute the cumulative incidence of severe or life threatening (grade 3 or 4) anemia from birth to six months of age.1 There were 1,877 live singleton and first-born twin infants born to the 1930 women enrolled in the two parent studies. Ninety infants became HIV infected; of those remaining who did not die (n=61) or were not lost to follow-up and remained eligible, 691 infants were included in the HAART-BF group, 503 infants in the ZDV-BF and 525 infants in the ZDV-FF group. Overall, 188 (7.4%) infants developed severe anemia over six months: 82 (12.5%) in the HAART-BF group, 25 (5.3%) in the ZDV-BF group, and 11 (2.5%) in the ZDV-FF group [HAART-BF vs. ZDV-BF, or vs. ZDV-FF (p<0.001). The majority of these (n=105) were grade 3 anemia. There were no significant differences among the groups in the rate of treatment-modifying anemia (2.0-4.1%) detected between birth and follow-up visits. In multivariate analysis, compared to the ZDV-FF group, odds of developing severe anemia were: HAART-BF group (aOR 5.8, 95% CI 3.0-11.0), ZDV-BF (aOR 2.2, CI 1.1-4.6); gestational age per week (aOR 0.9, CI.8-0.96), male sex (1.53, CI 1.03-2.3), and low maternal personal income (aOR 2.0, CI 1.1-3.7); maternal CD4 count, viral load, maternal hemoglobin (Hgb) level, type of HAART regimen, or duration of maternal antenatal HAART were not associated with incident anemia in infants. The majority of episodes of severe anemia resolved with multivitamin and iron supplementation, or cessation of ZDV exposure; severe anemia persisted from more than three months for 18 infants, and 11 infants required transfusion (all in the HAART-BF group); severe anemia may have contributed to the death of six infants. At the time of severe anemia, microcytosis was more common than macrocytosis (21.2% and 2.5% of infants, respectively). Hypochromia was present in 29.3% of anemias.
Infants who are exposed to maternal HAART are at a significantly higher risk of developing severe anemia during the first 6 months of life, compared to those who are exposed to maternal ZDV alone. Being exposed to HAART both in utero and through breast milk increases the odds of becoming anemic by 2.6 fold, compared to being exposed to ZDV in utero and postnatally; infants who were exposed to ZDV in utero but were formula fed and received only one month of ZDV postpartum treatment were at the lowest risk of anemia.
This was a high quality study. Details of the initial randomized studies were not provided here, but were referenced.
The results of this study agree with findings of observational studies of mostly formula-fed cohorts in the US and Europe that have found lower Hgb levels among infants exposed to in utero HAART compared to those exposed to monotherapy or no in utero antiretroviral therapy.(2, 3, 4) A trial in Malawi of post-natal maternal HAART showed rates of severe anemia to be similar between infants who were also exposed to HAART in breastmilk to those who were not,(5) suggesting that in utero exposure may be one of the important factors in causing anemia. Data published earlier from the Mashi study did not identify an increased risk of anemia with HAART.(6) The difference in finding may have been to the large difference in the sample size in each analysis (only 178 in the earlier study).
This study showed that maternal HAART started in pregnancy and continued during breastfeeding was associated with increased severe infant anemia. Further studies are needed. The etiology of the anemia is not entirely clear: ZDV is usually associated with anemia; however, if it were the primary cause, the greatest incidence of severe anemia would have been in the ZDV-BF group; however, the fact that the HAART-BF groups had the most severe anemias suggests that timing of exposure, and /or the combination of ZDV with other antiretrovirals may be contributing. The large potential impact in reducing MTCT by using HAART means that clinicians need to watch for infant anemia, and consider infant iron supplementation particularly if microcytic and hypochromic anemia is present. Mild or moderate anemia due to iron deficiency has been associated with impaired child development.
- Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004. 2004, with update from 2009.
- Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS. Sep 26 2003;17(14):2053-2061.
- Pacheco SE, McIntosh K, Lu M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study. J Infect Dis. Oct 15 2006;194(8):1089-1097.
- Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr. May 1 2007;45(1):43-51.
- Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. Jun 17 2010;362(24):2271-2281.
- Bae WH, Wester C, Smeaton LM, et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. Aids. Aug 20 2008;22(13):1633-1640.