Anaemia more likely in infants exposed to maternal ARVs during pregnancy and breastfeeding

HIV-uninfected infants born to mothers in Botswana and exposed during pregnancy to maternal antiretroviral treatment were at increased risk for severe anaemia during the first six months of life compared to infants exposed to short-term zidovudine alone, Scott Dryden-Peterson and colleagues reported in an analysis of the Mashi and Mma Bana PMTCT intervention trials published in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

Formula-fed infants on short-term zidovudine had the lowest risk for anaemia.

The decreased odds, compared to breastfed infants exposed to maternal ART and for those exposed to short-term zidovudine, were 5.8 fold and 2.2 fold, respectively. Observational studies of large cohorts in the United States and Europe had similar findings.

In a separate report on infants born to mothers participating in the two trials Kathleen M Powis and colleagues reported that while lower birth weight was associated with infant exposure to maternal antiretroviral treatment compared to exposure to short-term zidovudine, rapid weight gain within the first three months brought the infants close to the norm for age and gender. 

While this is reassuring low birth weight nonetheless is associated with the potential for early infant mortality and/or morbidity, note the authors.

Their findings were published in the February 1 edition of the Journal of Acquired Immune Deficiency Syndromes.

Maternal ART during pregnancy and breastfeeding for the prevention of mother-to-child transmission is an effective public health intervention. The World Health Organization (WHO) now recommends ART for all pregnant women with CD4 cell counts of 350 cells/mm³or lower and as an MTCT prevention strategy in women with higher CD4 cell counts. This is of particular relevance for women in resource-poor settings where formula-feeding may be neither safe nor feasible.

So it is important to look at the potential toxicity of infant exposure to maternal ART during pregnancy, as well as the short- and long-term growth implications for infants. Evidence is limited, especially in resource-poor settings.

Zidovudine and other nucleoside reverse transcriptase inhibitors (NRTIs) are known to cause anaemia in adults and children. Studies in resource-rich settings suggest ART causes mild but reversible anaemia. However, in resource-poor settings malnutrition and limited access to blood transfusions make the risk for, and adverse effects of severe anaemia of critical clinical significance.

Scott Dryden-Petersen and colleagues compared severe anaemia rates among three groups: infants exposed to maternal ART during pregnancy, breastfeeding and one month of postnatal zidovudine (ART-BF); infants exposed to maternal zidovudine during pregnancy, six months of postnatal zidovudine and breastfeeding (ZDV-BF); and infants exposed to maternal zidovudine during pregnancy, one month of postnatal zidovudine and formula-feeding (ZDV-FF).

Among 1719 infants severe anaemia was found in 7.4% (118). By six months 12.5% of the ART-BF group had severe anaemia compared with 5.3% of the ZDV-BF group and 2.5%in the ZDV-FF group.

The authors note the apparent contradiction between their findings and an earlier analysis (Bae et al) is due to small sample size (178 compared to 1719 infants), inclusion of HIV-infected infants and most importantly use of the 1994 version of the DAIDS toxicity table. Exclusion of the HIV-infected infants and use of the 2004 table in the Bae analysis gave similar results to their study.

The authors suggest that timing of exposure to ART or the combination of zidovudine with other antiretrovirals may help explain why those in the ART-BF group had the most severe anaemia. A study in Malawi suggested exposure to ART during pregnancy increased the risk for anaemia.

The types of anaemia found corresponded to iron-deficiency. All mothers in both the Mashi and Mma Bana studies were given iron supplements as part of antenatal care. So ART may affect the absorption of iron from mother to foetus as well as make the infant vulnerable because of nutrient deficiencies and infections, they add.

Limitations include: most of the ART-exposed infants were breastfed so separation of antiretroviral and feeding effects were not possible. There is no way of knowing the effect of antenatal and postnatal ART exposure on anaemia.

The authors note that while these limitations may underestimate the effect of maternal ART on anaemia, conclusive causality between ART exposure during pregnancy and infant anaemia was not found suggesting the need for further study.

Most anaemias were asymptomatic and improved with iron and vitamin supplements and stopping ziodvudine.

It is unknown whether anaemia not caused by iron deficiency affects child development. The authors note this warrants further study of the aetiology of anaemia in ART-exposed infants.

Kathleen M Powis and colleagues undertook the first study to compare early growth patterns of breastfed infants after ART or zidovudine exposure during pregnancy.

Growth patterns of 619 ART-exposed and 440 zidovudine-exposed HIV-uninfected infants were analysed.

ART-exposed and zidovudine-exposed infants had mean birth weights (WAZ) of 3.01kg and 3.15 kg, p<0.01, respectively.  All ART-exposed infants had lower length for age (LAZ) and weight for length (WLZ) scores at birth compare to zidovudine-exposed infants.

However, from birth until two months of age ART-exposed infants showed the greatest improvements in weight for age and weight for length. And, from three to six months of age there was no difference in weight for age between the groups.

In the first 28 days of life a study from Tanzania showed that lower birth weight among HIV-exposed infants presented a higher risk for death than HIV transmission. The authors stress that infants exposed to maternal ART “may benefit from programmes to optimise growth in the first several months of life in an effort to mitigate morbidity and mortality.”

Length for age was lower in ART-exposed infants. The authors note Mma Bana infants will be followed beyond six months allowing for a re-evaluation of morbidity and mortality outcomes.

Limitation include the difference in protocols: zidovudine-exposed infants got zidovudine throughout the six month breastfeeding period, while ART-exposed infants got zidovudine for four weeks.

The authors conclude “this analysis is the first to provide reassurance that lower birth weight associated with in utero ART-exposed infants does not persist during early infancy. It also highlights [as does the analysis by Dryden-Peterson and colleagues] the importance of early and routinely scheduled health care for ART-exposed HIV-uninfected infants.”

Powis KM et al. Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana. J Acquir Immune DeficSyndrVol 56, Number 2, February 1, 2011.

Dryden-Peterson S et al. Increased risk of severe infant anemia following exposure to maternal HAART, Botswana.Advance online edition. J Acquir Immune DeficSyndr. February 2011 DOI: 10.1097/QAI.0b013e31820bd2b6.