Combination antiretroviral therapy is being delivered to increasing numbers of rural HIV-infected pregnant women in developing countries 
. Goals of treatment include protecting the health of these women and promoting the birth of HIV-uninfected, healthy infants. However, cART alone may not be sufficient to achieve these goals, particularly when these women also often face other challenges besides HIV, including food insecurity and malnutrition 
In our cohort of HIV-infected pregnant women in rural Uganda initiating cART, TS and prenatal care, we found evidence of significant nutritional deficiencies. These women had low BMIs upon study entry and well into their pregnancy, despite having relatively preserved CD4 cell counts. Their mean weight gain of 0.17 kg/week was far below the 0.5 kg/week recommended by the Institute of Medicine for underweight women in industrialized countries in the second and third trimester 
. Although all infants were HIV-uninfected at delivery, adverse birth outcomes were highly prevalent and likely attributable at least in part to poor maternal nutritional status.
Interestingly, HIV severity, measured as baseline CD4 count, viral load, or WHO stage, was not predictive of adverse birth outcomes. This could have been due to our sample size and the relatively small proportion of women with severe immune suppression. Indeed, 50% of our cohort had baseline CD4 counts above 350 and the majority of the women (91.8%) were WHO stage 1.
Maternal nutritional predictors of preterm delivery and growth restriction have primarily been evaluated among HIV-infected women not receiving cART. The Pregnancy and HIV Study Group of 177 ARV-naïve women in Rwanda found that each kg increment in final weight before delivery was associated with a 6% decreased odds of LBW 
. Villamor et al. found that low maternal weight at first prenatal visit was associated with lower mean birth weight and SGA but not preterm delivery among 1002 ARV-naïve women in Tanzania 
. Similar to our study, the prevalence of gestational weight loss was 10%, and weight loss was associated with LBW, preterm delivery and fetal death. In Zambia, Banda et al. found infant birth weight increased by 28.3 g for every unit increase in BMI at 36 weeks of gestation; they did not assess the risk of preterm delivery or other markers of growth restriction 
. Finally, Mehta et al. analyzed outcomes of 2294 ARV-naïve pregnant women enrolled in HIVNET 024 
. They found enrollment maternal BMI in the lowest tertile to be associated with LBW and preterm delivery. As observed in our study, weight gain <0.1 kg per week was associated with increased risk of LBW.
Very few studies have evaluated nutritional predictors of pregnancy outcomes among HIV-infected women on cART. Ekouevi and colleagues studied 151 pregnant women receiving cART as part of the ANRS Ditrame Plus and the MTCT-Plus Projects in Cote d’Ivoire 
. Similar to the Pregnancy and HIV Study Group in Rwanda, these researchers found maternal BMI at delivery to be predictive of LBW. In particular, the odds of LBW was 2.43 fold higher among women with a delivery BMI <25. Conversely, Powis et al recently reported that change in BMI one month following the initiation of cART in pregnancy was not significantly associated with preterm delivery among 530 HIV-infected pregnant women in Botswana 
It is reasonable to postulate that pregnant women treated with cART would have improved nutritional status compared to those without access to cART. Women receiving effective cART should experience less HIV morbidity, including diarrhea and wasting, which should outweigh the toxicity of the antiretroviral agents. However, our study and the two others examining nutritional markers among pregnant women receiving cART can neither support nor refute this assumption because all women received cART, and it would be unethical to randomize to non-cART treatment regimens. Furthermore, even if cART does improve nutritional status, we demonstrate in this cohort that there remain significant nutritional deficiencies and that these are associated with poor birth outcomes.
Mechanisms to explain these poor outcomes are likely numerous and not yet fully understood. For example, head-sparing, or asymmetric, growth restriction is thought to be due to preferential blood flow to the brain in the setting of placental insufficiency 
. Indeed, the inverse association between head-sparing growth restriction and weekly GWG suggests a nutritional basis for this placental insufficiency.
Much work is needed to determine factors that contribute to low GWG and weight loss among HIV-infected pregnant women, including the impact of initiating HAART during pregnancy versus use of HAART prior to conception. It is also necessary to develop strategies to identify those women at greatest risk for poor birth outcomes. Pre-pregnancy BMI has consistently been associated with adverse birth outcomes. However, because most women do not know their pre-pregnancy weight and do not have regular access to preconception care, this indicator is not clinically useful. In order to identify another relevant maternal anthropometric predictor of adverse fetal outcomes, Kelly and colleagues conducted a meta-analysis of 25 studies including over 111,000 births worldwide 
. They found that low maternal weight attained at 7 months gestation was a significant risk factor for fetal growth restriction, particularly among women with below average pre-pregnancy weight. Indeed in our study, those women with low weight at 7 months gestation were at particularly high risk of LBW. Because increased GWG in the 3rd
trimester was associated with a diminished odds of LBW, preterm delivery, and overall adverse birth outcome, these women with low weight at 7 months may benefit from a nutritional intervention.
Preterm delivery, LBW, neonatal stunting, SGA, and wasting are strong predictors of infants’ future health trajectories 
. With the increased availability of cART during pregnancy and breastfeeding, there is an expanding generation of HIV-exposed, uninfected children. Nutritional interventions that increase maternal weight gain during pregnancy have the potential to decrease the burden of a range of adverse birth outcomes among women infected with HIV. As such, the improvement of maternal nutritional status may be a golden opportunity to not only protect the health of the mother, but to improve birth outcomes and create a thriving generation of HIV-exposed, uninfected offspring.
There are several limitations to our study. Small sample size may have impaired our ability to find statistically significant predictors of head-sparing fetal growth restriction and other poor outcomes. Our findings may not be generalizable to other cohorts of HIV-infected pregnant women receiving cART (e.g. 
) because our participants were older, nearly all were multigravidae and mean BMI was lower 
. Further, our results may not be generalizable to those women on cART prior to conceiving. We excluded multiple births because of its known effect on adverse birth outcomes, which may further limit the generalizability of our findings. Our finding that higher SES was associated with an increased odds of an adverse birth outcome may be spurious because the SES measure was generated using principal component analysis of specific asset holding questions and not a validated poverty scale. Such a measurement could have been vulnerable to unmeasured confounding. Finally, we analyzed data from an on-going randomized trial and differences by study treatment arm cannot be addressed until study completion and data unblinding.
In conclusion, initiating cART during pregnancy among HIV–infected women in rural Uganda successfully prevented HIV transmission to their infants but did not prevent poor nutritional status during pregnancy that independently predicted poor birth outcomes. More attention is needed to characterize the scope and causes of nutritional deficiencies among this population and to design interventions that improve both the health of HIV-infected mothers and optimize the health and development of their offspring.