Birth outcomes with antiretroviral exposure

Polly Clayden, HIV i-Base

In a session at the IAS 2010 conference entitled Antiretrovirals during pregnancy and breastfeeding: Importance of surveillance, data were presented describing what we know (or don’t know) about outcomes among infants exposed to antiretrovirals in utero. [1]

New data from the US was shown by George Siberry that evaluated growth parameters in tenofovir exposed infants. [2]

Lynne Mofenson provided a useful overview of the implications for women and children in developing countries. Nathan Ford presented findings from a meta-analysis looking at the safety of efavirenz in the first trimester of pregnancy (which we reported in the June 2010 edition of HTB) [3, 4, 5]. And Karen Beckerman showed data from the Antiretroviral Pregnancy Registry (APR) that looked at preterm delivery (PTD) and low birth weight (LBW) in this  cohort. [6]

There was agreement among the presenters on the importance of surveillance, both from industrialised and resource-limited settings. Nathan Ford rightly  pointed out that, although the largest data set contributing to their review was from the APR, the second largest set came from one centre, the Frere  Hospital in South Africa. It is very likely that much important pregnancy outcome data is simply not being captured.

During discussions with the audience, Graham Taylor emphasised the role of reporting bias, particularly with respect to efavirenz. This is the only  antiretroviral with preclinical primate data and in turn has the strongest FDA category and the most scrutiny in pregnancy. The point was made that the  only report of myelomeningocele in the prospective reports section of the APR was of a child exposed to efavirenz during the first trimester. However, the absence of other reports of myelomeningocele in the registry, that might be expected given a general background rate in the order of 1 per 1000 births, despite almost 12,000 evaluable prospective case reports was also commented upon.

There was agreement that when a mother needs treatment for her own health the benefits of antiretrovirals in pregnancy hugely outweigh any theoretical risks.

Tenofovir exposure and low birth weight and infant growth

Preclinical studies showed that tenofovir crosses the placenta. There have been
concerns that undermineralisation of foetal bones was observed in animal studies. Tenofovir use in pregnancy is on the increase but there are limited human data describing infant outcomes.

George Siberry presented data on behalf of the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of Antiretroviral Toxicity (SMARTT) study. SMARTT enrols antiretroviral exposed uninfected children in the US at two weeks of age (dynamic cohort) and at one year to 12 years of age (static cohort).

This study was conducted to evaluate the association of maternal tenofovir use and growth measures (weight, length, head circumference) at birth and at one year of age.

Maternal information is collected prospectively for dynamic cohort and retrospectively for static cohort.

In this study, LBW was defined as <2.5kg. Z-score < -1.5 was used to define small-for-age for length and HC at birth and length, weight and HC at one year.

Logistic regression models for LBW and growth outcomes were fit, controlling for potential confounders, including demographic and socioeconomic characteristics, maternal health status (CD4< 250, viral load>1000 copies/mL, genital infections) and substance use during pregnancy.

The evaluation revealed 1887 children with birth weight data for which birth length and HC measurements were available from 739 children from the dynamic cohort. Growth measurements at one year were recorded for 532 children (weight length and HC), of which 356 were from the dynamic and 176 from the static cohorts.

The investigators found that maternal tenofovir use increased from 15% in 2003 to 39% in 2009. Overall 21% of the cohort was exposed to tenofovir including 12% receiving it from the first trimester.

Among the 20% of infants with LBW, there was no difference in those exposed to tenofovir (20.7 vs 19.5%). After adjusting for confounders there remained no effect (aOR: 1.03, 95% CI 0.75-1.40, p=0.87). Neither was there an association between tenofovir use and short length or small HC at birth.

However, at one year of age children exposed in utero to tenofovir in this cohort had a marginally increased risk of low weight (aOR:1.76, 95% CI1.01-3.05).

The investigators suggested that this observation requires confirmation in further studies.

Preterm birth in the Antiretroviral Pregnancy Registry

Some reports suggest increase prevalence of PTD and LBW associated with protease inhibitor (PI) exposure, while reports from other cohorts do not.

Karen Beckerman presented data from an evaluation from the Antiretroviral Pregnancy Registry (APR) of birth weight and estimated gestational age of live births reported to this registry.

We have reported findings from the APR in previous issues of HTB. It is a prospective registry with which providers register pregnant women with antiretroviral exposure during their pregnancy and in turn provide outcome data.

In this analysis the investigators compared the prevalence of PTD at <37 and <32 weeks gestation, and LBW <2.5kg and very LBW <1.5kg among infants exposed to one antiretroviral or regimens of two or more antiretrovirals that either included a protease or did not.

Since 1989 and as of January 31st 2009 the APR had enrolled 12451 pregnancies; 426 (3.4%) had outcomes pending and 1082 (8.7%) were lost to follow up. There were 9513/10022 (95%) singleton live births with evaulable data.

Dr Beckerman reported that, in this analysis, the investigators found no differences in the prevalence of either PTD <37 weeks, 14.7% vs 13.0%, or LBW <2.5kg, 15.4% vs 16.1%, between the 1404 infants exposed to one antiretroviral compared to 8109 infants exposed to combination antiretroviral regimens.

Of those exposed to combination antiretroviral regimens, PTD <37 weeks was higher among those receiving PI-containing regimens (n=4658) compared to non PI-containing regimens (n=3451), 14.1% vs 11.8%, p=0.003, as was LBW <2.5kg p=0.001.

But PTD <32 weeks was no different between those exposed to regimens containing a PI compared to regimens without a PI, 2.3% vs 1.8%, p=0.16.

They also found that very LBW <1.5kg was more prevalent in infants exposed to PI-containing regimes compared to those without a PI, 17.4% vs 14.0%. But after controlling for race very LBW <1.5kg, for each exposure group, overlapped prevalence in the background population.

They found that there was no difference in very LBW <1.5kg in infants exposed to PI containing regimens compared to those exposed to one antiretroviral. They also found exposure to PI-containing regimens was protective against PTD <32 weeks, p=0.05.

They noted that very LBW <1.5kg was lower in all groups exposed to combination antiretroviral regimens than published reports of cohorts of HIV-exposed infants not exposed to antiretrovirals.

They concluded that optimised combination antiretroviral regimens offer profound benefit to maternal survival and vertical transmission prevention.

They added: “We hypothesise that exposure to PI could be a surrogate marker for immunologic and other factors contributing to preterm parturition and low birth weight syndromes in HIV-exposed neonates.”


The debate on whether combination therapies, particularly PI-based HAART are
associated with PTD continues.

Given that most of the data suggesting that there is no association has come from the US and that most of the data (85%) in the APR is also from the US, it should perhaps come as no surprise that no strong link with HAART was found.

The data suggesting a link with PTD is mostly from Europe, however in her presentation Lynne Mofenson drew attention to the recent RCT from Botswana investigating HAART during pregnancy and breastfeeding to reduce HIV transmission in which an increased rate of PTD was found in the PI-based arm
compared with the triple NRTI.


Unless otherwise stated, all references are to the Programme and Abstracts of the 17th International AIDS Conference, 18-23 July 2010, Vienna.

  1. Antiretrovirals during pregnancy and breastfeeding: Importance of surveillance. Session WEAX01
  2. Siberry G et al. Safety of tenofovir use during pregnancy: associations with low birth weight and early growth in HIV-exposed uninfected infants. Oral abstract WEAX0103.
  3. Mofenson L. Overview on antiretrovirals during pregnancy and breastfeeding: importance of surveillance and implications for developing countries. Session introduction WEAX0101.
  4. Ford N et al.Safety of efavirenz in the first trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. Oral abstract WEAX0102.
  5. Clayden P. Pregnancy outcomes with efavirenz. HTB. Volume Volume 11 Number 5/6 May/June 2010.
  6. Beckerman K et al. Preterm Birth (PTB), low birth weight (LBW) and fetal antiretroviral (ARV) exposure: Gestational age (EGA) and birth weight data from 10022 singleton live births (LB) reported to the Antiretroviral Pregnancy Registry (APR) 1989 through 31 January 2009. Oral abstract WEAX0105.

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