By Carole Leach-Lemens
Analyses of 20 years of data from the Antiretroviral Pregnancy Register (APR)
shows no risk of birth defects or other defects from antiretroviral use, either
in combination or as individual drugs, when compared with observed rates in a
population-based surveillance system, researchers reported at the Eighteenth
International Conference on AIDS in Vienna.
However, further research from the Antiretroviral Pregnancy Register showed
that exposure to protease inhibitors (PIs) may potentially contribute to
pre-term birth (PTB) and low birth weight (LBW), while the Pediatric HIV/AIDS
Cohort Study (PHACS) Surveillance Monitoring of Antiretroviral Toxicity (SMARTT)
reported that exposure to tenofovir (TDF, Viread) may slow infant
growth.
Efavirenz: no evidence of increased risk of birth defects
The first trimester is a time of intensive growth of vital organs, when the
foetus is especially susceptible to the harmful effects of drugs or other
substances.
Efavirenz exposure during early pregnancy has been shown in animal studies to
lead to birth defects, leading to a recommendation that it should not be used in
pregnancy, especially in the first trimester.
Nathan Ford, of the University of Cape Town, and colleagues, elaborated on
results, published earlier this month, of a systematic
review and meta-analysis suggesting that efavirenz taken in the first
trimester did not affect birth outcomes. However, given the small sample size
involved, the researchers called for further studies using larger numbers.
He also cautioned of the risks associated with acting on suspicion of
efavirenz causing birth defects. He stressed the need for careful counselling
since the findings showed that a high rate of termination of pregnancy was being
driven by suspicion and not by evidence. He also highlighted the need for
standardisation of outcome data collection and the need for a more robust data
set.
The need for long-term surveillance of antiretroviral-exposed infants
Antiretroviral therapy has had a significant effect on improving maternal
health and reducing mortality, as well as preventing the transmission of HIV to
infants. “As maternal triple-drug use increases, it is critical to enhance
surveillance for complications in pregnancy and [the] long-term outcomes in
infants,” stated Lynne Mofenson in her overview and introduction to the session.
She gave the example of a drug given to pregnant women in the 1950s,
diethylstibesterol (DES), the effects of which were not recognised in the female
offspring for decades, who were at increased risk for cervical as well as other
cancers.
The Antiretroviral Pregnancy Register is an ongoing international registry
started in 1989 to collect reports from healthcare providers about adverse
outcomes, such as birth defects or other abnormalities among infants born to
women taking antiretrovirals during pregnancy.
A total of 11,261 live births to women with HIV receiving antiretroviral
drugs were reported to the Antiretroviral Pregnancy Register. Of infants exposed
to antiretrovirals from January 1989 to January 2010, the overall prevalence
was 2.7 defects per 100 births (95% CI: 2.4 to 3.0), Vani Vannappagari
reported. Of the 4864 infants exposed during the first trimester, the prevalence
rate was 2.8% (95% CI: 2.4 to 3.4). These rates are comparable both to the
general population-based surveillance system, with a rate of 2.7%, (95%CI: 2.68
to 2.76) and the internal comparator of those exposed during the second and
third trimesters – 2.5% (95%CI: 2.2 to 3.0).
Understanding of the association between exposure to antiretrovirals,
pre-term births and low birth-weight (under 2500 grammes) is poorly understood.
Some evidence from small cohorts has suggested the increased prevalence of
pre-term birth and low birth weight is associated with exposure to protease
inhibitors. Other studies have not reproduced this finding.
In a separate analysis of the Antiretroviral Pregnancy Register, Karen
Beckerman and colleagues analysed 7334 of 10,022 reported births from January
1989 to January 2009. The researchers compared the prevalence of pre-term births
at less than 37 weeks into the pregnancy, at less than 32 weeks, birth weight
under 2500 grammes, and birth weight under 1500 grammes among infants exposed to
one antiretroviral, two or more antiretrovirals (combination therapy) that
included a protease inhibitor (PI), and combination therapy that did not include
a PI.
No differences were reported in pre-term births and birth weight under 2500
grammes in those newborns exposed either to one drug or to a combination of
antiretrovirals.
However, more infants exposed to combination therapy that included a PI were
born weighing less than 1500 grammes (17.4%) than those exposed to combination
therapy without a PI (14%).
Pre-term birth (under 37 weeks) was higher in those women on a PI-containing
regimen than without, 14.1% compared to.11.8% (p 0.003). However, there was no
significant difference in the proportion of pre-term births that occurred before
32 weeks of gestation according to the dose of drug the mother took.
The prevalence of birth weight under 1500 grammes in those exposed to a
combination that included a PI, while higher than in those exposed to a
combination without a PI, was the same as those exposed to one antiretroviral
and was protective against pre-term birth under 32 weeks (p 0.05).
Nonetheless, the prevalence of birth weight under 1500 grammes was lower in
all combination groups than in previously published reports of cohorts of
HIV-exposed newborns with no antiretroviral exposure.
Very low birth weights, Karen Beckman cautioned, are seen in very small
numbers of infants. For example, in their analysis of 10,000 live births, 188
babies were born weighing less than 1500 grammes.
She added that pre-term birth is better described as pre-term delivery
syndrome. “Multiple causes are involved, including infectious and immunological
ones,” she noted, adding, “We do not know how maternal disease stage and
activity may affect pregnancy.”
Potential effect of tenofovir on infant growth
The PHACS SMARTT study set up in the United States to look at adverse effects
of infants exposed to antiretrovirals during pregnancy, with annual follow-up,
looked at the effects of tenofovir on low-birth weight and infant growth. Animal
studies had raised concerns about the potential of maternal tenofovir slowing
infant growth.
Tenofovir is a recommended component of first-line treatment for adults, with
increasing use in pregnant women. The Antiretroviral Pregnancy Register study
showed low birth weight was not associated with the use of tenofovir. Use of
tenofovir had increased from 15% in 2003 to 39% in 2009. George Siberry and
colleagues reported no increased risk for low birth weight of the 20% (380) of
infants exposed to tenofovir, compared to those not exposed (20.7 vs 19.5%,
p=0.46).
However, results suggested that tenofovir may slow infant growth, its effect
being delayed. Among 532 one-year-old infants, those exposed to tenofovir during
pregnancy had almost twice the risk for low weight compared to those not exposed
(aOR=1.76, 95% CI: 1.01 to 3.05). Differences in length and size of head
circumference were not significant.
Responding to a comment from the audience, Dr. Siberry said he would look
again whether this may have resulted from mothers with hepatitis B co-infection,
but he was doubtful since all confounders had been considered.
The researchers concluded that more evidence is needed on the impact of
tenofovir exposure on infant growth rates. Chewe Luo, Senior HIV/AIDS Adviser,
Technical Scale-Up Cluster, UNICEF, commented “This is a concern. We need to
look at this more critically,” and suggested “a nested case-control study to
evaluate these results”.
Dr Nathan Shaffer of the World Health Organization (WHO), co-chair of the
session, noted that the Antiretroviral Pregnancy Register was based primarily on
data from the United States and Europe. In response to his concern about how
this would expand to include other regions of the world, Dr. Vannappagari noted
that there was now a toll-free number operating in a number of African
countries, as well as Brazil, for data reporting, in addition to internet
reporting for those with access. Further details can be obtained from www.apregistry.com.
References
Siberry G et al. Safety of tenofovir use during pregnancy: associations
with low birth weight and early growth in HIV-exposed uninfected infants.
Eighteenth International Conference on AIDS, Vienna, abstract WEAX0103,
2010.
Vannappagari V et al. Monitoring birth defects among HIV positive, ART
exposed pregnant women: 20 years of antiretroviral pregnancy registry data.
Eighteenth International Conference on AIDS, Vienna, abstract WEAX0104,
2010.
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 January 31 2009. Eighteenth International
Conference on AIDS, Vienna, abstract WEAX0105, 2010.
Mofenson L. Overview on antiretrovirals during pregnancy and
breastfeeding: importance of surveillance and implications for developing
countries. Eighteenth International Conference on AIDS, Vienna, abstract
WEAX0101, 2010.
Ford N et al. Safety of efavirenz in first-trimester of pregnancy: a
systematic review and meta-analysis of outcomes from observational cohorts.
Eighteenth International Conference on AIDS, Vienna, abstract WEAX0102,
2010.
Further information
Presentations by the
speakers and their related abstracts are available on the official
conference website.