Pre-term delivery and HAART
Polly Clayden, HIV i-Base
A poster discussion session at CROI 2011 looked at HAART during pregnancy and pre-term delivery. 
Discussant Claire Thorne, from the MRC Centre of Epidemiology for Child Health and the Institute of Child Health, began with a quick overview of the inconsistent findings on this controversial topic to date.
Pre-term delivery is defined as birth before 37 weeks of gestation. Recent WHO estimates suggest about one in ten infants are born prematurely. The rate varies across the world with the lowest in Europe and highest in Africa. Pre-term infants account for 75% of perinatal mortality and 85% of all pre-term births occur in Africa and Asia. Dr Thorne noted that why this happens is still not completely understood.
An association between HAART and pre-term delivery was first observed in Europe in 2000. Since then several (mainly European) studies have reported similar findings and other (mainly American) reports have not found an association. Dr Thorne stressed that issues of populations and methods are critical to the interpretation of these diverse findings.
While the benefits to mothers and PMTCT from HAART are unequivocable, pre-term infants have higher morbidity and mortality risks than those carried to full term. Approximately 80% of pre-term infants of women receiving HAART are born between 32 and 36 weeks, when these risks are relatively low at least in industrialised countries. However striking inequalities exist in the chance of survival of pre-term infants between these settings and those with more limited resources.
This session included cohort data from France, Spain and Botswana and from a randomised trial in Botswana.
Jeanne Sibiude showed findings from the National ANRS French Perinatal Cohort.  This study investigated trends in pre-term delivery between 1990 and 2009 among all singleton pregnancies included in the cohort (n=13957). Risk factors were identified in a subgroup of women (n=2631) for which more detailed data were collected between 2005 and 2009.
The investigators performed multivariate analyses adjusted for maternal age, intravenous drug use, BMI, smoking, assisted conception, HCV coinfection, timing of initiation of ART and baseline viral load
They observed a steady rise in pre-term delivery by time period reflecting changes in routine management: 9.2% in 1990 to 1993 (no ART during pregnancy) and 9.6% in 1994 to 1996, (AZT monotherapy for 90% of women), to 12.4% during 1997 to 1999 (double NRTI treatment for the majority and HAART for selected women), and 14.3% in 2005 to 2009 (HAART), p<0.01. This exceeded the background rate in France of 4.3% in 1995 and 5.9% in 2005.
Between 1990 and 2009 the risk of pre-term delivery overall was higher for HAART and double NRTI treatment than for AZT monotherapy, AOR 1.69 (95% CI 1.38- 2.07) and 1.24 (95% CI 0.96-1.6) respectively, p<0.001.
Among the subgroup of women initiating HAART during pregnancy in 2005-2009 pre-term delivery rates were similar between women already receiving HAART at conception and those initiating HAART in pregnancy, respectively 14.2% and 13.6%, p=0.6.
Pre-term delivery was also associated with maternal age, IV drug use, smoking, BMI, marital status and late access to care.
Most women received a RTV-boosted PI. There was a higher risk of pre-term delivery among women receiving a boosted, compared to a non-boosted PI (very few women received NNRTI-based regimen in this cohort), 14.4 vs 9.1%, AOR 2.03 (95% 1.06-3.89), p=0.03.
Women initiating HAART with a boosted PI during pregnancy were more likely to be hospitalised for any cause, particularly premature labour, metabolic or vascular disease and infections, compared to those receiving a non-boosted PI, p<0.001. The investigators suggested this might be due to increased toxicity at the end of pregnancy.
Maria Isabel González-Tomè resented data from the Spanish Cohort for the Study of HIV MTCT.  This was a prospective cohort study of 803 children in 7 Spanish hospitals. MTCT interventions were: none, AZT monotherapy, double NRTI, HAART with PI and HAART without PI. Risk factors were evaluated for pre-term delivery and low birth weight <2500 grams.
This study found 175 (21%) pre-term deliveries and 200 (25%) infants with low birth weight.
Older age, HCV coinfection, prenatal care and no antiretroviral treatment during pregnancy were associated with pre-term delivery in univariate analysis.
In multivariate analysis, only illegal drug use was associated with pre-term delivery, OR 2.9 (95% CI 2.2-4.0), p=0.0001 and CD4 >250 cells/mm3 was protective, OR 0.4 (95% CI 0.2-0.65), p=0.0001.
In this cohort, unlike the other presentations, HAART with or without PI was not significantly associated with pre-term delivery or low birth weight.
The first presentation from Botswana was by Natasha Parekh from the Harvard School of Public Health who showed data from 16,203 deliveries from October 2007 to March 2010.  Data were taken from obstetric records of women with live births at 26 weeks or longer gestational age across 6 hospitals. Out of 15,326 women in this cohort with HIV status recorded, 4,343 were HIV-positive.
The investigators evaluated rates of pre-term delivery, very pre-term delivery (<32 weeks) and very small for gestational age (<3rd percentile on Botswana-specific weight-for-age curves). They then looked at risk factors for very pre-term delivery and very small for gestational age among all women and HIV-positive women.
They found a prevalence very pre-term delivery of 4.3% and respective rate of neonatal death of 26%, OR 49 (95% CI 38-64) and a prevalence of very small for gestational age of 3.7% with a respective rate of neonatal death of 8%, OR 5.2 (95% 3.8-7.1).
In multivariate analysis, very preterm delivery was associated with history of poor obstetric outcome (including stillbirth, preterm delivery, or low birth weight), AOR 2.12 (95% CI 1.54-2.93), hypertension in pregnancy AOR (1.75, 95% CI 1.17-2.63), and maternal HIV infection AOR 1.65 (95% CI 1.26-2.17). Very small for gestational age was also associated with a history of poor obstetric outcome AOR 1.77 (95%CI 1.23-2.53), hypertension in pregnancy AOR 3.44, (95%CI 2.40-4.93), and maternal HIV infection AOR 1.90 (95%CI 1.41-2.55).
Initiating HAART before conception was associated with very small for gestational age, AOR 1.75, (95% CI 1.21-2.52), but not with very pre-term delivery, AOR 0.78, (95% CI 0.49-1.26). Among HIV-positive women. HAART initiation before conception was also associated with hypertension in pregnancy, AOR 1.34 (95% CI 1.00-1.77).
Kathleen Powis presented the only data from a randomised controlled trial in the second presentation from Botswana. 
This study analysed 530 women (267 receiving PI-based and 263 triple NRTI HAART) in the randomised treatment arms of Mma Bana who received a median of 11.3 weeks (IQR 8.3-12.9 weeks) of HAART in pregnancy.
The investigators found higher rates of pre-term delivery in the women receiving a PI compared to those receiving triple NRTI treatment, 21.4% vs 11.8%, p=0.003. This was regardless of duration of HAART in pregnancy.
In multivariate analysis, PI-based HAART in the third trimester of pregnancy was associated with a two-fold increase in pre-term delivery AOR 2.03 (95% CI 1.26-3.27).
The investigators noted a lower maternal weight gain in the women receiving PI-based treatment compared to triple NRTI but this had no association with the likelihood of pre-term delivery.
They found a 2-fold higher rate of hospitalisation (22.7 vs 12.7%, p=0.02) and 5-fold higher rate of mortality (6.8 vs 1.4%, p=0.002) in the first 6-months of life among infants born pre-term but they did not observe a difference by maternal treatment regimen.
Much discussion following the presentations focused on the difficulties of accurately determining pre-term delivery, which has contributed to uncertainty, particularly with observational data. PI-based HAART does appear to show increased likelihood of pre-term delivery from the controversial data to date.
All references from 18th Conference on Retroviruses and Opportunistic Infections, Boston, February 2011 unless otherwise indicated.
- Themed discussion: HAART during pregnancy and pre-term delivery. Tuesday, 1pm.
- Sibiude J et al. Large increase in prematurity between 1990 and 2009 in HIV-infected women in the National ANRS French Perinatal Cohort: does ritonavir boost play a role? Poster abstract 743.
- González-Tomé MI et al. Risk factors of preterm delivery and low birth weight in a multicentre cohort of HIV-positive pregnant women. Poster abstract 744.
- Parekh N et al. Risk factors for very premature and very mall for gestational age infants in Botswana. Poster abstract 745.
- Kathleen Powis et al. Protease inhibitor-based ART was Associated with pre-term delivery, but not adverse infant outcomes, in a randomised MTCT prevention study in Botswana. Poster abstract 746.