Increased rates of pre-term delivery are associated with the Initiation of HAART during pregnancy: a single-centre cohort study

3 September 2007. Related: Pregnancy.

Polly Clayden, HIV i-Base

A paper authored by Fabiola Martin and Graham Taylor from St Mary’s published in the July 9, 2007 edition of The Journal of Infectious Diseases, looked at the association between pre-term delivery (PTD ie delivery before 37 weeks) and use of HAART during pregnancy. [1]

PTD occurs in 6-8% of all pregnancies. The authors explain that many factors contribute to the risk of PTD, including history of previous PTD, genitourinary infections, uterine distension, cervical incompetence, uteroplacental insufficiency, and recreational use of drugs, alcohol, and tobacco. Whether the use of HAART in pregnancy is associated with increased PTD risk remains controversial.

Previous findings conflict: the European Collaborative and Swiss HIV Mother and Child Cohort studies found combination therapy (but not AZT monotherapy) to be associated with an increased risk of PTD, compared with no antiretroviral therapy (PI-containing, odds ratio [OR], 2.6; non-PI OR, 1.8). [2]

In the Women and Infants Transmission Study (WITS), PTD rates were decreased with late use of AZT-containing HAART (any time after 25 weeks) and increased with late use of HAART that did not contain AZT. They also found treatment containing a NRTI other than AZT, used during early and late pregnancy was associated with a decreased risk for PTD at <32 weeks (OR, 0.3). [3]

The authors note that the overall rate of PTD was high (17%) in both of these large cohorts.

Additionally, in a recent report, a single-centre cohort of 999 mothers in Miami found PTD to be greater with PI-containing HAART than with a non-PI regimen and AZT monotherapy (OR, 1.8). [4]

In the context of these controversies the authors evaluated the incidence of PTD in their own single-centre cohort.

At St. Mary’s Hospital, treatment and care follows BHIVA pregnancy guidelines, which describe four treatment scenarios for mothers presenting during the first and second trimesters: (1) mothers who conceive while receiving HAART and continue treatment; (2) mothers with low CD4 counts and high viral loads who initiate HAART during pregnancy; (3) mothers who do not yet need HAART for their own health but initiate short-term HAART (START) for prevention of mother-to-child transmission only up to delivery (these mothers will have CD4 counts >200 cells/mm3); and (4) mothers who choose to receive AZT monotherapy and deliver by pre-labour, pre-rupture of membranes caesarean section (this is only recommended for some mothers with viral loads<10,000 copies/mL and CD4 counts >200 cells/mm3). [5]

The authors performed a case note review of all deliveries to HIV-positive women since 1995. Between 1995 and 1998 women were managed according to the ACTG 076 protocol and from 1998 according to BHIVA guidelines.

They reported 227 deliveries between December 1995 and November 2006. Of the St Mary’s cohort, 84.5% of mothers were black African; 11.9% were white European; and 3.5% were of other ethnicity. The majority of women acquired (95%) HIV through heterosexual sex and 1.8% through IV drug use.

Three (50%) of 6 infants not exposed to any maternal antiretrovirals and 1/52 (1.92%) in the AZT monotherapy group were HIV-positive. Seven mothers who received two drugs (no PTD), 6 who received no treatment (1 had PTD), and 3 for whom no gestational age was recorded, were excluded from the final analysis (n=16).

They reported that, of the remaining 211 deliveries, 178 (84.4%) were term deliveries and 30 (14.2%) were PTDs (19 [9%] were at <34 and 5 [2%] were at <32 weeks). There were 3 intrauterine deaths (1 was at term and 2 were PTDs [one at <34 and another at 34–37 weeks]).

The majority of mothers delivered by caesarean section: 122 (57.8%) pre-labour, and 38 (18%) by emergency caesarean section; and 33 mothers (15.6%) delivered by spontaneous vaginal delivery, 6 (2.8%) by induced vaginal delivery. There was no recorded mode of delivery for 12 mothers (5.7%) documented, including 2 PTDs at <34 weeks.

The majority of pre-labour caesareans were performed at 37 weeks; 4 (3%) were performed <37 weeks; 2 for pre-eclampsia, 1 for hydrops fetalis, and 1 for maternal cardiac failure. There were 7 PTDs (17.9%) among mothers delivering vaginally, of which 6 were <34 weeks.

Overall 30 mothers (14%) had PTDs. The PTD group were slightly older than the mothers with term delivery: mean age 32 years vs 29 years. Additionally, they had lower median CD4 cell count (260 [range, 10–860] cells/mm3) than mothers with term deliveries (350 [range, 210–500] cells/mm3) (p=0.04). There was no significant difference in median viral load in the two groups: 2377 (range, 49–18,285) copies/mL for term deliveries vs. 7715 (range, 49–21,826) copies/mL for PTD.

Three (10%) mothers received AZT monotherapy and 27(90%) received HAART during pregnancy. Of the HAART group, 23% were already receiving HAART, 30% received START, and 37% initiated HAART in the pregnancy and continued. Sixty-seven percent of all PTDs occurred in 85 mothers (40%) who started HAART during this pregnancy.

In the multivariate analysis, initiating HAART during pregnancy remained the only risk factor for PTD (OR, 5.03 [95% CI, 1.4 –17.8]; p=0.013).

The median change in CD4 counts between first ANC and delivery (median, 59 [range, 13–143] cells/L) was not significantly associated with PTD nor was viral load, neither at first ANC alone nor when correlated with prophylaxis or treatment arm. The odds of having a PTD was 0.3 for AZT monotherapy, 0.6 for preconception HAART, 2.2 for START, 2.4 for new continuous HAART, and 3.5 when START and new continuous HAART were combined.

They found no significant difference in PTD rates comparing a PI- with an NNRTI-containing HAART regimen. Initiating a PI-containing regimen showed a trend toward a higher risk of developing PTD than an NNRTI-containing regimen, without statistical significance (OR, 1.8 [95% CI, 0.7–4.3]).

In their discussion the authors write: “The lack of an association of PTD with change in CD4+ T cell count from first ANC to delivery could imply that the HAART effect represents drug toxicity or that in pregnancy changes in CD4+ T cell count may not fully reflect the impact of therapy on immune reconstitution due to the physiological reduction of CD4 + T cell count during pregnancy.” They speculate: “Fiore et al. showed that the physiological Th1 to Th2 shift that occurs during pregnancy was reversed in HIV-1–infected mothers who had conceived while receiving HAART and may account for PTD seen with HAART. It is biologically plausible that such an effect may be more dramatic if effective antiretroviral therapy is initiated during the pregnancy.” [6]

And they recommend: “that a fully informed choice by the mother should be made after consideration of all factors including not only the higher morbidity of pre-labour caesarean section compared with vaginal delivery but also the lower risk of adverse events such as PTD and pre-eclampsia with AZT monotherapy”.

Comment

This study adds to the growing evidence of a higher rate of PTD in women receiving HAART in pregnancy.

The observation that more than 50% of the PTDs occurred prior to 34 weeks gestation is also a concern. Again, HAART containing a protease inhibitor was associated with a higher rate of PTD than HAART with an NNRTI.

Where this study differs from previous reports, is the finding that initiating HAART during pregnancy, regardless of indication, was associated with more PTD than if HAART was started before pregnancy. If these observations are confirmed, the dilemma will be the timing of initiating therapy for mothers taking a short course of HAART for prevention of HIV mother-to-child transmission only. Early to ensure undetectable viraemia by the time of (pre-term) delivery or later to avoid initiating severe (<32 weeks) pre-term delivery?

AZT monotherapy was not associated with PTD in this cohort.

References:

1. Martin F and Taylor GP. Increased rates of preterm delivery are associated with the initiation of highly active antiretrovial therapy during pregnancy: a single-centre cohort study. The Journal of Infectious Diseases, 2007;196:558-561.
   
2. European Collaborative Study and Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000; 14:2913–30
3. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. JAIDS 2005; 38:449–73.
   
4. Cotter AM, Garcia AG, Duthely ML, Luke B, O’Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis 2006; 193:1195–201.
   
5. British HIV Association Pregnancy Guidelines Writing Committee 2005. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV.
   http://www.bhiva.org/cms1191558.asp
   
6. Fiore S, Newell M-L, Trabattoni D, et al. Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women. J Reprod Immunol 2006; 70:143–50.