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Possible Mechanisms for Adverse Pregnancy Outcomes in HIV-Positive Women

By Polly Clayden

January/February 2013

HIV positive women experience higher levels of adverse pregnancy outcomes than the general population. The mechanisms responsible for this remain unknown.

Two studies by researchers in Toronto exploring possible hypotheses to explain these adverse events were presented at the 3rd International Workshop on Women and HIV.1,2

Proper angiogenesis (the formation of blood vessels) is needed for the optimal formation of the placenta. A balance between pro- and anti-angiogenic factors is needed. An anti-angiogenic state has been associated with low birth weight, preterm delivery, and preeclampsia. HIV and antiretrovirals -- protease inhibitors in particular -- have been associated with altered levels of some angiogenic factors. However, this phenomenon has not been studied in HIV positive pregnant women.

Lena Serghides, on behalf of the Angiogenesis and Adverse Pregnancy Outcomes in Women with HIV (AAPH) study group, described their ongoing study. The overall study hypothesis is infection with HIV and/or ART disrupt the angiogenic balance required for a successful pregnancy and so contribute to adverse outcomes in HIV positive women.

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The study is currently enrolling 100 HIV positive pregnant women at five sites in Toronto. Women are recruited in their first trimester or early in their second and 4-9 blood samples are collected throughout pregnancy. A control group of 100 HIV negative pregnant women matched for gravidity, age, ethnicity, and educational levels are being enrolled as controls.

Maternal, placental, and cord blood, and placenta tissue are collected at delivery. Women are divided into three groups: those with full-term pregnancies and no complications, those delivering a small for gestational age neonate, and those that delivering preterm.

So far, 50 HIV positive women have been enrolled and 36 women have completed the study. A further 11 controls have been enrolled of whom three have completed the study. About 70% of women are black with a median age of 31.5 years undergoing their first second or third pregnancy. Over a third have experienced a previous miscarriage.

The majority of the HIV positive women received a boosted protease inhibitor-containing regimen.

Of the 36 HIV positive women who have completed the study, 6 delivered preterm (28, 32, 33, 2×34 and 36 weeks), this gave a rate of 16.7% compared to background rate of 8.1% in Ontario. A further 7 infants were small for gestational age (<10th percentile), 19.4% compared to background rate of 9.3%. There was one foetal death at 12 weeks.

The investigators found, compared to the 50th percentile for gestational age, HIV positive women had significantly lower birth weight (approximately 400g less, p=0.01), and placental weight (approximately 40g less, p=0.036). They observed a significant correlation between placental and foetal weight (R2=0.37, p=0.0005).

Several placental abnormalities were seen in the HIV positive women, including fibrotic lesions, intervillous thrombi, villous immaturity, inflammation, as well as higher than expected rates of succenturiate lobes (12%, normal rate 1-5%), and velamentous insertions (20%, normal rate 1-2%).

Although the study is incomplete the findings to date are an indication that adverse outcomes are high in this cohort of HIV positive women, including a high incidence of low birth weight and placental abnormalities. Dr Serghides asked whether angiogenic factors might be useful as biomarkers of pregnancy outcome and whether they are potential therapeutic targets. This research is ongoing.

A related presentation by Eszter Papp from the same research group showed findings from a study which looked in vitro and vivo at whether protease inhibitor-containing ART could influence progesterone production in placental cells, and how ART exposure influences progesterone levels and birth outcomes in a mouse model.

It is known that protease inhibitors inhibit enzymes involved in the synthesis of steroid hormones (contraceptive drugs) including progesterone. Progesterone is needed to maintain pregnancy and decreased levels have been linked to low birth weight and preterm delivery in humans. The investigators exposed placental cytotrophoblast (BeWo) cells to human plasma equivalent concentrations of NRTIs AZT and 3TC and protease inhibitors atazanavir, darunavir, lopinavir, and ritonavir either individually or in clinically relevant combinations with hypoxia control. Progesterone levels were measured by immunoassay.

In addition, pregnant mice were exposed to human-equivalent doses of ART, AZT/3TC plus boosted lopinavir or water as control throughout gestation (day 0-18). Pregnancy failure, number of implantations or foetuses, viability and foetal weight were recorded. Placental weight was also collected and progesterone levels were quantified from maternal plasma. The investigators found BeWo cells exposed to protease inhibitors had significantly lower progesterone production, while NRTIs had no effect on progesterone expression. Exposure to boosted protease inhibitor plus two NRTI combinations yielded lower progesterone levels in all cases.

Pregnant mice exposed to lopinavir/r and two NRTIs showed similar patterns. Mice exposed throughout gestation had more foetal loss (approximately 30% increase), less viable offspring per litter as well as significantly lower foetal and placental weights. There were significantly lower progesterone levels after ART exposure, which positively correlated with foetal weight (R2, 0.4595, p<0.05). Early (pre-implantation) exposure appeared to have more severe effect on birth outcomes than delayed (post implantation) exposure but even with sustained progesterone levels, foetal viability decreased.

The group plans further investigations into the fate of implants exposed pre-implantation only, the benefits of progesterone supplementation and comparing different antiretroviral combinations. They will also investigate correlations between progesterone levels and birth outcomes in humans (AAHP study participants).


References

  1. Papp E et al. Angiogenesis and Adverse Pregnancy Outcomes in Women with HIV: the AAPH study. 3rd International Workshop on HIV & Women. 14-15 January 2013, Toronto, Canada. Oral abstract O_012.
  2. Papp E et al. Progesterone level changes after cART exposure in vitro and in vivo are possibly linked to adverse birth outcomes. 3rd International Workshop on HIV & Women. 14-15 January 2013, Toronto, Canada. Oral abstract O_013.

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