HIV infection does not increase the risk of complications caused by dangerously high blood pressure that develops during pregnancy – pre-eclampsia and eclampsia – but more investigation is needed of the impact of different classes of antiretrovirals on these conditions, two studies published in the journal Pregnancy Hypertension report.
Pre-eclampsia is a condition that may develop in the second half of pregnancy, starting with raised blood pressure and protein in the urine, leading to severe headaches, swelling and vision problems. In a small proportion of cases the condition leads to the development of eclampsia, in which mothers may suffer seizures.
Pre-eclampsia affects between 3 and 8% of pregnant women, while eclampsia affects around 1% of pregnant women. Eclampsia is more likely to be life-threatening in settings where medical monitoring is less frequent or perinatal care is less developed.
There is some evidence that inflammatory conditions increase the risk of pre-eclampsia, although the most important risk factors are obesity, diabetes, age over 35, pre-existing high blood pressure or kidney disease, carrying twins or triplets, or a family history of pre-eclampsia.
HIV and pre-eclampsia
Several studies have investigated whether HIV infection affects the risk of developing pre-eclampsia, since immune suppression might affect the pathways that lead to the development of the condition. Studies have produced conflicting findings; some have shown a reduced risk, others have not, and not all studies have looked at the laboratory markers associated with pre-eclampsia.
Researchers at universities in Iran carried out a meta-analysis and systematic review of published studies on pre-eclampsia and HIV. They identified 22 studies (11 prospective and 11 retrospective cohort studies) with comparison groups of pregnant HIV-negative women, comprising 90,514 women with HIV and just over 66 million HIV-negative women.
The meta-analysis found no significant difference in the incidence of pre-eclampsia between HIV-positive and HIV negative women (4.33% vs 3.98%, relative risk 1.04, 95% confidence interval 0.89-1.21). When studies were considered on a regional basis, no region showed a significant difference. The meta-analysis found no difference between retrospective and prospective studies. The meta-analysis found a declining risk of pre-eclampsia in studies published between 1990 and 2018.
Looking at eclampsia, the meta-analysis found a slightly higher incidence in HIV-positive women, but the difference was not statistically significant (1.71% vs 1.2%, RR 1.05, 95% CI 0.63-1.75). Retrospective studies, but not prospective studies, did show a significantly increased risk (RR 1.42, 95% CI 1.34-1.50), as did studies carried out in Italy and the United States, leading the investigators to call for further large, prospective studies.
The investigators identified six studies which looked at levels of angiogenic and anti-angiogenic factors in blood. An imbalance between these factors may lead to changes in placenta that result in pre-eclampsia, but the six studies showed no association between HIV and increased levels of anti-angiogenic factors.
Antiretroviral treatment and pre-eclampsia
As World Health Organization treatment guidelines recommend antiretroviral treatment for all pregnant women with HIV, it is important to know whether any antiretroviral drug class or combination raises or reduces the risk of pre-eclampsia. Dr Ashish Premkumar and colleagues at Northwestern University, Chicago, carried out a systematic review of randomised and observational studies which reported on hypertensive disorders in pregnant women with HIV – the onset of hypertension during pregnancy, pre-eclampsia or eclampsia.
"Only seven of the 28 studies were judged to be of 'good' quality."
The investigators identified 28 studies, none of them randomised trials. Nineteen were cohort studies, but eight included no control group and only seven of the 28 studies were judged to be of 'good' quality, meaning that they had matched control groups and adjusted for potential confounding factors in their analysis.
The investigators also identified numerous variations in definition of hypertensive disorder in pregnancy, depending on the date and location of the study, as well as the measured study outcomes. For example, whereas some studies measured pre-eclampsia, others combined a diagnosis of gestational hypertension or pre-eclampsia into one outcome.
These differences resulted in very wide variations in reported rates of hypertensive disorders – between 0.8 and 54% – and relative risks.
Only five studies compared women who were exposed to antiretrovirals to a control group of women with HIV who did not take antiretroviral drugs during pregnancy. Each study reported an increased risk of hypertensive disorders during pregnancy, with increased odds ranging from 1.27 to 8.90. The investigators note that in most of these studies, the number of women on antiretroviral therapy who developed pre-eclampsia was very low, making any estimates of risk akin to a wild stab in the dark.
The issue of low sample size similarly afflicted studies which sought to compare risks according to antiretroviral drug class. Although several studies found an association between protease inhibitor treatment and hypertensive disorders, the investigators concluded that they were underpowered to reach a conclusion on the relationship.
The study investigators conclude that larger, better-designed studies are needed to identify whether specific antiretrovirals are associated with hypertensive disorders in pregnant women with HIV, and whether immune reconstitution has any impact on the risk. They recommend that studies should also investigate whether hypertension in pregnancy in women taking antiretrovirals is caused directly by antiretrovirals (toxicity) or is a consequence of treatment or immune reconstitution perturbing the balance between angiogenic and anti-angiogenic factors.
Premkumar A et al. Combined antiretroviral therapy for HIV and the risk of hypertensive disorders of pregnancy: a systematic review. Pregnancy Hypertension 17: 178-190, 2019.
Shiadeh MN et al. Human immunodeficiency virus and risk of pre-eclampsia in pregnant women: a meta-analysis on cohort studies. Pregnancy Hypertension 17: 269-275, 2019.