Cumulative time on HAART increases health risks to both mother and foetus

On the final working day of the Fifteenth International AIDS Conference in Bangkok, Spanish researchers reported a new, unexpected side-effect of HAART in HIV-positive pregnant women. They found an increasing rate of pre-eclampsia – a rapidly progressive condition found only in pregnant women characterised by high blood pressure and the presence of protein in the urine – and foetal death, and associated the increased risk with time on HAART prior to pregnancy.

What is pre-eclampsia?

Pre-eclampsia – also known as pregnancy-induced hypertension (high blood pressure) or toxaemia – is a disorder that occurs only during pregnancy and the postpartum period and affects both mother and foetus. Affecting at least 5-8% of all pregnancies in the general population, it is a rapidly progressive condition characterised by high blood pressure and the presence of protein in the urine.

Pre-eclampsia is often silent, showing up unexpectedly during a routine blood pressure check and urine test, however swelling, sudden weight gain, headaches and changes in vision are important symptoms.

Pre-eclampsia can appear at any time during the pregnancy, delivery and up to six weeks postpartum, although it most frequently occurs in the final trimester and resolves within 48 hours of delivery. Pre-eclampsia can develop gradually, or come on quite suddenly, even flaring up in a matter of hours, although the signs and symptoms may have been present for months undetected or unnoticed.

Pre-eclampsia and other hypertensive disorders of pregnancy are a leading global cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 deaths worldwide each year, although most maternal deaths due to this condition occur in resource-limited countries.

Most women with pre-eclampsia still deliver healthy babies. A few develop a condition called eclampsia (seizures caused by toxaemia), which is very serious for the mother and foetus, or other serious problems. Fortunately, pre-eclampsia is usually detected early in women who get regular prenatal care, and most problems can be prevented. Delivery of the baby is the best way to protect both mother and foetus, but if this isn’t possible, then medications and/or bed rest to reduce blood pressure are prescribed until delivery is possible.

What the study found

All pregnant women, both HIV-positive and -negative, attending Hospital Clínic in Barcelona between January 2001 to August 2003 were included in this analysis. Out of 8768 women delivering babies, 82 (0.9%) were HIV-positive. Overall, there were 237 (2.9%) case of pre-eclampsia and 40 (0.5%) instances of foetal death. The researchers found that rates of pre-eclampsia were much higher in the HIV-positive women (11%) compared with the HIV-negative women (2.8%), and same was seen in instances of foetal death, which occurred in 6.1% of infants of HIV-positive women compared with 0.5% in HIV-negative women. This translated into a fivefold increased relative risk (RR) of pre-eclampsia (RR 4.9, 95% CI 2.4-10.1) and a thirteen-fold increased relative risk of foetal death (RR 13.7, 95%CI 5.3-35.6) amongst HIV-positive mothers compared to HIV-negative mothers (p < 0.01).

Once the researchers found this data, then then examined all the data they had on file for all of their HIV-positive pregnant patients, from October 1985 to August 2003. Data from 472 HIV-positive pregnant women were available: 258 from 1985 to 1994 (termed the ‘no antiretroviral therapy period’), 74 from 1994 to 1998 (‘the mono/double therapy period’), and 140 from 1998 to 2003 (‘the HAART period’).

Although, mother-to-child transmission of HIV was markedly reduced to zero in the HAART period (12%, 4%, and 0%, in the no therapy, mono/double therapy and HAART periods, respectively), cases of pre-eclampsia and foetal death were: 0 (0%) and 2 (0.8%), 0 (0%) and 0 (0%), and 8 (6.6%), and 5 (4.1%), in the same periods, respectively. Most of the cases of pre-eclampsia and foetal death occurred between 2002 and 2003. This, according to the researchers, was due to the long-term toxicities of HAART. In recent years, they said, only 20% of pregnant women had their HIV diagnosed during pregnancy, which suggests many pregnant women had been taking HAART for some time prior to their pregnancy.

In more detail, 122 HIV-positive pregnant women took HAART between 1998 and 2003, and there were eight cases (6.6%) of pre-eclampsia only, five cases (4.1%) of foetal death by any cause, and three cases (2.5%) of foetal death caused by pre-eclampsia. The single independent risk factor for any of these was found to be taking any kind of HAART before pregnancy (OR 5.6, 95% CI 1.7-17.9). Additionally, the risk increased for every month on HAART prior to pregnancy (OR 1.09 per month, 95% CI 0.001-0.018, p = 0.04).

Can smoking reduce the risk?

Controversially, smoking was found to be the single significantly protective factor for both pre-eclampsia and foetal death. This is sensitive information which goes against the grain of all public health messages to women regarding smoking in pregnancy. Currently, women are warned of the myriad hazards of smoking during pregnancy, which include a greater risk of low-birth weight babies, ectopic pregnancy, miscarriage, abnormal placental implantation, premature placental detachment, vaginal bleeding, premature delivery, and infant death. However, in this study, smoking reduced the risk of pre-eclampsia and/or foetal death amongst all women by about one third (RR 0.71, 95% CI 0.52-0.96; p = 0.02).

The protective effect of smoking was even more marked in HIV-positive women. Here HIV-positive pregnant smokers were five-times less likely to experience pre-eclampsia or foetal death (RR 0.2, 95% CI 0.05-0.5, p = 0.002) and 20 times less likely to experience pre-eclampsia (RR 0.05, 95% CI 0.006-0.40, p = 0.005). HIV-positive women smokers on HAART had a similar outcome for either pre-eclampsia or foetal death (adjusted OR 0.265, 95% CI 0.087-1.054, p = 0.059), although the higher confidence interval suggests smoking is somewhat less protective when HAART is also taken.

The study’s conclusions

• Incidence of pre-eclampsia and foetal death has increased in HIV-positive pregnant women, despite stable incidence in the general population.
• HIV infection was identified as a risk factor for either pre-eclampsia or foetal death or both, but only in recent years, most notably since 2002.
• Duration of HIV infection, and particularly cumulative exposure to HAART were the main significant risk factors.
• No specific antiretroviral class or drug was associated with either pre-eclampsia or foetal death or both.
• Endothelial dysfunction (selectin P and E) and insulin resistance were markers for pre-eclampsia in HIV-positive women on HAART, based on a small substudy with nine cases of pre-eclampsia and nine controls.
• Smoking is protective of both pre-eclampsia or foetal death, but may cause other health problems for the mother or infant later in life.
• Use of HAART before and during pregnancy “should not be discouraged because there is strong evidence that the benefits (to both mother and infant) clearly outweigh the potential risks.”