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Objective To investigate the effect of pregnancy on disease progression and survival i? women infected with HIV by a systematic review of the literature and meta-analysis.
Methods Appropriate publications were identified using electronic and hand searching of relevant journals from 1983 to 1996. Studies were included in the review if they were cohort studies, either prospective or retrospective, or case-control studies which investigated disease progression of pregnant women infected with HIV and included a control group of non-pregnant women infected with HIV for comparison. Methodological quality was assessed for each study. Data were extracted for predetermined outcome measures. Sensitivity analyses were performed to explore the association between pregnancy and disease progression for the following study characteristics: clinical setting (developed or developing countries), methodological quality (high or poor) and whether studies had controlled for potential confounding.
Results Seven studies, all prospective cohorts, were eligible to be included in the rediew. The summary odds ratio for the risk of an adverse maternal outcome related to HIV infection and pregnancy were as follows: death 1.8 (85% CI 0.99–3.3); HIV disease progression 1.41 (95% C1 0.85–2.33); progression to an AIDS-defining illness 1.63 (95% CI 1.00–2.67) and fall of CD4 cell count to below 200×106/L 0.73 (95% CI 0.17–3.06). Sensitivity analyses showed that HIV progression in pregnancy was significantly more common in a developing country setting (odds ratio 3.71, 95% CI 1.82–7.75) than in developed countries (odds ratio 0.55, 95% 0.27–1.11) and also significantly more common in high quality studies when compared to low quality ones, odds ratios 3.71 (95% CI 1.82–7.57) and 0.55 (95% CI 0.27–1.11), respectively. However, there appears to be less progression of HIV disease and progression to AIDS when studies attempted to control for confounding by matching or restriction techniques, although this was not statistically significant in either case.
Conclusions The findings of this review have implications for women infected with HIV who are pregnant or are considering a pregnancy. There does appear to be an association between adverse maternal outcomes and pregnancy in women infected with HIV, although this association is not strong. The relation may be due to the result of bias including residual confounding. Further large scale observational studies with long term follow up are required before this issue can be fully resolved.
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Although all of the studies included in the review were observational, and therefore generally more prone to bias, it is highly unlikely that the outcomes measured would be affected by the knowledge of whether or not a woman infected with HIV was or had been pregnant. There is the potential for bias if adverse events of HIV-infected mothers such as progression from one Centres for Disease Control stage to another is reported earlier as a consequence of closer follow up during their pregnancy and the post-partum period. In the studies included in this review, however, this seems unlikely.
There is great potential for selection bias when trying to measure outcomes of HIV-pregnant women infected with HIV with those HIV women infected with HIV who are not pregnant. There may be a variety of reasons why some women infected with HIV do not become pregnant, and this may be related to factors influencing their survival. For example, women with severe symptomatic HIV or AIDS may be too ill to become pregnant or if they do conceive may be more likely to chose to terminate the pregnancy, although if pregnancy does affect survival the relative effects of a termination or miscarriage and that of a full term pregnancy may be similar. There may also be differences with regards to socioeco-nomic status, ethnic origin, age and transmission group between pregnant and non-pregnant women. An American study2, monitoring a large cohort of HIV-infected women, found that those who were under 25 years of age and those who were black were more likely to become pregnant. Another source of selection bias is that pregnant women infected with HIV may be obtaining medical care for the first time because of their pregnancy rather than their HIV infection, and may have been unaware of their HIV status prior to antenatal screening. This may have two effects. Firstly, the non-pregnant group may be recognised because they have presented with some minor HIV related symptoms, whereas the pregnant group are recognised because they are screened in the antenatal clinic. Thus the two groups may not be comparable at study entry with respect to their HIV disease status (although this difference is likely to be more subtle than a difference in their Centres for Disease Control stage). Secondly, many women would have been enrolled into studies late into their pregnancy or even at delivery and therefore any progression of disease that had happened during the pregnancy would be unaccounted for.
Another source of bias in this review is that of publication bias. Studies which find no association or negative associations between HIV infection and maternal outcomes may be less likely to be published either because they were not submitted for publication or because journals are less likely to publish them. This phenomena has been well documented with trials, and there is no reason to believe it is not the case with observational studies also16. Publication bias cannot be easily demonstrated but the possibility of publication bias should be considered in interpreting the results of any review.
Women in developed countries are more likely to be on anti-retroviral therapy and opportunistic infection prophylaxis, which may be discontinued during pregnancy and which may lead to an increased risk of disease progression in this setting when the cases and controls are compared. Weisser et al.18 noted that pregnant women infected with HIV, when compared with non-pregnant women with HIV had a significant increase in risk of recurrent bacterial infection, hazard ratio 7.98 (95% CI 1.73–36.8). The authors concluded that this was most probably due to pregnant women discontinuing their prophylactic treatment for pneumocystis carinii pneumonia due to fear of its toxic effects on the fetus.
The poor maternal prognosis in developing countries may be due to factors other than just HIV infection, such as lack of antenatal care, malnutrition and a greater risk of infection after delivery19.
The differences between findings of the high and low quality studies could be explained by two factors. Follow up of both cases and controls and control of confounding were included in the quality scoring system. Therefore these studies are more likely to reflect the ‘true’ underlying relationship more than the lower quality studies.
The control of confounding in the study design may not necessarily eliminate confounding. For example, in developed countries drug use is probably a major confounding factor and restriction of entry to the study to drug users would seem an appropriate way of controlling its effect on the outcome. Drug users may not always admit to using drugs and pregnancy can effect drug taking patterns: for example, there is a decline of intravenous drug use reported during pregnancy20. In addition, drug users are not a homogenous group of women. Drug using women may occasionally use marijuana or regularly inject heroin. The pregnancy outcomes of these two categories of drug users is likely to be different.
Immunological changes during pregnancy have been well documented. The percentage and absolute number of CD4 cells have been reported to decrease, returning to their normal range three to four months post delivery5. There was concern that if an HIV-infected woman's CD4 cell count dropped substantially during pregnancy, she would be at a greater risk of opportunistic infections and other AIDS defining illnesses. The effect that this has on pregnant women with HIV is still unclear, with some studies reporting a detrimental effect of pregnancy on immune function11,12 and others reporting no significant effect8,10. This review was unable to determine the effect pregnancy had on the immune system of women infected with HIV.
To date, studies measuring the association between HIV infection and maternal outcomes have involved relatively small numbers and will have been unable to detect modest differences in survival or disease progression. This review has reported the available data from all the available studies and is still unable to determine with any certainty the effect of pregnancy on HIV disease progression and survival, although it seems unlikely that any major effect exists. There is a need for further large observational cohorts of pregnant and non-pregnant women infected with HIV to be undertaken which include long-term follow up. Data on immune function should be available before pregnancy. Ideally, a known date of seroconversion or at least an estimate should be established as date of diagnosis or CD4 count, by themselves, may not accurately reflect disease stage.
The majority of women who become infected with HIV are of reproductive age22. More of these women may be deciding to become pregnant due to the availability of interventions which decrease the risk of mother-to-child transmission23. If clinically indicated, mothers need to be encouraged to continue taking any relevant opportunistic infection prophylaxis unless this is specifically contraindicated in pregnancy24. Pregnant women and those women thinking about becoming pregnant need to be counselled and advised about the possible risks to their own health as well as any transmission risks before they can make an informed decision on how to proceed.
In summary, there may be an association between HIV disease progression and pregnancy, although this association is not strong. The observed relationship may be due to the result of bias including residual confounding and further, larger studies will be necessary before this issue can be resolved.
We would like to thank Ms L. Kumiega for her help with the literature searching, and Dr C. Hocke29 and Dr C. Rudin18 for providing us with extra information from their studies which was relevant to the review. In addition we would like to thank Dr J. Stephenson and Ms A. Petruckevitch.