Introduction
Increasing clinical expertise and routine use of HAART have led to a dramatic and sustained decrease in mortality and morbidity in HIV infection [1,2] as well as in the risk of mother-to-child transmission [3]. In this scenario, it is not surprising that fertile HIV-infected women may decide to become pregnant expecting an offspring free of HIV infection and no more complications during pregnancy than in non-HIV-infected women. HIV-infected pregnant women are currently recommended to receive similar HAART regimens as non-pregnant ones, except for considerations of potential adverse effects of such therapy on the fetus [4].
Despite the positive impact on HIV-related morbidity and mortality, the duration of exposure to antiretroviral therapy has been associated with long-term complications such as lipodystrophy [5] and cardiovascular disease [6]. Outcomes and adverse effects of antiretroviral therapy in HIV-infected pregnant women have mainly focused on the fetus and the infant, rarely on the mother [7]. Fetal adverse outcomes such as preterm birth, low birth weight, intrauterine growth retardation and fetal death are more common in untreated HIV-infected women than in women without HIV infection and correlate with the stage of HIV disease in mothers from developing countries. However, many of these data from developed countries have not demonstrated an association between HIV infection and adverse outcomes when compared with appropriate control groups [8,9]. With the widespread prescription of HAART, fetal adverse outcomes, with the exception of preterm birth, have been reported to occur at similar rates to those seen in the general population [10,11].
Pre-eclampsia was an uncommon complication of pregnancy in HIV-infected women in the pre-HAART era, even less frequent than in the general population [12]. With the routine use of HAART, the reported incidence of pre-eclampsia in HIV-infected pregnant women has increased to a level at least similar to that of HIV-uninfected women [13]. Moreover, a recent survey of 36 hospitals from 11 European countries has identified pre-eclampsia as the most common adverse event in HIV-infected pregnant women receiving antiretroviral therapy, followed by congenital abnormalities and fetal death [14]. We have recently detected an unexpected increase in the number of cases of pre-eclampsia and fetal death in HIV-infected pregnant women receiving HAART and in the co-occurrence of both [15]. Among other factors, pre-eclampsia has been associated with hyperinsulinaemia [16] and increased serum selectins [17], which are markers of insulin resistance and endothelial inflammation, respectively.
This study analyses the incidence and the risk factors for pre-eclampsia, fetal death or both in all pregnant women and in HIV-infected pregnant women who delivered at our institution. Insulin and P- and E-selectin in stored plasma samples from HIV-infected patients with and without pre-eclampsia were also measured to assess the potential role of insulin resistance or endothelial inflammation in the development of pre-eclampsia in HIV-infected pregnant women.
Methods
Population
The Institution of Biomedical Investigations is a referral centre offering public medical care to pregnant women in an urban area comprising the city and metropolitan area of Barcelona (Spain). Starting on January 2001, a perinatal database was prospectively created to include all consecutive pregnant women cared for at the centre. A similar but more specific database had been in use since November 1985 for HIV-infected pregnant women and included additional variables on HIV infection, AIDS-related illnesses, and antiretroviral therapy. Since 1992, data from the HIV-infected pregnant women were reported to the European Collaborative Study. Only women delivering after at least 22 weeks of pregnancy were considered for this study. For the purpose of the study, the cut-off date for inclusion was July 2003.
Analyses
Every pregnant woman received standard medical care and had their blood cells and chemistry measured every trimester. Routine screening for HIV in every pregnant woman with unknown HIV serostatus was carried out from July 1990; prior to this date, screening was restricted to women at known risk for HIV. Additional standard care was provided for women with other health conditions. HIV-infected women were informed about their pregnancy care, the risk of vertical transmission and the known antiretroviral toxicity for the mother and the newborn. Any individual decision to discontinue pregnancy complied with Spanish laws. Besides standard blood tests, CD4 cell count (flow cytometry) and plasma HIV-1 RNA (Amplicor HIV Monitor, Roche Diagnostic Systems, Branchburg, New Jersey, USA) were also measured for HIV-infected individuals at least every 3 months. Whenever available, antiretroviral therapy was administered to all pregnant HIV-infected women following the recommendations at the time of pregnancy. For HIV-infected women, a sample of the plasma obtained for routine blood tests was kept at −80°C for further non-scheduled laboratory assessments.
A case–control substudy measured insulin (IRMA, Med-Genix Diagnostics, Fleunes, Belgium), and P- and E-selectin (R & D System, Minneapolis, Minnesota, USA) on stored plasma samples. The samples used were those closest (less than 3 months) to the estimated date of conception, during pregnancy, and in the puerperium for HIV-infected pregnant women who developed pre-eclampsia and at similar time-points for randomly selected HIV-infected pregnant women who did not develop pre-eclampsia. Because the volume of stored samples was scarce, insulin could only be measured during pregnancy.
Definitions
The date of conception was estimated according to the last menstrual period or by sonographic evaluation [18]. Pre-eclampsia was defined as new onset of hypertension, with two readings at least 6 h apart of more than 140 mmHg systolic or more than 90 mmHg diastolic during gestation, delivery or immediate postpartum period, plus a dipstick reading of at least 1+ for proteinuria (0.1 g/l) confirmed by > 300 mg/24 h urine collection after 22 weeks of pregnancy [19]. Fetal death was an intrauterine death after 22 weeks of pregnancy [20]. The perinatal mortality hospital committee, which included obstetricians, pediatricians and pathologists, reviewed all fetal demise. Fetal necropsy and caryotype were routinely carried out.
Statistical analysis
Statistical analysis was performed with Stata software version 7.0 (Stata Corp., College Station, Texas, USA). Incidence was calculated as the number of new events per 1000 deliveries (including also fetal deaths). The odds of pre-eclampsia, fetal death, or either pre-eclampsia or fetal death in the general and in the HIV-infected population at different time-points were compared using χ-squared test for linear trend.
The risks were estimated with multivariate analyses through logistic regression models in both populations. Variables considered for the analysis of risk factors in the general population included race, age, tobacco smoking, intravenous drug use, number of prior deliveries, number of fetuses in current pregnancy, and HIV serostatus. In the HIV-infected population, additional variables for the analysis of risk factors were known duration of HIV infection, antiretroviral therapy prior to and during pregnancy, duration of exposure to individual antiretroviral drugs, and CD4 and CD8 cell counts immediately prior to or at the time of pregnancy, depending when HIV infection was diagnosed. Multivariate models were constructed through stepwise selection of those variables showing a univariate P value < 0.1. A significance level of 95% was considered in all the statistical procedures.
Insulin, and P- and E-selectin measurements in the case–control substudy were compared with the Mann–Whitney test. Simple comparisons used a two-sided α level of 0.05.
Results
Pre-eclampsia and fetal death in the general population
From January 2001 until July 2003, 8768 pregnant women were included, of whom 82 (0.9%) were HIV infected (Table 1). There were 244 (28 per 1000) cases of pre-eclampsia without fetal death, 39 (4 per 1000) cases of fetal death without pre-eclampsia, and 7 (0.8 per 1000) cases of pre-eclampsia with fetal death. The incidence per 1000 deliveries of pre-eclampsia, fetal death, and either pre-eclampsia or fetal death in the study period was 28.6 [95% confidence interval (CI), 25.2–32.4], 5.3 (95% CI, 3.5–7.0) and 33.1 (95% CI, 29.4–37.1), respectively. The distribution over time for pre-eclampsia and fetal death remained relatively constant (Fig. 1). In this period, comparison of HIV-infected women with HIV-negative women showed significantly higher rates in the former for pre-eclampsia [109.8/1000 versus 28.6/1000; crude odds ratio (OR), 4.3; 95% CI, 1.9–9.0; P < 0.001] and fetal death (61.0/1000 versus 5.3/1000; crude OR, 13.7; 95% CI, 5.3–35.6; P < 0.001).
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Table 1: Characteristics of the general population of women and the population of HIV-infected women studied.
Fig. 1: Proportion of cases of pre-eclampsia (black columns), fetal death (white columns) or adverse outcome (either pre-eclampsia or fetal death; hatched columns) in the general population of pregnant women from January 2001 until July 2003. At risk population in 2001, 2002 and 2003 was 3113, 3634 and 2021, respectively. There were no significant changes over this period for pre-eclampsia (P = 0.483), fetal death (P = 0.886) or adverse outcome (P = 0.629) using the χ-squared test for linear trend.
In multivariate models, multiple gestation (adjusted OR, 3.6; 95% CI, 2.3–5.6; P < 0.001), HIV infection (adjusted OR, 4.9; 95% CI, 2.4–10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58–0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46–0.90; P = 0.010) were identified as independent factors associated with pre-eclampsia (n = 251). The variables associated with fetal death (n = 46) in the univariate analysis were intravenous drug use during pregnancy (crude OR, 8.6; 95% CI, 2.6–28.5; P < 0.001) and HIV infection (crude OR, 13.7; 95% CI, 5.3–35.6; P < 0.001). No adequate multivariate model to assess risk factors for fetal death in the general population could be found.
When the outcome was the development of either pre-eclampsia or fetal death (n = 290; 33/1000 deliveries), the multivariate analysis identified multiple gestation (adjusted OR, 3.0; 95% CI, 1.9–4.6; P < 0.001), HIV infection (adjusted OR, 4.6; 95% CI, 2.3–9.1; P < 0.001), multiparity (adjusted OR, 0.70; 95% CI, 0.54–0.90; P = 0.005) and tobacco smoking (adjusted OR, 0.71; 95% CI, 0.52–0.96; P = 0.024) as independent risk factors associated with this adverse outcome.
Pre-eclampsia and fetal death in the population of HIV-infected women
From November 1985 until July 2003, 472 HIV-infected pregnant women were included in this study, of whom 86 (18%) had received HAART prior to pregnancy (Table 1). The proportion of HIV-infected pregnant women with HAART (defined by any combination including at least three antiretroviral drugs) prior to or during pregnancy was 5% in 1997, 50% in 1998, 87% in 1999, 87% in 2000, 87% in 2001, 97% in 2002 and 91% in 2003. There were six (13/1000) cases of pre-eclampsia without fetal death, five (11/1000) cases of fetal death without pre-eclampsia, and three (6/1000) cases of pre-eclampsia and fetal death (Table 2). Pre-eclampsia and fetal death remained very low until 2001 and sharply increased thereafter (Fig. 2). The incidence per 1000 deliveries of pre-eclampsia, fetal death, or either pre-eclampsia or fetal death in the study period was 19.1 (95% CI, 8.7–36.2), 17.0 (95% CI, 7.3–33.4) and 29.7 (95% CI, 16.2–49.8), respectively. No evident cause of fetal death was identified in the necropsy or caryotype of fetuses carried by HIV-infected women.
Table 2: Characteristics of the HIV-infected patients who developed pre-eclampsia or fetal death.
Fig. 2: Proportion of cases of pre-eclampsia (black columns), fetal death (white columns), or adverse outcome (either pre-eclampsia or fetal death; hatched columns) in the HIV-infected population from November 1985 until July 2003. The at-risk group was 86, 104, 83, 54, 63 and 82, respectively, in 1985–88, 1989–91, 1992–94, 1995–97, 1998–2000 and 2000–03. There were significant changes over this period for pre-eclampsia (P < 0.001), fetal death (P = 0.006), or adverse outcome (P < 0.001) using the χ-squared test for linear trend.
In multivariate models, the use of HAART prior to pregnancy (adjusted OR, 8.9; 95% CI, 1.7–45.5; P = 0.009) and tobacco smoking (adjusted OR, 0.065; 95% CI, 0.008–0.547; P = 0.012) were independent factors associated with the development of pre-eclampsia (n = 9) in HIV-infected women. The variables associated with fetal death (n = 8) in the HIV-infected population in the univariate analysis were age (crude OR, 1.178 per year; 95% CI, 1.030–1.346; P = 0.017), known duration of HIV infection (crude OR, 1.020 per month; 95% CI, 1.008–1.031; P = 0.001), and HAART prior to pregnancy (crude OR, 7.881; 95% CI, 1.846–33.639; P = 0.005). No adequate multivariate model was found to assess risk factors for fetal death in the HIV-infected population. When the outcome was either pre-eclampsia or fetal death (n = 14; 30/1000 deliveries), the multivariate analysis identified the use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7–18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054–0.627; P = 0.007) as independent factors associated with this adverse outcome.
Plasma insulin and selectins in HIV-infected pregnant women
P-selectin increased over pregnancy in both those who did develop pre-eclampsia (n = 9) and those who did not (n = 9), but the increase in the former was significantly higher at all time points (Table 3). There was a trend towards higher E-selectin values prior to pregnancy and in the puerperium in those who did develop pre-eclampsia compared with those who did not, but the differences were not statistically significant during pregnancy itself (Table 3). Insulin during pregnancy was significantly higher in those who did develop pre-eclampsia (median 17.6 mU/l; interquartile range, 15.1–54.4) than in those who did not (median 7.1 mU/l; interquartile range, 5.0–11.1) (P = 0.001) (Table 3).
Table 3: Comparisons of the measurements of P- and E-selectin and insulin at different time-points in HIV-infected women who did and did not develop pre-eclampsia.
Discussion
The incidences of pre-eclampsia and fetal death have sharply increased in our cohort of HIV-infected pregnant women from those seen in the pre-HAART era; these complications were formerly uncommon. Although the censorship date for this analyisis was July 2003, there have been four additional cases of pre-eclampsia among 38 new pregnancies in HIV-infected women from July 2003 until December 2004. These data are in accord with the increasing rates described in this study and they argue against mere anecdotal findings. These increasing trends were not seen in our general population of pregnant women, in which these complications developed at relatively stable low rates concordant with those reported for the population of pregnant women in Spain [21,22]. In our study, the contribution of HIV infection in recent years has been important enough to emerge as an independent risk factor for pre-eclampsia and fetal death in the general population. One randomized trial and several cohort analyses have not found a negative impact of zidovudine monotherapy on the outcome of pregnancy [10,23,24]. Some European studies have suggested that combination therapy might increase the incidence of preterm birth [10,11,24], although this finding had not been reproduced from cohorts in the United States [3,25]. Recent data from a single institution in the United Kingdom [13] and from several centres participating in the European Collaborative Study have shown increasing rates of pre-eclampsia and fetal death in HIV-infected pregnant women receiving HAART [14], which agrees with our observations.
Pre-eclampsia and fetal death coexisted more frequently in our cohort of HIV-infected women than in the general population of pregnant women. Causes of fetal death in HIV-infected pregnant women are not clearly understood. Although pre-eclampsia is a well-recognized cause of fetal death in the general population [20], only some HIV-infected patients with pre-eclampsia had fetal death and there were cases of fetal death not coexisting with pre-eclampsia in our study. Nevertheless, a potential common pathogenesis may exist in HIV-infected pregnant women given the higher than expected coexistence of these conditions.
Despite considerable research, the pathogenesis of pre-eclampsia remains unclear and many hypotheses have been proposed to explain its occurrence, including immunological derangements, genetic factors, increased insulin resistance, dietary calcium deficiency, increased oxidative stress and prostaglandin imbalance [26]. We identified risk factors for pre-eclampsia (multiple gestation, multiparity and tobacco) and for fetal death (intravenous drug use) that have been already described for the general population [27]. Tobacco smoking has been paradoxically associated with a higher risk for fetal death [28] and a decreased risk for pre-eclampsia [29]. Of note, tobacco smoking was three times more prevalent among HIV-infected pregnant women than in the general population of pregnant women (Table 1). We did not find tobacco smoking associated with a higher risk for fetal death but a decreased risk for pre-eclampsia. Despite the reasons for the potential positive role of tobacco smoking in pre-eclampsia, its substantial negative effects on maternal and fetal morbidity cancel any potential benefit.
We found that HIV infection was an independent risk factor both for pre-eclampsia and for fetal death in our general population of pregnant women followed in recent years. This finding has not been previously reported [26,27]. Potential explanations may be a failure to include HIV-infected women in the general population studied, studies carried out on the general population in years prior to the HAART era, and the possibility that the risk associated with treated HIV infection may have been too low to be detected even in studies focused on the adverse outcomes of pregnancy in HIV-infected women [7,25]. When we restricted the analysis to the HIV-infected population, the use of HAART before pregnancy was identified as a factor for pre-eclampsia or fetal death although we failed to find a higher risk for any individual antiretroviral drug or class. We recognize that our study did not have sufficient numbers for an evaluation of the risk by individual drugs. The duration of exposure to HAART in HIV-infected patients has been also associated with the risk of adverse events such as lipodystrophy [30] and myocardial infarction [6], and these problems are considered to be long-term adverse effects of current antiretroviral therapy. The finding of increased insulin levels in the HIV-infected pregnant women with pre-eclampsia compared with those without suggests an underlying insulin resistance state, which has already been reported in pre-eclampsia in the general population [31–33]. We also found increased plasma levels of P-selectin, although not of E-selectin, at different time-points during pregnancy in HIV-infected women developing pre-eclampsia compared with those who did not. The P- and E-selectins are endothelial adhesion molecules that have been implicated in the pathogenesis of pre-eclampsia in the general population [16,17].
In summary, we have found that the risk of pre-eclampsia and fetal death is increased in HIV-infected pregnant women, that this risk is associated with the exposure to HAART prior to pregnancy, and that insulin resistance and endothelial inflammation may be potential underlying mechanisms. If our results are confirmed, close monitoring for pre-eclampsia and fetal distress in HIV-infected pregnant women will be needed. Despite these results, we believe that the use of HAART prior to and during pregnancy should not be discouraged because there is strong evidence that the benefits of HAART clearly outweigh the potential risks.
Sponsorship: This study was supported in part by grants PI02590, Fondo de Investigaciones Sanitarias, and RIS G03/173, Red Temática Cooperativa de Investigación en SIDA, Ministerio de Sanidad y Consumo (Spain).
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Appendix
Additional authors are Sonia Pisa, Ricard Vidal and Vicenç Cararach (Obstetric and Gynecological Service), Laura Zamora, Marta Segarra, Montserrat Laguno, Omar Sued, Alejandra Biglia, Felipe García and José M. Miró (Infectious Diseases Service).
