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Vasculoplacental complications in pregnant women with HIV infection: a case-control study
Accepted Manuscript Vasculoplacental complications in pregnant women with HIV infection: a case-control study Geoffroy Canlorbe, MD, Sophie Matheron, MD, Laurent Mandelbrot, MD, PhD, Barbara Oudet, Dominique Luton, MD, PhD, Elie Azria, MD, PhD PII:
S0002-9378(15)00265-3
DOI:
10.1016/j.ajog.2015.03.035
Reference:
YMOB 10323
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 2 November 2014 Revised Date:
21 January 2015
Accepted Date: 16 March 2015
Please cite this article as: Canlorbe G, Matheron S, Mandelbrot L, Oudet B, Luton D, Azria E, Vasculoplacental complications in pregnant women with HIV infection: a case-control study, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.03.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Vasculoplacental complications in pregnant women with HIV infection: a case-control study Geoffroy Canlorbe, MD1,2, Sophie Matheron MD3,4, Laurent Mandelbrot MD, PhD2,5,
Service de gynécologie obstétrique, Hôpital Bichat-Claude Bernard, Université Paris
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1
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Barbara Oudet1,2, Dominique Luton MD, PhD1,2, Elie Azria MD, PhD1,2,6
Diderot, Paris, France DHU Risk in Pregnancy
3
Service de maladies infectieuses et tropicales, Hôpital Bichat-Claude Bernard, Université
Paris Diderot, Paris, France
5
INSERM, IAME, UMR 1137, Paris, France
APHP Hôpital Louis Mourier, Service de Gynecologie-Obstetrique, Colombes and
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2
Université Paris Diderot, Paris, France 6
INSERM, U-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical,
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Perinatal and Pediatric Epidemiology Team, Paris, France
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Corresponding author Elie Azria
INSERM, U-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical, Perinatal and Pediatric Epidemiology Team, Maternité Port-Royal, 53 avenue de l'Observatoire, Paris 75014, France Telephone number: 00 33 6 11 52 54 32 email: [email protected]
ACCEPTED MANUSCRIPT Funding None
The authors report no conflict of interests.
Word count Main text: 2837
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Abstract: 177
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Competing interests
ACCEPTED MANUSCRIPT Condensation Maternal HIV infection does not appear to be associated with the risk of vasculoplacental complications during pregnancy.
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Short version of title
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Vasculoplacental complications in pregnant women with HIV infection
ACCEPTED MANUSCRIPT Abstract
Introduction: Data from the international literature suggest that there may be an association
Studies on this subject have reached discordant conclusions.
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between maternal HIV infection and vasculoplacental complications during pregnancy.
Objective: The aim of this study was to assess the incidence of vasculoplacental complications during pregnancy in women with and without HIV infection.
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Materials and methods: This single-center case-control study compared the incidence of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular intrauterine growth
parity, and geographic origin.
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restriction in 280 women with HIV and 560 women not infected with HIV, matched for age,
Results: The incidence rates of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular growth restriction did not differ between the women with and without HIV infection.
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The overall incidence of vasculoplacental complications did not differ between the two groups (7.5% vs 9.8% respectively, p= 0.27). The risk of these was not associated with
pregnancy.
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exposure to antiretroviral treatments, viral load, or CD4 T-cell counts at the beginning of
Conclusion: This study shows no difference in the incidence of vasculoplacental
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complications between women with and without HIV infection.
Key words: Antiretroviral therapy, HIV, ischemic placental disease, low birth weight, preeclampsia, pregnancy-related hypertension
ACCEPTED MANUSCRIPT Introduction
The pregnancy-related diseases referred to as vasculoplacental (also called ischemic placental disease), such as preeclampsia, eclampsia, and intrauterine growth restriction (IUGR) of
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vasculoplacental origin, are a major cause of morbidity and mortality in both mothers and fetuses.
Some studies suggest that maternal infection by HIV may be associated with these conditions,
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regardless of whether or not the patient is receiving antiretroviral treatment (ARV). The data from the literature are nonetheless discordant; some report an association with an increased
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risk of vasculoplacental complications.1, 2 Inversely, others find results suggesting a protective effect3, and others show no association4. These data are often difficult to interpret, especially because they frequently lack information about the stage and severity of these women’s HIV infections, their treatment5, and whether confounding factors, such as geographic origin3, drug
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use, and smoking were taken into account6-11.
The appearance of new ARV drugs and changes in guidelines and practices for this treatment may also explain these discordances, at least in part. The prescription of these drugs at the
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beginning of the second trimester is now recommended, even if the mother's condition does not indicate a need for treatment12, because the combination of three antiretroval drugs
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(HAART: highly active antiretroviral therapy) is associated with a reduction in the maternal viral load, in infant mortality, and in the rate of mother-to-child transmission13. The benefits of this strategy in terms of the prevention of mother-child transmission are incontestable, but the safety of these drugs7,14,15 is nonetheless questionable, and their toxicity16 might promote the development of vasculoplacental diseases17-20. The principal objective of this retrospective case-control study was to determine whether HIV infection and ARV exposure are associated with an increased risk of vasculoplacental disease.
ACCEPTED MANUSCRIPT The demonstration of an increased risk would not only allow obstetricians to provide better information to their patients but also to adapt the prenatal monitoring of infected pregnant
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women and their fetuses to reduce the morbidity associated with this disease.
Materials and methods
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This single-center retrospective case-control study took place in the obstetrics department of the Bichat-Claude Bernard University Hospital, in Paris, France, a level IIb maternity ward. It
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considered for inclusion all women who gave birth from December 2006 through October 2010.
The Paris North Institutional Review Board (CEERB) approved this study (approval n° 11.090).
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The women in the case group met the following inclusion criteria: HIV infection known at the time of delivery, delivery after 20 weeks of gestation, regardless of pregnancy outcome, management and delivery planned at Bichat-Claude Bernard, regardless of the actual place of
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delivery, and singleton pregnancy.
The control group, unexposed to HIV (negative serology results during pregnancy, for this
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screening test was routinely proposed to all pregnant women), were identified from the delivery and transfer registers for the pregnant women signed up for delivery in our institution, and otherwise met the same inclusion criteria. One-to-two matching was performed according to the following three criteria: maternal age group (≤19, 20-22, 23-25, 26-28, 29-31, 32-34, 35-37, 38-40, ≥41 years), geographic origin (Europe, North Africa, West Indies, Asia, sub-Saharan Africa), and parity.
ACCEPTED MANUSCRIPT The exclusion criteria were: pregnancy ended before 20 weeks, fetal malformation, chromosomal abnormalities, multiple pregnancy, fetal CMV infection, HIV serologic status unknown or not reported in the file, woman already included in the study for a later pregnancy (only the last pregnancy was included).
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The number of subjects necessary was calculated based on the following hypotheses: we assume a frequency of preeclampsia and/or vascular IUGR of 8% in the population unexposed to HIV (2010 data from the Bichat-Claude Bernard obstetrics department
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database) and twice this rate for women with HIV and treated by antiretroviral drugs. To
power: 80%, two-tailed test).
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show such a doubled rate, the study required 270 cases and 540 controls (alpha risk: 5%,
All pregnant women with HIV infection were followed and treated according to the French guidelines then applicable.21
We collected data about the women's medical and obstetric history, the characteristics of their
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HIV infection and its management, especially ARV treatment before and during pregnancy, and the course and outcome of the pregnancy.
Pregnancy-related hypertension (PRH) was defined by systolic blood pressure (SBP) >140
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mm Hg and/or diastolic blood pressure (DBP) >90 mm Hg that developed after 20 weeks of gestation and disappeared before the end of the sixth week postpartum. Preeclampsia was
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defined by the combination of PRH and proteinuria (> 0.3 g/24 h), and HELLP syndrome by the combination of hemolysis, hepatic cytolysis, and thrombocytopenia. Preeclampsia was defined as severe when the patient also had any one or more of the following: severe hypertension (SBP > 160 mm Hg or DBP > 110 mm Hg), kidney damage (oliguria (< 500 mL/24 h) or creatinine levels > 135 µmol/L or proteinuria > 5 g/day), acute pulmonary edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia,
ACCEPTED MANUSCRIPT intractable neurological disorders (visual disorders, polykinetic deep tendon reflexes, or headaches), thrombocytopenia <100,000 plt/L, or abruptio placentae. Uterine artery Doppler waveforms were defined as abnormal when the resistance index (RI) was high22 or when a unilateral or bilateral notch was observed, confirmed at 22 weeks.
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Vascular intrauterine growth restriction (IUGR) was defined by the combination of IUGR (<10th percentile) with at least one of the following: a history of vasculoplacental complication, abnormal uterine Doppler waveforms, elevated umbilical artery IR, or a
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vasculoplacental complication after other causes were ruled out.
A composite vasculoplacental criterion was defined by the presence of PRH, or preeclampsia,
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or IUGR <10th percentile from a vascular cause.
Term at delivery was determined from the date the pregnancy began, measured by the crownrump length from the first-trimester ultrasound, if available, and otherwise from the date of the last menstrual period.
Stata Corp LP).
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The statistical analyses were performed with STATA software v. 10 (College Station, TX,
Measurements for birth weight (in grams) and head circumference (in cm) at birth were
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standardized and expressed as percentiles after adjustment for the newborn's gestational age (in completed weeks of gestation) and sex, according to the reference curves from the French
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Audipog network (www.audipog.net/). The categorical variables were compared with Chi-2 tests or Fisher's exact test, as appropriate. The discrete variables in two classes were compared with Student's t test and continuous variables (with normal or non-normal distributions) with Wilcoxon's test. The associations between vasculoplacental complications and candidate risk factors were first explored by calculation of the crude odds ratios (OR). Adjusted odds ratios (ORa) were then calculated with two different regression models. The first was a logistic regression model and
ACCEPTED MANUSCRIPT considered the population of women with HIV infection and tested disease indicators (CDC stage, CD4 T-cell count, and viral load, measured at some point between the beginning of pregnancy and week 14), after adjustment for age and parity. The second was a cox proportional hazard model suited for matched cohort. This model was used to examine the
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entire study population and tested the variable of HIV infection by adjusting for the known risk factors of vascular complications and for gestational age at delivery (3 classes: ≥37 weeks, 32-37, <32). Schoenfeld’s residual test was used to test the proportional hazards
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assumption.
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For all of these statistical tests, a P value<0.05 was considered statistically significant.
Results
During the study period, 8273 women gave birth to singleton infants after 20 weeks'
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gestation. Among them, 307 had HIV infection and met the study's inclusion criteria. We excluded 27 already included in the study with a more recent pregnancy. Finally, 280 women were included in the case group (273 subtype 1; 5 subtype 2, and 2 simultaneously infected by
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subtypes 1 and 2) and matched with 560 uninfected women. Data for 832 of these 840 patients were available in records stored onsite. The 8 missing or
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incomplete records were those of women who gave birth in other maternity units; we were able to obtain all of them from the hospital of birth (Figure 1).
Table 1 summarizes the data about the status of the HIV infection of the 280 infected women. The diagnosis had been made during a previous pregnancy in 27.1% of the cases and during the pregnancy studied here in 15.4%, no case of seroconversion during pregnancy has been identified. The CDC stage was 1 for 78.2% of the women. Of the women whose infection was
ACCEPTED MANUSCRIPT known before the study pregnancy, 47.9% had received ARV before the beginning of the pregnancy. At the beginning of this pregnancy, 44.7% had an undetectable viral load (threshold 50 copies/mL) and 21% a CD4 T-cell count < 300/mm3. During the third trimester of the pregnancy, 94% of the infected women received ARV
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treatment. In a very large percentage of cases, this consisted of a combination of two nucleoside analogs and a protease inhibitor (90.5%). Much more rarely (6.8%), it was two
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nucleoside analogs with a non-nucleoside analog. Other combinations were extremely rare.
Checking the quality of the matching, we observed that the two groups were comparable for
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age, parity, and geographic origin. No difference was observed for a history of hypertensive diseases, of nephropathy, of diabetes, of smoking or consumption of illegal drugs, of in utero death, or of IUGR (Table 2).
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The case and control groups did not differ in their prevalence of the composite vasculoplacental criterion (9.8% vs 7.7%, respectively, p=0.269), or of PRH, preeclampsia or severe preeclampsia. We observed a higher prevalence of abnormal uterine artery Doppler
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waveforms in the HIV-infected group (16.8% vs 12.5%, p=0.02). The rates of preterm birth before 37 weeks and before 32 weeks were significantly higher in
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the HIV group (18.6% vs 8.0%, P<0.001 and 5.0% vs 2.3%, P=0.04 respectively) (Table 3). This difference affected only spontaneous preterm births; induced preterm births did not differ at all (3.6% vs 3.6%, p=1).
We observed a higher prevalence of neonatal deaths in the HIV infected group (3.6% vs 1.1%, p=0.01) (Table 3). Neonatal deaths were mainly associated with extreme preterm birth. Among the 16 cases, 12 were observed in infant born before 25 weeks (9/10 in HIV infected women, 3/6 in controls).
ACCEPTED MANUSCRIPT Both the univariate and multivariate analyses failed to show any evidence of a relation between vasculoplacental complications and any of the CD4 count, viral load, or CDC status of the women with HIV or their ARV treatments before or at the beginning of pregnancy (model 1). Moreover, we observed no association between HIV infection and
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vasculoplacental complications, even after adjustment for the known risk factors for these complications and for gestational age at delivery (model 2) (Table 4).
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Comment
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This study, intended to test the association of HIV infection and its treatment to pregnancyrelated vasculoplacental complications, shows no association for either preeclampsia or IUGR from vascular causes.
Nor are the first trimester HIV indicators — CD4 T cell count and viral load — associated
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with the risk of vasculoplacental complications.
Although we found no elevated risk of vasculoplacental complications, we did observe that HIV-infected women have a significantly higher risk of preterm delivery. This risk, which is
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not due to induced preterm births, may be associated with the use of boosted protease inhibitors, as previously reported.23 The difference observed between cases and controls in
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neonatal death prevalence could be related to the elevated risk of preterm delivery. Those questions will be studied in secondary analyses. One of the strengths of this study lies in the comparability of the case and control groups for important medical and demographic characteristics, such as age, weight, BMI, geographic origin, parity, history of hypertension, nephropathy, diabetes, and drug use. All women received regular prenatal care during pregnancy with homogeneous management of HIV for the entire inclusion period, which was deliberately relatively short (2006-2010). The size of
ACCEPTED MANUSCRIPT our study is larger than the sample size calculated before inclusion. Accordingly, lack of statistical power cannot be invoked to explain the lack of association. Nonetheless, as a retrospective study, it is not exempt from the biases inherent in this method. Moreover, the population of this study (cases and controls) is a closer reflection of the
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population of pregnant women with HIV in France than of the general population, since 85.7% of the entire study population comes originally from sub-Saharan Africa.
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Some earlier studies comparing women with HIV untreated by ARV to uninfected women also failed to observe any evidence of a significant difference in their rates of
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preeclampsia.1,5,24-26 They nonetheless come from older cohorts, when management in terms of preventing mother-child transmission differed substantially from current standards. It is thus difficult to interpret these data. In one study Frank et al. studied 704 women with untreated HIV infection and 1896 unmatched uninfected patients who gave birth in Soweto in
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2002. The rates of eclampsia or preeclampsia were very similar: 5.7% for the infected women and 5.2% for those with no infection. The disease indicators (CD4 count and viral load) of the study population were nonetheless unknown.5
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The data from more recent studies with higher proportions of infected women treated by ARV are also contradictory.1-3,7,15,27,28
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Some attribute the pathogenesis of preeclampsia in these women to ARV drugs and more particularly HAART.1,2 Wimalasundera et al1 reported results from a cohort of 137 women infected with HIV (61 without ARV) and 214 uninfected women. The rate of preeclampsia was significantly lower in the group of infected untreated women than in either the infected HAART-treated or uninfected groups. Similarly Suy et al2 showed in a cohort of 472 HIV+ and 8768 HIV- pregnant women that HAART before pregnancy is associated with a higher preeclampsia rate than in the HIV- control population. One hypothesis advanced to explain
ACCEPTED MANUSCRIPT the increased risk of preeclampsia in women treated by HAART is its supposed direct toxicity of the liver, through disruption of the secretion of retinol-binding protein (RBP) and the reduction of blood levels of retinol or vitamin A, which play a role in oxidative stress phenomena.16
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For other authors, the preeclampsia rate is lower3,7 or identical1,27 in HIV+ women treated by HAART compared with HIV- patients. In 2004, in a study of 123 HIV+ women under treatment (a single drug or HAART) and 1708 HIV- women, Mattar et al3 showed a
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significantly lower preeclampsia rate in the HIV+ group under treatment (0.8%) than in the HIV- group (10.6%), p=0.002. This result is totally discordant with Suy's data, but this study
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also has a bias linked to the women's geographic origin, which are very different in the two groups. In 2007, Boer et al4 published a study of 143 HIV+ patients treated by more than one drug and 196 HIV- patients and reported preeclampsia rates of 2% and 1% respectively — not a significant difference.
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It is very difficult to reach any conclusion from the previously published data given the problems of comparability between the infected case patients and the uninfected controls. The discordance of our results with some earlier reports may be explained by our strategy of
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matching and adjustment.
Although we were attentive to this indicator, our study did not show any relation between the
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CD4 T-cell count before or during pregnancy and the rate of vasculoplacental complications. That may be due to the high mean CD4 level in our population. The current data in the literature nonetheless justify the suspicion of an association between immune status and vasculoplacental complications. If we consider preeclampsia to be a generalized and excessive inflammatory response29, immune depression during HIV infection could inhibit this excessive immune response and thereby reduce the risk of preeclampsia, as observed in some studies30. From the immunological point of view, a normal pregnancy is also associated
ACCEPTED MANUSCRIPT with the transition of maternal immunity from a Th1 predominance toward Th2, for persistence of Th1 immunity leads to an inflammatory response to the fetus and its rejection.31 The blood levels of maternal immune regulatory cells, such as CD4+ FOXP3+, normally increase during pregnancy to limit rejection of the fetus32, and their diminution is associated
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with the persistence of fetal rejection phenomena and with preeclampsia33,34. These studies show the importance of assessing and analyzing women's immune status in studies of preeclampsia and HIV, which is not always done.5
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Although we have not shown any association between viral load and the rate of vasculoplacental complications, recent pathophysiologic data lead us to hypothesize that HIV
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itself might be directly responsible for a vascular dysfunction promoting preeclampsia. The human arterial smooth muscle cells can be activated by gp120, an HIV envelope glycoprotein, through the two co-receptors, CXCR4 and CCR5, in the presence of functional CD4 cells; the tissue factor thus synthesized is responsible for the initiation of the coagulation cascade.35
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Apart from any treatment, there is also a significant correlation between viral load and the levels of vascular activation markers (soluble vascular cell adhesion molecule (sVCAM)-1
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and Von Willebrand factor).36
In conclusion, in this study, we found that the prevalence of vasculoplacental complications is
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the same among women infected with HIV, regardless of whether or not they are treated before pregnancy), and in women without HIV infection. Recent findings about HIV pathophysiology and its impact on the immune and vascular systems nonetheless indicate the value of continuing to explore the associations between immune and viral markers and the risk of vasculoplacental complications during pregnancy.
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Figure and tables legends
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Figure 1: Study groups
Figure 1 is a flow chart describing the constitution of case and control groups.
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Table 1: Baseline characteristics of HIV-infected patients
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Table 2: Baseline characteristics of the HIV+ and HIV- groups
Table 3: Pregnancy complication and outcomes in the HIV+ and HIV- groups * Severe preeclampsia: Preeclampsia with severe hypertension (SBP > 160 mm Hg and/or DBP > 110
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mm Hg) and/or renal damage with any one or more of the following: oliguria (< 500 mL/24 h), creatinine > 135 µmol/L, proteinuria > 5 g/d, acute lung edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia, intractable neurological disorders (visual disorders,
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polykinetic deep tendon reflexes, headaches) and/or thrombocytopenia <100 g/L-1 and/or abruptio placentae, and/or effects on the fetus.
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† Composite vasculoplacental variable: Combination of any two or more of the following: pregnancyrelated hypertension, preeclampsia, vascular intrauterine growth restriction <10th percentile (associated with any of: abnormal uterine Dopplerǂ or an elevated umbilical RI, or vasculoplacental complications after other causes are ruled out) ǂ Abnormal uterine Doppler: elevated uterine index resistance or notch, either unilateral or bilateral, tested at 25 weeks. § Admission to special care nursery or NICU.
ACCEPTED MANUSCRIPT Table 4: Risk factors for vasculoplacental complications* * Pregnancy-related hypertension, or preeclampsia, or fetal growth restriction<10th percentile from a vascular cause
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**Schoenfeld’s residual not significant for all covariates
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273 (97.5) 5 (1.8) 2 (0.7)
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43 (15.4) 76 (27.1) 48 (17.1) 28 (10.0) 9 (3.2) 76 (27.1) 0
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HIV diagnosed more than 1 year ago n (%) HIV serotype n (%) Type 1 Type 2 Type 1+2 Circumstances of diagnosis n (%) Current pregnancy Previous pregnancy Voluntary screening Marker HIV+ partner Unknown Seroconversion during this pregnancy Mode of transmission n (%) Sexual Drug dependence Transfusion Workplace accident Unknown CDC stage n (%) 1 2 3 Unknown
HIV+ women n = 280 231 (82.5)
93 (33.2) 1 (0.4) 4 (1.4) 1 (0.4) 166 (59.3) 219 (78.2) 30 (10.7) 13 (4.6) 18 (6.4)
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Treatment before this pregnancy n (%) Antiretroviral treatment 134 (47.9) Bactrim® 8 (2.9) Laboratory test status before the pregnancy among the 237 patients with known HIV infection CD4 T cell count n (%) < 300/mm3 38 (16.0) > 300/mm3 140 (59.1) Unknown 59 (24.9) Viral load n (%) < 50 copies/mL 106 (44.7) > 50 copies/mL 79 (33.3) Unknown 52 (21.9)
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Table 1: Baseline characteristics of HIV-infected patients
ACCEPTED MANUSCRIPT HIV- womenn = 560 30.9 +/-5 1.66 +/-0.06 68.9 +/-13.8 25.1 +/-4.8
0.82 0.75 0.65 0.70
103 (36.8) 37 (13.2)
151 (27.0) 217 (38.7)
0.34 0.69
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46 (8.2) 24 (4.3) 8 (1.4) 480 (85.7) 2 (0.4) 13 (2.3) 9 (1.6) 7 (1.2) 14 (2.5)
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8 (2.9) 0 1 (0.4) 5 (1.8)
P
RI PT
23 (8.2) 12 (4.3) 4 (1.4) 240 (85.7) 1 (0.4)
1
0.09 0.51
3 (1.1) 0 3 (1.1) 16 (5.7) 47 (16.8) 0
15 (2.7) 1 (0.2) 10 (1.8) 5 (0.9) 39 (7.0) 0
<0.001 <0.001 -
22 (8.1) 4 (1.5) 1 (0.37) 1 (0.4) 1 (0.4) 0 3.7 +/-2.1 203 (72.5)
29 (5.2) 15 (2.7) 0 0 0 2 (0.4) 3.4 +/-1.8 404 (72.1)
0.96 0.28 0.15 0.15 0.15 0.32 0.99 0.91
136 (48.6) 60 (21.4) 7 (2.5) 7 (2.5) 7 (2.5) 29 (10.4) 93 (33.2) 19 (6.8)
176 (31.4) 136 (24.3) 13 (2.3) 10 (1.8) 15 (2.7) 43 (7.7) 104 (18.6) 9 (1.6)
<0.001 0.36 0.87 0.49 0.88 0.19 <0.001 <0.001
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Age (years), mean ± SD Height (m), mean +/- SD Prepregnancy weight (kg), mean +/- SD Prepregnancy BMI (kg/m2), mean +/- SD BMI (kg/m2), n (%) BMI>25 BMI>30 Geographic origin n (%) Europe North Africa West Indies Sub-Saharan Africa Asia History of hypertension n (%) Essential hypertension Pregnancy-related hypertension Preeclampsia Nephropathy n (%) Diabetes n (%) Type I Type II Pregnancy-related History of tuberculosis n (%) History of malaria n (%) Sickle-cell disease SS n (%) Use of toxic substances n (%) Smoking Alcohol Cocaine Crack Heroin Cannabis Number of pregnancies (mean +/- SD) Multiparous n (%) Obstetrical history n (%) Elective termination of pregnancy Early miscarriage Late miscarriage Medical termination of pregnancy In utero fetal death Intrauterine growth restriction Cesarean Loop electrosurgical excision
HIV+ women n = 280 31.0 +/-5 1.66 +/-0.06 69.4 +/-13.6 25.2 +/-4.9
Table 2: Baseline characteristics of the HIV+ and HIV- groups
0.32
HIV+ women ACCEPTED MANUSCRIPT n = 280 22 (7.9) 4 (1.43) 10 (3.6) 4 (1.4) 21 (7.5) 47 (16.8)
11 (2.0) 28 (5.0) 10 (1.8) 55 (9.8) 70 (12.5)
0.70 0.269 0.021
31.2 +/-9.2
34.2 +/-5.0
0.08
19 (6.8) 5 (1.8) 4 (1.4) 34 (12.1) 30 (10.7) 37.7 +/-3.2
43 (7.7) 18 (3.2) 4 (0.7) 31 (5.5) 38 (6.8) 39.0 +/-2.3
52 (18.6) 14 (5.0) 10 (3.6)
45 (8.0) 13 (2.3) 20 (3.6)
<0.001 0.04 1
119 (42.5) 8 (2.9) 121 (43.2) 32 (11.4)
377 (67.3) 35 (6.2) 79 (14.1) 69 (12.3)
<0.001
19/127 (15.0) 87/127 (68.5) 37/127 (29.1) 2/127 (1.6) 1/127 (0.8)
135/412 (32.8) 267/412 (64.8) 134/412 (32.5) 10/412 (2.4) 1/412 (0.2)
<0.001
139 (49.6)
297 (53.0)
0.35
2902 +/-705 41.6 +/-28.5 17 (6.1) 45 (16.1)
3201 +/-591 46.6 +/-28.6 21 (3.7) 67 (12.0)
<0.001 0.02 0.12 0.09
34.1 +/-2.4 48.3 +/-30.8 20 (7.1)
34.4 +/-1.9 52.2 +/-28.1 14 (2.5)
0.03 0.07 0.001
5 (1.8) 46 (16.4) 22 (7.9) 10 (3.6)
22 (3.9) 66 (11.8) 71 (12.7) 6 (1.1)
0.11 0.03 0.09 0.01
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P 0.16 0.69
0.43
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Long-term aspirin during pregnancy n (%) Vasculoplacental complication n (%) Pregnancy-related hypertension Preeclampsia Severe preeclampsia * Composite vasculoplacental variable** Abnormal uterine Doppler *** Gestational age at diagnosis of vasculoplacental complications, in weeks (mean +/- SD) Pregnancy-related diabetes n (%) Dietary treatment only Insulin Acute pregnancy-related cholestasis n (%) Threatened preterm delivery n (%) Fetal lung maturation by corticosteroid therapy n (%) Gestational age at delivery, in weeks (mean+/-SD) Preterm delivery n (%) <37 weeks <32 weeks Induced premature birth Mode of delivery (%) Spontaneous vaginal delivery Instrumental vaginal delivery Cesarean before labor Cesarean during labor Perineal lesions among women with vaginal deliveries n (%) Episiotomy None (except episiotomy) Simple tear Complete perineum, uncomplicated Complete perineum, complicated Child’s sex n (%) Girl Birth weight (mean +/- SD) Birth weight in g Birth weight in percentile <3d percentile n (%) <10d percentile n (%) Head circumference (mean +/– SD) Head circumference in cm Head circumference in percentile 5-min Apgar score < 7 (%) Arterial pH at birth < 7.10 n (%) Hospitalization of the child **** n (%) Neonatal jaundice (phototherapy) n (%) Neonatal deaths n (%)
HIV- womenn = 560 30 (5.4)
0.31 0.001 0.049 <0.001
0.65
Table 3: Pregnancy complication and outcomes in the HIV+ and HIV- groups * Severe preeclampsia: Preeclampsia with severe hypertension (SBP > 160 mm Hg and/or DBP > 110 mm Hg) and/or renal damage with any one or more of the following: oliguria (< 500 mL/24 h), creatinine > 135 µmol/L, proteinuria > 5 g/d, acute lung edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia, intractable neurological disorders (visual disorders, polykinetic deep tendon reflexes, headaches) and/or thrombocytopenia <100 g/L-1 and/or abruptio placentae, and/or effects on the fetus. ** Composite vasculoplacental variable: Combination of any two or more of the following: pregnancy-related hypertension, preeclampsia, vascular intrauterine growth restriction <10th percentile (associated with any of: abnormal uterine Doppler *** or an elevated umbilical RI, or vasculoplacental complications after other causes are ruled out) *** Abnormal uterine Doppler: elevated uterine index resistance or notch, either unilateral or bilateral, tested at 25 weeks. **** Admission to special care nursery or NICU.
ACCEPTED MANUSCRIPT Model 1 – infected patients OR 1.15 0.84 0.46 0.95 1.68 0.59
95%CI 0.47 2.82 0.29 2.46 0.14 1.52 0.26 3.43 0.98 2.90 0.36 0.97
0.59 1.68 1.53 11.10 3.29 7.63 1.78 5.61 0.74
0.36 0.98 0.82 6.73 1.17 2.60 0.91 3.59 0.44
Model 2** – entire sample
95%CI 0.22 5.08
0.55
0.11
2.62
1.18 0.82
0.34 0.24
4.18 2.80
0.53 1.88 0.98 9.59 3.68 2.19 0.87 1.89 1.07
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0.97 2.90 2.86 21.31 9.29 22.37 3.45 8.75 1.26
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Multiparous Age > 35 years BMI > 30 Abnormal uterine artery Doppler Hypertension when not pregnant History of preeclampsia Pregnancy-related diabetes Gestational age at delivery HIV infection
aOR 1.06
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Periconceptional ARV treatment CD4 ≥ 300/mm3 during the first trimester VL>50 copies/mL during the first trimester CDC stage 2 or 3 Age > 35 years Multiparous
0.29 1.04 0.42 5.48 1.13 1.05 0.36 1.04 0.58
0.96 3.42 2.29 16.75 12.00 4.54 2.12 3.42 1.98
Table 4: Risk factors for vasculoplacental complications*
*Pregnancy-related hypertension, or preeclampsia, or fetal growth restriction<10th percentile from a vascular cause
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**Schoenfeld’s residual not significant for all covariates
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ACCEPTED MANUSCRIPT
S0002-9378(15)00265-3
DOI:
10.1016/j.ajog.2015.03.035
Reference:
YMOB 10323
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 2 November 2014 Revised Date:
21 January 2015
Accepted Date: 16 March 2015
Please cite this article as: Canlorbe G, Matheron S, Mandelbrot L, Oudet B, Luton D, Azria E, Vasculoplacental complications in pregnant women with HIV infection: a case-control study, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.03.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Vasculoplacental complications in pregnant women with HIV infection: a case-control study Geoffroy Canlorbe, MD1,2, Sophie Matheron MD3,4, Laurent Mandelbrot MD, PhD2,5,
Service de gynécologie obstétrique, Hôpital Bichat-Claude Bernard, Université Paris
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1
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Barbara Oudet1,2, Dominique Luton MD, PhD1,2, Elie Azria MD, PhD1,2,6
Diderot, Paris, France DHU Risk in Pregnancy
3
Service de maladies infectieuses et tropicales, Hôpital Bichat-Claude Bernard, Université
Paris Diderot, Paris, France
5
INSERM, IAME, UMR 1137, Paris, France
APHP Hôpital Louis Mourier, Service de Gynecologie-Obstetrique, Colombes and
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4
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2
Université Paris Diderot, Paris, France 6
INSERM, U-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical,
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Perinatal and Pediatric Epidemiology Team, Paris, France
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Corresponding author Elie Azria
INSERM, U-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical, Perinatal and Pediatric Epidemiology Team, Maternité Port-Royal, 53 avenue de l'Observatoire, Paris 75014, France Telephone number: 00 33 6 11 52 54 32 email: [email protected]
ACCEPTED MANUSCRIPT Funding None
The authors report no conflict of interests.
Word count Main text: 2837
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Abstract: 177
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Competing interests
ACCEPTED MANUSCRIPT Condensation Maternal HIV infection does not appear to be associated with the risk of vasculoplacental complications during pregnancy.
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Short version of title
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Vasculoplacental complications in pregnant women with HIV infection
ACCEPTED MANUSCRIPT Abstract
Introduction: Data from the international literature suggest that there may be an association
Studies on this subject have reached discordant conclusions.
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between maternal HIV infection and vasculoplacental complications during pregnancy.
Objective: The aim of this study was to assess the incidence of vasculoplacental complications during pregnancy in women with and without HIV infection.
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Materials and methods: This single-center case-control study compared the incidence of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular intrauterine growth
parity, and geographic origin.
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restriction in 280 women with HIV and 560 women not infected with HIV, matched for age,
Results: The incidence rates of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular growth restriction did not differ between the women with and without HIV infection.
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The overall incidence of vasculoplacental complications did not differ between the two groups (7.5% vs 9.8% respectively, p= 0.27). The risk of these was not associated with
pregnancy.
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exposure to antiretroviral treatments, viral load, or CD4 T-cell counts at the beginning of
Conclusion: This study shows no difference in the incidence of vasculoplacental
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complications between women with and without HIV infection.
Key words: Antiretroviral therapy, HIV, ischemic placental disease, low birth weight, preeclampsia, pregnancy-related hypertension
ACCEPTED MANUSCRIPT Introduction
The pregnancy-related diseases referred to as vasculoplacental (also called ischemic placental disease), such as preeclampsia, eclampsia, and intrauterine growth restriction (IUGR) of
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vasculoplacental origin, are a major cause of morbidity and mortality in both mothers and fetuses.
Some studies suggest that maternal infection by HIV may be associated with these conditions,
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regardless of whether or not the patient is receiving antiretroviral treatment (ARV). The data from the literature are nonetheless discordant; some report an association with an increased
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risk of vasculoplacental complications.1, 2 Inversely, others find results suggesting a protective effect3, and others show no association4. These data are often difficult to interpret, especially because they frequently lack information about the stage and severity of these women’s HIV infections, their treatment5, and whether confounding factors, such as geographic origin3, drug
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use, and smoking were taken into account6-11.
The appearance of new ARV drugs and changes in guidelines and practices for this treatment may also explain these discordances, at least in part. The prescription of these drugs at the
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beginning of the second trimester is now recommended, even if the mother's condition does not indicate a need for treatment12, because the combination of three antiretroval drugs
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(HAART: highly active antiretroviral therapy) is associated with a reduction in the maternal viral load, in infant mortality, and in the rate of mother-to-child transmission13. The benefits of this strategy in terms of the prevention of mother-child transmission are incontestable, but the safety of these drugs7,14,15 is nonetheless questionable, and their toxicity16 might promote the development of vasculoplacental diseases17-20. The principal objective of this retrospective case-control study was to determine whether HIV infection and ARV exposure are associated with an increased risk of vasculoplacental disease.
ACCEPTED MANUSCRIPT The demonstration of an increased risk would not only allow obstetricians to provide better information to their patients but also to adapt the prenatal monitoring of infected pregnant
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women and their fetuses to reduce the morbidity associated with this disease.
Materials and methods
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This single-center retrospective case-control study took place in the obstetrics department of the Bichat-Claude Bernard University Hospital, in Paris, France, a level IIb maternity ward. It
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considered for inclusion all women who gave birth from December 2006 through October 2010.
The Paris North Institutional Review Board (CEERB) approved this study (approval n° 11.090).
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The women in the case group met the following inclusion criteria: HIV infection known at the time of delivery, delivery after 20 weeks of gestation, regardless of pregnancy outcome, management and delivery planned at Bichat-Claude Bernard, regardless of the actual place of
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delivery, and singleton pregnancy.
The control group, unexposed to HIV (negative serology results during pregnancy, for this
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screening test was routinely proposed to all pregnant women), were identified from the delivery and transfer registers for the pregnant women signed up for delivery in our institution, and otherwise met the same inclusion criteria. One-to-two matching was performed according to the following three criteria: maternal age group (≤19, 20-22, 23-25, 26-28, 29-31, 32-34, 35-37, 38-40, ≥41 years), geographic origin (Europe, North Africa, West Indies, Asia, sub-Saharan Africa), and parity.
ACCEPTED MANUSCRIPT The exclusion criteria were: pregnancy ended before 20 weeks, fetal malformation, chromosomal abnormalities, multiple pregnancy, fetal CMV infection, HIV serologic status unknown or not reported in the file, woman already included in the study for a later pregnancy (only the last pregnancy was included).
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The number of subjects necessary was calculated based on the following hypotheses: we assume a frequency of preeclampsia and/or vascular IUGR of 8% in the population unexposed to HIV (2010 data from the Bichat-Claude Bernard obstetrics department
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database) and twice this rate for women with HIV and treated by antiretroviral drugs. To
power: 80%, two-tailed test).
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show such a doubled rate, the study required 270 cases and 540 controls (alpha risk: 5%,
All pregnant women with HIV infection were followed and treated according to the French guidelines then applicable.21
We collected data about the women's medical and obstetric history, the characteristics of their
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HIV infection and its management, especially ARV treatment before and during pregnancy, and the course and outcome of the pregnancy.
Pregnancy-related hypertension (PRH) was defined by systolic blood pressure (SBP) >140
EP
mm Hg and/or diastolic blood pressure (DBP) >90 mm Hg that developed after 20 weeks of gestation and disappeared before the end of the sixth week postpartum. Preeclampsia was
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defined by the combination of PRH and proteinuria (> 0.3 g/24 h), and HELLP syndrome by the combination of hemolysis, hepatic cytolysis, and thrombocytopenia. Preeclampsia was defined as severe when the patient also had any one or more of the following: severe hypertension (SBP > 160 mm Hg or DBP > 110 mm Hg), kidney damage (oliguria (< 500 mL/24 h) or creatinine levels > 135 µmol/L or proteinuria > 5 g/day), acute pulmonary edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia,
ACCEPTED MANUSCRIPT intractable neurological disorders (visual disorders, polykinetic deep tendon reflexes, or headaches), thrombocytopenia <100,000 plt/L, or abruptio placentae. Uterine artery Doppler waveforms were defined as abnormal when the resistance index (RI) was high22 or when a unilateral or bilateral notch was observed, confirmed at 22 weeks.
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Vascular intrauterine growth restriction (IUGR) was defined by the combination of IUGR (<10th percentile) with at least one of the following: a history of vasculoplacental complication, abnormal uterine Doppler waveforms, elevated umbilical artery IR, or a
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vasculoplacental complication after other causes were ruled out.
A composite vasculoplacental criterion was defined by the presence of PRH, or preeclampsia,
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or IUGR <10th percentile from a vascular cause.
Term at delivery was determined from the date the pregnancy began, measured by the crownrump length from the first-trimester ultrasound, if available, and otherwise from the date of the last menstrual period.
Stata Corp LP).
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The statistical analyses were performed with STATA software v. 10 (College Station, TX,
Measurements for birth weight (in grams) and head circumference (in cm) at birth were
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standardized and expressed as percentiles after adjustment for the newborn's gestational age (in completed weeks of gestation) and sex, according to the reference curves from the French
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Audipog network (www.audipog.net/). The categorical variables were compared with Chi-2 tests or Fisher's exact test, as appropriate. The discrete variables in two classes were compared with Student's t test and continuous variables (with normal or non-normal distributions) with Wilcoxon's test. The associations between vasculoplacental complications and candidate risk factors were first explored by calculation of the crude odds ratios (OR). Adjusted odds ratios (ORa) were then calculated with two different regression models. The first was a logistic regression model and
ACCEPTED MANUSCRIPT considered the population of women with HIV infection and tested disease indicators (CDC stage, CD4 T-cell count, and viral load, measured at some point between the beginning of pregnancy and week 14), after adjustment for age and parity. The second was a cox proportional hazard model suited for matched cohort. This model was used to examine the
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entire study population and tested the variable of HIV infection by adjusting for the known risk factors of vascular complications and for gestational age at delivery (3 classes: ≥37 weeks, 32-37, <32). Schoenfeld’s residual test was used to test the proportional hazards
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assumption.
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For all of these statistical tests, a P value<0.05 was considered statistically significant.
Results
During the study period, 8273 women gave birth to singleton infants after 20 weeks'
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gestation. Among them, 307 had HIV infection and met the study's inclusion criteria. We excluded 27 already included in the study with a more recent pregnancy. Finally, 280 women were included in the case group (273 subtype 1; 5 subtype 2, and 2 simultaneously infected by
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subtypes 1 and 2) and matched with 560 uninfected women. Data for 832 of these 840 patients were available in records stored onsite. The 8 missing or
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incomplete records were those of women who gave birth in other maternity units; we were able to obtain all of them from the hospital of birth (Figure 1).
Table 1 summarizes the data about the status of the HIV infection of the 280 infected women. The diagnosis had been made during a previous pregnancy in 27.1% of the cases and during the pregnancy studied here in 15.4%, no case of seroconversion during pregnancy has been identified. The CDC stage was 1 for 78.2% of the women. Of the women whose infection was
ACCEPTED MANUSCRIPT known before the study pregnancy, 47.9% had received ARV before the beginning of the pregnancy. At the beginning of this pregnancy, 44.7% had an undetectable viral load (threshold 50 copies/mL) and 21% a CD4 T-cell count < 300/mm3. During the third trimester of the pregnancy, 94% of the infected women received ARV
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treatment. In a very large percentage of cases, this consisted of a combination of two nucleoside analogs and a protease inhibitor (90.5%). Much more rarely (6.8%), it was two
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nucleoside analogs with a non-nucleoside analog. Other combinations were extremely rare.
Checking the quality of the matching, we observed that the two groups were comparable for
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age, parity, and geographic origin. No difference was observed for a history of hypertensive diseases, of nephropathy, of diabetes, of smoking or consumption of illegal drugs, of in utero death, or of IUGR (Table 2).
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The case and control groups did not differ in their prevalence of the composite vasculoplacental criterion (9.8% vs 7.7%, respectively, p=0.269), or of PRH, preeclampsia or severe preeclampsia. We observed a higher prevalence of abnormal uterine artery Doppler
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waveforms in the HIV-infected group (16.8% vs 12.5%, p=0.02). The rates of preterm birth before 37 weeks and before 32 weeks were significantly higher in
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the HIV group (18.6% vs 8.0%, P<0.001 and 5.0% vs 2.3%, P=0.04 respectively) (Table 3). This difference affected only spontaneous preterm births; induced preterm births did not differ at all (3.6% vs 3.6%, p=1).
We observed a higher prevalence of neonatal deaths in the HIV infected group (3.6% vs 1.1%, p=0.01) (Table 3). Neonatal deaths were mainly associated with extreme preterm birth. Among the 16 cases, 12 were observed in infant born before 25 weeks (9/10 in HIV infected women, 3/6 in controls).
ACCEPTED MANUSCRIPT Both the univariate and multivariate analyses failed to show any evidence of a relation between vasculoplacental complications and any of the CD4 count, viral load, or CDC status of the women with HIV or their ARV treatments before or at the beginning of pregnancy (model 1). Moreover, we observed no association between HIV infection and
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vasculoplacental complications, even after adjustment for the known risk factors for these complications and for gestational age at delivery (model 2) (Table 4).
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Comment
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This study, intended to test the association of HIV infection and its treatment to pregnancyrelated vasculoplacental complications, shows no association for either preeclampsia or IUGR from vascular causes.
Nor are the first trimester HIV indicators — CD4 T cell count and viral load — associated
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with the risk of vasculoplacental complications.
Although we found no elevated risk of vasculoplacental complications, we did observe that HIV-infected women have a significantly higher risk of preterm delivery. This risk, which is
EP
not due to induced preterm births, may be associated with the use of boosted protease inhibitors, as previously reported.23 The difference observed between cases and controls in
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neonatal death prevalence could be related to the elevated risk of preterm delivery. Those questions will be studied in secondary analyses. One of the strengths of this study lies in the comparability of the case and control groups for important medical and demographic characteristics, such as age, weight, BMI, geographic origin, parity, history of hypertension, nephropathy, diabetes, and drug use. All women received regular prenatal care during pregnancy with homogeneous management of HIV for the entire inclusion period, which was deliberately relatively short (2006-2010). The size of
ACCEPTED MANUSCRIPT our study is larger than the sample size calculated before inclusion. Accordingly, lack of statistical power cannot be invoked to explain the lack of association. Nonetheless, as a retrospective study, it is not exempt from the biases inherent in this method. Moreover, the population of this study (cases and controls) is a closer reflection of the
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population of pregnant women with HIV in France than of the general population, since 85.7% of the entire study population comes originally from sub-Saharan Africa.
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Some earlier studies comparing women with HIV untreated by ARV to uninfected women also failed to observe any evidence of a significant difference in their rates of
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preeclampsia.1,5,24-26 They nonetheless come from older cohorts, when management in terms of preventing mother-child transmission differed substantially from current standards. It is thus difficult to interpret these data. In one study Frank et al. studied 704 women with untreated HIV infection and 1896 unmatched uninfected patients who gave birth in Soweto in
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2002. The rates of eclampsia or preeclampsia were very similar: 5.7% for the infected women and 5.2% for those with no infection. The disease indicators (CD4 count and viral load) of the study population were nonetheless unknown.5
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The data from more recent studies with higher proportions of infected women treated by ARV are also contradictory.1-3,7,15,27,28
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Some attribute the pathogenesis of preeclampsia in these women to ARV drugs and more particularly HAART.1,2 Wimalasundera et al1 reported results from a cohort of 137 women infected with HIV (61 without ARV) and 214 uninfected women. The rate of preeclampsia was significantly lower in the group of infected untreated women than in either the infected HAART-treated or uninfected groups. Similarly Suy et al2 showed in a cohort of 472 HIV+ and 8768 HIV- pregnant women that HAART before pregnancy is associated with a higher preeclampsia rate than in the HIV- control population. One hypothesis advanced to explain
ACCEPTED MANUSCRIPT the increased risk of preeclampsia in women treated by HAART is its supposed direct toxicity of the liver, through disruption of the secretion of retinol-binding protein (RBP) and the reduction of blood levels of retinol or vitamin A, which play a role in oxidative stress phenomena.16
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For other authors, the preeclampsia rate is lower3,7 or identical1,27 in HIV+ women treated by HAART compared with HIV- patients. In 2004, in a study of 123 HIV+ women under treatment (a single drug or HAART) and 1708 HIV- women, Mattar et al3 showed a
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significantly lower preeclampsia rate in the HIV+ group under treatment (0.8%) than in the HIV- group (10.6%), p=0.002. This result is totally discordant with Suy's data, but this study
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also has a bias linked to the women's geographic origin, which are very different in the two groups. In 2007, Boer et al4 published a study of 143 HIV+ patients treated by more than one drug and 196 HIV- patients and reported preeclampsia rates of 2% and 1% respectively — not a significant difference.
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It is very difficult to reach any conclusion from the previously published data given the problems of comparability between the infected case patients and the uninfected controls. The discordance of our results with some earlier reports may be explained by our strategy of
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matching and adjustment.
Although we were attentive to this indicator, our study did not show any relation between the
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CD4 T-cell count before or during pregnancy and the rate of vasculoplacental complications. That may be due to the high mean CD4 level in our population. The current data in the literature nonetheless justify the suspicion of an association between immune status and vasculoplacental complications. If we consider preeclampsia to be a generalized and excessive inflammatory response29, immune depression during HIV infection could inhibit this excessive immune response and thereby reduce the risk of preeclampsia, as observed in some studies30. From the immunological point of view, a normal pregnancy is also associated
ACCEPTED MANUSCRIPT with the transition of maternal immunity from a Th1 predominance toward Th2, for persistence of Th1 immunity leads to an inflammatory response to the fetus and its rejection.31 The blood levels of maternal immune regulatory cells, such as CD4+ FOXP3+, normally increase during pregnancy to limit rejection of the fetus32, and their diminution is associated
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with the persistence of fetal rejection phenomena and with preeclampsia33,34. These studies show the importance of assessing and analyzing women's immune status in studies of preeclampsia and HIV, which is not always done.5
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Although we have not shown any association between viral load and the rate of vasculoplacental complications, recent pathophysiologic data lead us to hypothesize that HIV
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itself might be directly responsible for a vascular dysfunction promoting preeclampsia. The human arterial smooth muscle cells can be activated by gp120, an HIV envelope glycoprotein, through the two co-receptors, CXCR4 and CCR5, in the presence of functional CD4 cells; the tissue factor thus synthesized is responsible for the initiation of the coagulation cascade.35
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Apart from any treatment, there is also a significant correlation between viral load and the levels of vascular activation markers (soluble vascular cell adhesion molecule (sVCAM)-1
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and Von Willebrand factor).36
In conclusion, in this study, we found that the prevalence of vasculoplacental complications is
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the same among women infected with HIV, regardless of whether or not they are treated before pregnancy), and in women without HIV infection. Recent findings about HIV pathophysiology and its impact on the immune and vascular systems nonetheless indicate the value of continuing to explore the associations between immune and viral markers and the risk of vasculoplacental complications during pregnancy.
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Figure and tables legends
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Figure 1: Study groups
Figure 1 is a flow chart describing the constitution of case and control groups.
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Table 1: Baseline characteristics of HIV-infected patients
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Table 2: Baseline characteristics of the HIV+ and HIV- groups
Table 3: Pregnancy complication and outcomes in the HIV+ and HIV- groups * Severe preeclampsia: Preeclampsia with severe hypertension (SBP > 160 mm Hg and/or DBP > 110
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mm Hg) and/or renal damage with any one or more of the following: oliguria (< 500 mL/24 h), creatinine > 135 µmol/L, proteinuria > 5 g/d, acute lung edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia, intractable neurological disorders (visual disorders,
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polykinetic deep tendon reflexes, headaches) and/or thrombocytopenia <100 g/L-1 and/or abruptio placentae, and/or effects on the fetus.
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† Composite vasculoplacental variable: Combination of any two or more of the following: pregnancyrelated hypertension, preeclampsia, vascular intrauterine growth restriction <10th percentile (associated with any of: abnormal uterine Dopplerǂ or an elevated umbilical RI, or vasculoplacental complications after other causes are ruled out) ǂ Abnormal uterine Doppler: elevated uterine index resistance or notch, either unilateral or bilateral, tested at 25 weeks. § Admission to special care nursery or NICU.
ACCEPTED MANUSCRIPT Table 4: Risk factors for vasculoplacental complications* * Pregnancy-related hypertension, or preeclampsia, or fetal growth restriction<10th percentile from a vascular cause
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**Schoenfeld’s residual not significant for all covariates
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273 (97.5) 5 (1.8) 2 (0.7)
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43 (15.4) 76 (27.1) 48 (17.1) 28 (10.0) 9 (3.2) 76 (27.1) 0
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HIV diagnosed more than 1 year ago n (%) HIV serotype n (%) Type 1 Type 2 Type 1+2 Circumstances of diagnosis n (%) Current pregnancy Previous pregnancy Voluntary screening Marker HIV+ partner Unknown Seroconversion during this pregnancy Mode of transmission n (%) Sexual Drug dependence Transfusion Workplace accident Unknown CDC stage n (%) 1 2 3 Unknown
HIV+ women n = 280 231 (82.5)
93 (33.2) 1 (0.4) 4 (1.4) 1 (0.4) 166 (59.3) 219 (78.2) 30 (10.7) 13 (4.6) 18 (6.4)
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Treatment before this pregnancy n (%) Antiretroviral treatment 134 (47.9) Bactrim® 8 (2.9) Laboratory test status before the pregnancy among the 237 patients with known HIV infection CD4 T cell count n (%) < 300/mm3 38 (16.0) > 300/mm3 140 (59.1) Unknown 59 (24.9) Viral load n (%) < 50 copies/mL 106 (44.7) > 50 copies/mL 79 (33.3) Unknown 52 (21.9)
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Table 1: Baseline characteristics of HIV-infected patients
ACCEPTED MANUSCRIPT HIV- womenn = 560 30.9 +/-5 1.66 +/-0.06 68.9 +/-13.8 25.1 +/-4.8
0.82 0.75 0.65 0.70
103 (36.8) 37 (13.2)
151 (27.0) 217 (38.7)
0.34 0.69
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46 (8.2) 24 (4.3) 8 (1.4) 480 (85.7) 2 (0.4) 13 (2.3) 9 (1.6) 7 (1.2) 14 (2.5)
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8 (2.9) 0 1 (0.4) 5 (1.8)
P
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23 (8.2) 12 (4.3) 4 (1.4) 240 (85.7) 1 (0.4)
1
0.09 0.51
3 (1.1) 0 3 (1.1) 16 (5.7) 47 (16.8) 0
15 (2.7) 1 (0.2) 10 (1.8) 5 (0.9) 39 (7.0) 0
<0.001 <0.001 -
22 (8.1) 4 (1.5) 1 (0.37) 1 (0.4) 1 (0.4) 0 3.7 +/-2.1 203 (72.5)
29 (5.2) 15 (2.7) 0 0 0 2 (0.4) 3.4 +/-1.8 404 (72.1)
0.96 0.28 0.15 0.15 0.15 0.32 0.99 0.91
136 (48.6) 60 (21.4) 7 (2.5) 7 (2.5) 7 (2.5) 29 (10.4) 93 (33.2) 19 (6.8)
176 (31.4) 136 (24.3) 13 (2.3) 10 (1.8) 15 (2.7) 43 (7.7) 104 (18.6) 9 (1.6)
<0.001 0.36 0.87 0.49 0.88 0.19 <0.001 <0.001
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Age (years), mean ± SD Height (m), mean +/- SD Prepregnancy weight (kg), mean +/- SD Prepregnancy BMI (kg/m2), mean +/- SD BMI (kg/m2), n (%) BMI>25 BMI>30 Geographic origin n (%) Europe North Africa West Indies Sub-Saharan Africa Asia History of hypertension n (%) Essential hypertension Pregnancy-related hypertension Preeclampsia Nephropathy n (%) Diabetes n (%) Type I Type II Pregnancy-related History of tuberculosis n (%) History of malaria n (%) Sickle-cell disease SS n (%) Use of toxic substances n (%) Smoking Alcohol Cocaine Crack Heroin Cannabis Number of pregnancies (mean +/- SD) Multiparous n (%) Obstetrical history n (%) Elective termination of pregnancy Early miscarriage Late miscarriage Medical termination of pregnancy In utero fetal death Intrauterine growth restriction Cesarean Loop electrosurgical excision
HIV+ women n = 280 31.0 +/-5 1.66 +/-0.06 69.4 +/-13.6 25.2 +/-4.9
Table 2: Baseline characteristics of the HIV+ and HIV- groups
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HIV+ women ACCEPTED MANUSCRIPT n = 280 22 (7.9) 4 (1.43) 10 (3.6) 4 (1.4) 21 (7.5) 47 (16.8)
11 (2.0) 28 (5.0) 10 (1.8) 55 (9.8) 70 (12.5)
0.70 0.269 0.021
31.2 +/-9.2
34.2 +/-5.0
0.08
19 (6.8) 5 (1.8) 4 (1.4) 34 (12.1) 30 (10.7) 37.7 +/-3.2
43 (7.7) 18 (3.2) 4 (0.7) 31 (5.5) 38 (6.8) 39.0 +/-2.3
52 (18.6) 14 (5.0) 10 (3.6)
45 (8.0) 13 (2.3) 20 (3.6)
<0.001 0.04 1
119 (42.5) 8 (2.9) 121 (43.2) 32 (11.4)
377 (67.3) 35 (6.2) 79 (14.1) 69 (12.3)
<0.001
19/127 (15.0) 87/127 (68.5) 37/127 (29.1) 2/127 (1.6) 1/127 (0.8)
135/412 (32.8) 267/412 (64.8) 134/412 (32.5) 10/412 (2.4) 1/412 (0.2)
<0.001
139 (49.6)
297 (53.0)
0.35
2902 +/-705 41.6 +/-28.5 17 (6.1) 45 (16.1)
3201 +/-591 46.6 +/-28.6 21 (3.7) 67 (12.0)
<0.001 0.02 0.12 0.09
34.1 +/-2.4 48.3 +/-30.8 20 (7.1)
34.4 +/-1.9 52.2 +/-28.1 14 (2.5)
0.03 0.07 0.001
5 (1.8) 46 (16.4) 22 (7.9) 10 (3.6)
22 (3.9) 66 (11.8) 71 (12.7) 6 (1.1)
0.11 0.03 0.09 0.01
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P 0.16 0.69
0.43
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Long-term aspirin during pregnancy n (%) Vasculoplacental complication n (%) Pregnancy-related hypertension Preeclampsia Severe preeclampsia * Composite vasculoplacental variable** Abnormal uterine Doppler *** Gestational age at diagnosis of vasculoplacental complications, in weeks (mean +/- SD) Pregnancy-related diabetes n (%) Dietary treatment only Insulin Acute pregnancy-related cholestasis n (%) Threatened preterm delivery n (%) Fetal lung maturation by corticosteroid therapy n (%) Gestational age at delivery, in weeks (mean+/-SD) Preterm delivery n (%) <37 weeks <32 weeks Induced premature birth Mode of delivery (%) Spontaneous vaginal delivery Instrumental vaginal delivery Cesarean before labor Cesarean during labor Perineal lesions among women with vaginal deliveries n (%) Episiotomy None (except episiotomy) Simple tear Complete perineum, uncomplicated Complete perineum, complicated Child’s sex n (%) Girl Birth weight (mean +/- SD) Birth weight in g Birth weight in percentile <3d percentile n (%) <10d percentile n (%) Head circumference (mean +/– SD) Head circumference in cm Head circumference in percentile 5-min Apgar score < 7 (%) Arterial pH at birth < 7.10 n (%) Hospitalization of the child **** n (%) Neonatal jaundice (phototherapy) n (%) Neonatal deaths n (%)
HIV- womenn = 560 30 (5.4)
0.31 0.001 0.049 <0.001
0.65
Table 3: Pregnancy complication and outcomes in the HIV+ and HIV- groups * Severe preeclampsia: Preeclampsia with severe hypertension (SBP > 160 mm Hg and/or DBP > 110 mm Hg) and/or renal damage with any one or more of the following: oliguria (< 500 mL/24 h), creatinine > 135 µmol/L, proteinuria > 5 g/d, acute lung edema, persistent severe epigastric pain (Chaussier sign), HELLP syndrome, eclampsia, intractable neurological disorders (visual disorders, polykinetic deep tendon reflexes, headaches) and/or thrombocytopenia <100 g/L-1 and/or abruptio placentae, and/or effects on the fetus. ** Composite vasculoplacental variable: Combination of any two or more of the following: pregnancy-related hypertension, preeclampsia, vascular intrauterine growth restriction <10th percentile (associated with any of: abnormal uterine Doppler *** or an elevated umbilical RI, or vasculoplacental complications after other causes are ruled out) *** Abnormal uterine Doppler: elevated uterine index resistance or notch, either unilateral or bilateral, tested at 25 weeks. **** Admission to special care nursery or NICU.
ACCEPTED MANUSCRIPT Model 1 – infected patients OR 1.15 0.84 0.46 0.95 1.68 0.59
95%CI 0.47 2.82 0.29 2.46 0.14 1.52 0.26 3.43 0.98 2.90 0.36 0.97
0.59 1.68 1.53 11.10 3.29 7.63 1.78 5.61 0.74
0.36 0.98 0.82 6.73 1.17 2.60 0.91 3.59 0.44
Model 2** – entire sample
95%CI 0.22 5.08
0.55
0.11
2.62
1.18 0.82
0.34 0.24
4.18 2.80
0.53 1.88 0.98 9.59 3.68 2.19 0.87 1.89 1.07
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0.97 2.90 2.86 21.31 9.29 22.37 3.45 8.75 1.26
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Multiparous Age > 35 years BMI > 30 Abnormal uterine artery Doppler Hypertension when not pregnant History of preeclampsia Pregnancy-related diabetes Gestational age at delivery HIV infection
aOR 1.06
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Periconceptional ARV treatment CD4 ≥ 300/mm3 during the first trimester VL>50 copies/mL during the first trimester CDC stage 2 or 3 Age > 35 years Multiparous
0.29 1.04 0.42 5.48 1.13 1.05 0.36 1.04 0.58
0.96 3.42 2.29 16.75 12.00 4.54 2.12 3.42 1.98
Table 4: Risk factors for vasculoplacental complications*
*Pregnancy-related hypertension, or preeclampsia, or fetal growth restriction<10th percentile from a vascular cause
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