Pregnancy Loss in Women with HIV is not Associated with HIV Markers: Data from a National Study in Italy, 2001-2018
Received: May 14, 2019
Accepted: August 8, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019050 DOI 10.4084/MJHID.2019.050
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Abstract Background:
There is limited information on pregnancy loss in women with HIV, and
it is still debated whether HIV-related markers may play a role. |
Introduction
Methods
For the present analysis we considered all the centres who reported at least one case of pregnancy loss (miscarriage, before 22 weeks of gestation; stillbirth, at or after 22 weeks) from December 2001 (study start) to October 2018, and compared the pregnancies ending in a pregnancy loss with all the pregnancies with a live birth concurrently reported from the same centres. Voluntary terminations and cases with a diagnosis of HIV during the third trimester of pregnancy were excluded. The study period (2001-2018) was divided into three intervals of six years each (2001-2006, 2007-2012, 2013-2018). The possible role of HIV-related variables was evaluated considering periconception values of CD4 cell count and plasma HIV-RNA as potential predictors of pregnancy loss. We considered for this analysis as periconception values all available CD4 cell counts and HIV-RNA values with a time distance no greater than 13 weeks before or after the date of the last menstrual period. HIV-RNA was categorized at a threshold of 50 copies per ml and CD4 cell levels at two different thresholds, of 200 cells/mm3 and 500 cells/mm3, respectively. Quantitative variables were summarized as medians with interquartile ranges (IQR) and compared using the Mann-Whitney U-test. Categorical variables were compared using the chi-square test, with odds ratios (OR) and 95% confidence intervals (CI) calculated. Temporal trends were analyzed using the chi-square test for trend. In order to adjust for potential confounders, pregnancy loss was also evaluated as a dependent variable in multivariable logistic regression analyses, and sensitivity analyses were conducted individually valuating miscarriage and stillbirth as dependent variables and introducing other possibly relevant covariates as independent variables. P values below 0.05 were considered statistically significant. All analyses were performed using the SPSS software, version 25.0 (IBM Corp, 2017, Armonk, NY, USA).
Results
The general characteristics of the population studied according to pregnancy loss are shown in Table 1. The main markers of HIV disease, represented by CD4 cell count, HIV-RNA viral load, and CDC HIV stage, showed no differences between the two groups of women with and without pregnancy loss. Additional analyses conducted on CD4 levels categorized at different thresholds confirmed this finding: rates of pregnancy loss were 6.8% for CD4<200/mm3 and 8.2% for CD4 ≥200/mm3 (OR 0.822, 95%CI 0.436-1.550, p=0.545), 8.2% for CD4≥500/mm3 and 8.0% for CD4 <500/mm3 (OR 1.018, 95% CI 0.740-1.400, p=0.912).
Table 1. Population characteristics at entry in pregnancy in women with and without pregnancy loss. |
Women with pregnancy loss were significantly older, HIV-infected from a longer time, more frequently diagnosed with HIV and on antiretroviral treatment before pregnancy, had received more frequently preconception counseling, and were more likely to have experienced previous pregnancy losses. No differences were observed between the two groups in other possible risk factors for pregnancy loss, such as parity, coinfections, sexually transmitted diseases, hypertension, smoking, alcohol, and substance use.
The above analyses were also conducted separately for miscarriage and stillbirth. For miscarriage, the results substantially overlapped those of the common analysis (data not shown). For stillbirth, the results showed significant associations with African nationality (odds ratio [OR]: 2.728, 95%CI 1.261-5.904, p=0.011) and with twin pregnancy (OR: 4.356, 95%CI 1.004-18.898, p=0.049).
The associations found in the above univariate analyses were evaluated in a multivariable logistic regression analysis that included as dependent variable (outcome) pregnancy loss, and as independent (predictive) variables age, African provenance, HIV diagnosis before conception, being on antiretroviral treatment (ART) at conception, twin pregnancy, and history of pregnancy loss. Other variables significantly associated in univariate analyses with pregnancy loss were excluded being considered either redundant compared to others already included in the model (months since HIV diagnosis, antiretroviral status at entry in pregnancy) or reflecting spurious associations (preconception counseling, apparently increasing risk of pregnancy loss). The results of the multivariable analysis are shown in Table 2. After adjusting for covariates, only older age, the timing of HIV diagnosis and history of pregnancy loss remained significantly associated with pregnancy loss. Sensitivity analyses that included additional covariates in the model consistently confirmed the above results (data not shown).
Table 2. Multivariable analysis of possible determinants of pregnancy loss. |
Discussion
As expected, most of the cases (198/226) of pregnancy loss were represented by miscarriages. The ratio between pregnancy loss and live birth remained relatively constant over time, with no significant change across the study period. In general, the observed rate (around seven percent of pregnancies) was lower compared to data reported for the general population in Italy (14% of all pregnancies in 2015),[22] and for pregnant women with HIV by others (15 and 20% in the studies by Hoffman and Stringer, respectively),[18,17] suggesting underreporting or missed enrolment of women with miscarriage in this surveillance. This occurrence might be favored by preferential access of women with early pregnancy loss to other structures, such as emergency departments. The observed rate of stillbirth (1.0%) is consistent with other studies, that usually showed rates between 0.8% and 4%.[17,18,23]
The main objective of this study was to identify preventable determinants of pregnancy loss among women with HIV. In this large series, the two major determinants of pregnancy loss were represented by two non-modifiable risk factors, represented by older age and history of a previous pregnancy loss. Both these associations have already been described.[9-12]
We found an association, apparently paradoxical, between pregnancy loss and preconception counseling. Our interpretation is that preconception counseling acted here as a proxy for the previous pregnancy losses or pregnancy at risk, with women with such a history more likely to seek preconception advise. The absence of a positive effect of preconception counseling in preventing pregnancy loss is nonetheless important, because is consistent with the absence of modifiable factors among the determinants found. Importantly, no significant role was found for smoking, alcohol, and recent substance use. This finding was confirmed in sensitivity analyses that included such variables in the main multivariable model (data not shown). We also found no effect of BMI, another potentially modifiable risk factor for pregnancy loss,[10] also when the risk was assessed specifically for the presence of overweight and/or obesity (data not shown). Finally, we found no significant role of smoking, in discordance with the observations by Flenady et al in the general population[10] and by Westreich et al in women with HIV.[16] We also found no association of pregnancy loss with hypertension and parity, that represented risk factors in larger studies evaluating the general population.[9,10] In univariate analysis twin pregnancy represented a predictor of stillbirth, as reported by others.[9] Although this association did not persist in the multivariable analysis, this lack of significance could be due to the limited number of stillbirth events, and we think that multiple pregnancy should be still considered as a potential risk factor for this adverse outcome.
This study also contributed information to the debate on the potential role of severity of HIV disease in increasing the risk of pregnancy loss. We did not find any role for clinical or laboratory markers of HIV, confirming the findings by Stringer et al. for CD4 and HIV-RNA,[17] but in discordance with the significant associations between pregnancy loss and HIV disease indicators (CD4, plasma HIV-RNA levels and clinical HIV stage) found in a previous study conducted in Zambia,[4] while another study had found conflicting results, with a small absolute increase in risk of pregnancy loss for the highest viral load category compared to the lowest category, and a simultaneous paradoxical protective effect of increased cumulative viremia against pregnancy loss.[15] Presence of ART at conception showed in the present series no association with pregnancy loss in multivariable analyses, confirming the findings of other studies and systematic reviews.[17,18, 23,24]
The interpretation of the study should take into account some limitations. Study population may have been selected because of different reasons, that include missing outcome information (the main reason for patient ineligibility), exclusion of women diagnosed with HIV in late pregnancy (that might have higher viral load and lower CD4), and referral bias (with specialized centres more likely to participate in this surveillance). The patient’s desire of acceptability may also have influenced the accurate reporting of personal risk factors/behaviors (e.g., smoking, substance use), and ascertainment of outcomes (particularly for miscarriage) is usually problematic. The low rate observed, actually, suggests incomplete coverage or underreporting of this outcome. Information on periconception HIV-RNA levels was also missing in a substantial number of cases, and this should prompt caution in the interpretation of the findings. Such a high rate of missing information, however, includes more than 500 cases in which HIV infection was diagnosed during pregnancy, and HIV-RNA analyzed for the first time at second or third trimester. This occurrence is also likely to have influenced through selection bias the finding of a higher risk of pregnancy loss in women diagnosed before current pregnancy, that should therefore also be considered cautiously.
Conclusions
The Italian Group on Surveillance of Antiretroviral Treatment in Pregnancy
Participants: M. Ravizza, E. Tamburrini, F. Di Lorenzo, G. Sterrantino, M. Meli, I. Campolmi, F. Vichi, B. Del Pin, R. Marocco, C. Mastroianni, V.S. Mercurio, D. Zanaboni, G. Guaraldi, G. Nardini, C. Stentarelli, B. Beghetto, A.M. Degli Antoni, A. Molinari, M.P. Crisalli, A. Donisi, M. Piepoli, V. Cerri, G. Zuccotti, V. Giacomet, S. Coletto, F. Di Nello, C. Madia, G. Placido, P. Milini, F. Savalli, V. Portelli, F. Sabbatini, D. Francisci, C. Papalini, L. Bernini, P. Grossi, L. Rizzi, M. Bernardon, G. Maso, E. Rizzante, C. Belcaro, S. Bussolaro, M. Rabusin, A. Meloni, A. Chiodo, M. Dedoni, F. Ortu, P. Piano, A. Citernesi, I. Bordoni Vicini, K. Luzi, A. Spinillo, M. Roccio, A. Vimercati, D. Calabretti, S. Gigante, B. Guerra, F. Cervi, G. Simonazzi, E. Margarito, M.G. Capretti, C. Marsico, G. Faldella, M. Sansone, P. Martinelli, A. Agangi, A. Capone, G.M. Maruotti, C. Tibaldi, L. Trentini, T. Todros, G. Masuelli, V. Frisina, V. Savasi, E. Cardellicchio, C. Giaquinto, M. Fiscon, E. Rubino, L. Franceschetti, R. Badolato, M.A. Forleo, B. Tassis, G.C. Tiso, O. Genovese, C. Cafforio, C. Pinnetti, G. Liuzzi, A.M. Casadei, A.F. Cavaliere, M. Cellini, A.M. Marconi, S. Dalzero, M. Ierardi, C. Polizzi, A. Mattei, M.F. Pirillo, R. Amici, C.M. Galluzzo, S. Donnini, S. Baroncelli, M. Floridia.
Advisory Board: A. Cerioli, M. De Martino, F. Parazzini, E. Tamburrini, S. Vella.
SIGO-HIV Group National Coordinators: P. Martinelli, M. Ravizza.
Acknowledgments
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