Pregnancy Loss in Women with HIV is not Associated with HIV Markers: Data from a National Study in Italy, 2001-2018
Marco Floridia1, Giulia Masuelli2, Beatrice Tassis3, Enrica Tamburrini4, Valeria Savasi5, Matilde Sansone6, Arsenio Spinillo7, Giuseppina Liuzzi8, Anna Degli Antoni9, Serena Dalzero10, Laura Franceschetti11, Giuliana Simonazzi12, Gianpaolo Maso13, Daniela Francisci14, Carmela Pinnetti8 and Marina Ravizza10. On behalf of The Italian Group on Surveillance of Antiretroviral Treatment in Pregnancy.
1 National Centre for Global Health, Istituto Superiore di Sanità, Rome, Italy.
2 Department of Obstetrics and Neonatology, Città della Salute e della Scienza Hospital, and University of Turin, Turin, Italy.
3 Obstetrics and Gynecology Unit, Fondazione IRCCS Ospedale Maggiore Policlinico di Milano, Milan, Italy.
4 Department of Infectious Diseases, Catholic University and Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
5 Department of Obstetrics and Gynaecology, Luigi Sacco Hospital and University of Milan, Milan, Italy.
6 Department of Neurosciences, Reproductive and Dentistry Science, University Federico II, Naples, Italy.
7 Department of Obstetrics and Gynaecology, IRCCS S. Matteo, Pavia, Italy.
8 I.N.M.I. Lazzaro Spallanzani, Rome, Italy.
9 Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma, Italy.
10 Department of Obstetrics and Gynaecology, DMSD San Paolo Hospital Medical School, University of Milan, Milan, Italy.
11 Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy.
12 Department of Medical and Surgical Sciences, Policlinico Sant'Orsola-Malpighi and University of Bologna, Bologna, Italy.
13 Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
14 Clinic of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
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.
There is limited information on pregnancy loss in women with HIV, and
it is still debated whether HIV-related markers may play a role.
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).
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.|
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), 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, 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 and by Westreich et al in women with HIV. 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. 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, 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, 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. 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.
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.
- Laursen T, Kesmodel US, Højgaard A, Østergaard L,
Ingerslev HJ, Wejse C. Reproductive patterns and fertility wishes among
HIV-infected patients: survey from six outpatient clinics in Denmark.
Int J Infect Dis 2013; 17: e851-6. https://doi.org/10.1016/j.ijid.2013.01.024 PMid:23499182
C, Desjardins F, Dec J, Platteau T, Hasker E; Eurosupport V Study
Group. Child desire in women and men living with HIV attending HIV
outpatient clinics: evidence from a European multicentre study. Eur J
Contracept Reprod Health Care 2013; 18: 251-63. https://doi.org/10.3109/13625187.2013.801072 PMid:23738886
- Berhan Y, Berhan A. Meta-analyses of fertility desires of people living with HIV. BMC Public Health 2013; 13: 409. https://doi.org/10.1186/1471-2458-13-409 PMid:23627965 PMCid:PMC3649930
M, Aho I, Thorsteinsson K, et al. Perception of sexuality and fertility
in women living with HIV: a questionnaire study from two Nordic
countries. J Int AIDS Soc 2015; 18: 19962. https://doi.org/10.7448/IAS.18.1.19962 PMid:26037151 PMCid:PMC4452736
V, Alejos B, Montero M, et al. Reproductive history before and after
HIV diagnosis: A cross-sectional study in HIV-positive women in Spain.
Medicine 2017; 96: e5991. https://doi.org/10.1097/MD.0000000000005991 PMid:28151893 PMCid:PMC5293456
de Souza M, do Amaral WN, Alves Guimarães R, Rezza G, Brunini SM.
Reproductive desire among women living with HIV/AIDS in Central Brazil:
Prevalence and associated factors. PLoS One 2017; 12: e0186267. https://doi.org/10.1371/journal.pone.0186267 PMid:29053712 PMCid:PMC5650151
CK, Kennedy VL, Yudin MH, Shapiro HM, Loutfy M. Access to fertility
services in Canada for HIV-positive individuals and couples: a
comparison between 2007 and 2014. AIDS Care 2017; 29: 1433-1436. https://doi.org/10.1080/09540121.2017.1332332 PMid:28553759
SE, Haddad LB, Sheth AN, et al. Parenting Desires Among Individuals
Living With Human Immunodeficiency Virus in the United States. Open
Forum Infect Dis 2018; 5: ofy232. https://doi.org/10.1093/ofid/ofy232
JE, Villar J, Victora CG, et al. The antepartum stillbirth syndrome:
risk factors and pregnancy conditions identified from the
INTERGROWTH-21st Project. BJOG 2018; 125: 1145-1153. https://doi.org/10.1111/1471-0528.14463 PMid:28029221 PMCid:PMC6055673
V, Koopmans L, Middleton P, et al. Major risk factors for stillbirth in
high-income countries: a systematic review and meta-analysis. Lancet
2011; 377: 1331-40. https://doi.org/10.1016/S0140-6736(10)62233-7
P, Zawiejska A, Wender-Ożegowska E, Brązert J. Maternal factors
predictive of first trimester pregnancy loss in women with
pregestational diabetes. Pol Arch Med Wewn 2013; 123: 21-8. https://doi.org/10.20452/pamw.1585 PMid:23302725
J, Cheraghi P, Cheraghi Z, Ghahramani M, Doosti Irani A. Predictors of
miscarriage: a matched case-control study. Epidemiol Health 2014; 36:
e2014031. https://doi.org/10.4178/epih/e2014031 PMid:25420952 PMCid:PMC4282085
AJ, Pintye J, Kinuthia J, et al. Sexually transmitted infections during
pregnancy and subsequent risk of stillbirth and infant mortality in
Kenya: a prospective study. Sex Transm Infect 2018. [Epub ahead of
print] https://doi.org/10.1136/sextrans-2018-053597 PMid:30228109 PMCid:PMC6525108
HY, Kasonde P, Mwiya M, et al. Pregnancy loss and role of infant HIV
status on perinatal mortality among HIV-infected women. BMC Pediatr
2012; 12: 138. https://doi.org/10.1186/1471-2431-12-138 PMid:22937874 PMCid:PMC3480840
JE, Westreich D, Edmonds A, et al. The Effects of Viral Load Burden on
Pregnancy Loss among HIV-Infected Women in the United States. Infect
Dis Obstet Gynecol 2015; 2015: 362357. https://doi.org/10.1155/2015/362357 PMid:26582966 PMCid:PMC4637076
- Westreich D, Cates J, Cohen M, et al. Smoking, HIV, and risk of pregnancy loss. AIDS 2017; 31: 553-560. https://doi.org/10.1097/QAD.0000000000001342 PMid:27902507 PMCid:PMC5263172
EM, Kendall MA, Lockman S, et al. Pregnancy outcomes among HIV-infected
women who conceived on antiretroviral therapy. PLoS One 2018; 13:
e0199555. https://doi.org/10.1371/journal.pone.0199555 PMid:30020964 PMCid:PMC6051581
RM, Brummel SS, Britto P, et al. Adverse Pregnancy Outcomes among Women
who Conceive on Antiretroviral Therapy. Clin Infect Dis 2018. [Epub
ahead of print] https://doi.org/10.1093/cid/ciy471 PMid:29868833 PMCid:PMC6321847
M, Mastroiacovo P, Tamburrini E, et al.Birth defects in a national
cohort of pregnant women with HIV infection in Italy, 2001-2011. BJOG
2013; 120:1466-75. https://doi.org/10.1111/1471-0528.12285 PMid:23721372
D, Fidler J, West R. Very low rate and light smokers: smoking patterns
and cessation-related behaviour in England, 2006-11. Addiction 2012;
107: 995-1002. https://doi.org/10.1111/j.1360-0443.2011.03739.x PMid:22126678
della Salute - Sistema Nazionale per le linee guida. Linee guida per la
gravidanza fisologica. Aggiornamento 2011. Available at: http://www.epicentro.iss.it/itoss/LineeGuida.asp. Accessed on january 10, 2019.
- ISTAT - Istituto Nazionale di statistica. La salute riproduttiva della donna. Available at https://www.istat.it/it/archivio/2100606. Accessed January 10, 2019.
L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission
from women with effective antiretroviral therapy starting before
conception. Clin Infect Dis 2015; 61: 1715-25. https://doi.org/10.1093/cid/civ578 PMid:26197844
OA, Nachega JB, Anderson J, et al. Timing of initiation of
antiretroviral therapy and adverse pregnancy outcomes: a systematic
review and meta-analysis. Lancet HIV 2017; 4: e21-e30. https://doi.org/10.1016/S2352-3018(16)30195-3