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A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women
OBSTETRICS
A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women Mark H. Yudin, MD, MSc,1 Daniela Caprara, MD, MSc,1 S. Jay MacGillivray, RM,1 Marcelo Urquia, PhD,2 Rajiv R. Shah, MD, MSc1 1
Department of Obstetrics and Gynecology, St. Michael’s Hospital, University of Toronto, Toronto, ON
2
Keenan Research Centre, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON
Abstract Objective: To review the incidence of antenatal complications among a cohort of HIV-positive pregnant women over a 10-year period. Methods: A retrospective review was performed of all HIV-positive pregnant women receiving multidisciplinary prenatal care at an urban tertiary care centre from March 2000 to March 2010. Collected data included the presence of additional infectious or medical conditions, genetic screening information, and the presence or absence of antenatal complications. Results: One hundred and forty-two singleton pregnancies during the study period were identified. Almost 95% of women were taking combination antiretroviral therapy during pregnancy, and greater than 90% had viral loads less than 1000 copies/ml at delivery. The presence of co-infections was low. Forty-one women (29%) had other medical comorbidities. Genetic screening occurred in 104 pregnancies (73%); 4% were abnormal screens. Rates of any hypertension, gestational diabetes, and fetal growth restriction were all low. Thirty-two percent of women were colonized with group B streptococcus. Conclusion: This study adds strength to the argument that good outcomes can be achieved for HIV-positive pregnant women with good access to both prenatal and HIV care, and appropriate management. Women with HIV should be optimally cared for in
Key Words: HIV, pregnancy, pregnancy complications, pregnancy outcomes This work was presented in part or in whole at: The Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada (SOGC), June 24, 2011, Vancouver, British Columbia, Canada The Annual Meeting of the Canadian Conference on HIV/AIDS Research, April 20, 2012, Montreal, Quebec, Canada The Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada (SOGC), June 11, 2015 Competing Interests: None declared.
advance of and during pregnancy in order to maximize the likelihood of good pregnancy outcomes.
Résumé Objectif : Analyser l’incidence, sur une période de 10 ans, des complications prénatales chez une cohorte de femmes enceintes séropositives pour le VIH. Méthodes : Nous avons mené une analyse rétrospective portant sur toutes les femmes enceintes séropositives pour le VIH qui ont reçu des soins prénataux multidisciplinaires au sein d’un centre urbain de soins tertiaires entre mars 2000 et mars 2010. Parmi les données recueillies, on trouvait la présence de troubles infectieux ou médicaux additionnels, les résultats du dépistage génétique et la présence ou l’absence de complications prénatales. Résultats : Au cours de la période d’étude, nous avons identifié 142 grossesses monofœtales. Pratiquement 95 % des femmes avaient reçu un traitement par association d’antirétroviraux pendant la grossesse et plus de 90 % d’entre elles présentaient des charges virales inférieures à 1 000 copies/ml au moment de l’accouchement. La présence de co-infections était faible. Quarante et une femme (29 %) présentaient d’autres comorbidités médicales. Un dépistage génétique avait été mené dans le cadre de 104 grossesses (73 %); 4 % d’entre elles ont obtenu des résultats anormaux. Les taux d’hypertension (quelle qu’elle soit), de diabète gestationnel et de retard de croissance intra-utérin étaient tous faibles. Une colonisation par des streptocoques du groupe B a été constatée chez 32 % de ces femmes. Conclusion : Cette étude soutient l’hypothèse selon laquelle il est possible pour les femmes enceintes séropositives pour le VIH d’obtenir de bonnes issues lorsqu’elles disposent d’un bon accès à des soins prénataux et contre le VIH, et à des services de prise en charge adéquats. Pour maximiser la probabilité d’obtenir de bonnes issues de grossesse, les femmes enceintes séropositives pour le VIH devraient faire l’objet de soins optimaux avant et pendant la grossesse. Copyright ª 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
Received on April 2, 2015 Accepted on July 24, 2015 http://dx.doi.org/10.1016/j.jogc.2015.10.013
J Obstet Gynaecol Can 2016;38(1):35e40
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INTRODUCTION
T
here are more than 71 000 HIV-positive individuals currently living in Canada, and over the past decade the proportion of these who are female has remained stable at approximately one quarter of all cases.1 At least 75% of Canadian HIV-positive women are of child-bearing age, and HIV infection is diagnosed in Canadian women at a younger age than in Canadian men.2 Individuals who are currently HIV-positive are likely to live a healthy and productive life, leading to increasing numbers of pregnancies among HIV-positive women in developed countries such as Canada.3,4 There is an emerging body of literature reporting on maternal and perinatal outcomes among HIV-positive women. Much of this information is conflicting, with some studies reporting increased rates of adverse outcomes (such as preterm birth, growth restriction, preeclampsia and gestational diabetes) and others reporting no increase in this risk, compared to HIV-negative women.5e19 Further, these studies have been conducted in a variety of geographic locations and with heterogeneous populations, varying degrees of medication adherence and immune function. These factors and others have been suggested as confounders which may affect the associations between HIV-positivity and adverse outcomes. We recently reported on a cohort of HIV-positive pregnant women cared for in Toronto, Ontario over a 10-year period.3 The majority of these women had prenatal care throughout their pregnancy and had well-controlled HIV infection, with 94% being treated with combination antiretroviral therapy (cART) and more than 90% having viral loads less than 1000 copies/mL at the time of delivery. The primary objective of this study was to report the antenatal complications and pregnancy outcomes of this cohort of well-controlled HIV-positive women having multidisciplinary prenatal care in one major Canadian centre.
losses were excluded. All charts were reviewed by a single reviewer (D.C.) and data were collected using a standardized data sheet and transferred to a Microsoft Excel (Microsoft Corp., Redmond, WA) file. Both electronic and paper charts were used for data collection and all data were anonymized before analysis. Data collected have been previously described,3 but, for the present analysis, relevant data included the presence of additional infections or medical conditions, genetic screening information, and the presence or absence of antenatal and intrapartum complications such as preterm birth (defined as birth < 37 weeks’ gestation), gestational diabetes (diagnosed by having an abnormal result from a 2-hour glucose tolerance test), hypertension (diagnosed as blood pressure greater than 140/90 or requiring antihypertensive medication with pre-existing/chronic hypertension either predating pregnancy or occurring up to 20 weeks gestation, and gestational hypertension occurring at 20 weeks gestation or greater), preeclampsia (defined as pre-existing/chronic or gestational hypertension combined with new or worsening proteinuria or one/more adverse conditions or one/more severe complications), fetal growth abnormalities (defined as growth less than the 10th percentile growth for gestational age by ultrasound assessment), abnormal ultrasound findings, and group B streptococcus (GBS) status. The distribution of study variables was examined using frequencies, with categorical variables expressed as counts and percentages, and continuous or discrete variables expressed as means and ranges. Bivariate analyses included cross-tabulations. Associations between categorical variables were assessed with the chi-square test. Assessment of trends was performed using the Cochrane-Armitage test for binomial proportions. A P-value < 0.05 was used as the cutoff for statistical significance. All statistical tests were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC). Approval for the study was obtained from the St Michael’s Hospital Research Ethics Board.
METHODS
This study was a retrospective chart review of all HIVpositive pregnant women cared for at St. Michael’s Hospital in Toronto, Ontario from March 2000 to March 2010. Cases were identified using an internal hospital obstetric database and using chart codes with the aid of hospital decision support. In this way, we were able to perform two independent searches to confidently identify all eligible women during the study period. The final cohort included all singleton pregnancies; first trimester
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RESULTS
Between March 2000 and March 2010, 142 singleton pregnancies in HIV-positive women were identified at our institution. Two sets of twins and one early pregnancy loss were excluded. Almost 94% (133/142) of women were on cART during pregnancy. Of 128 with recorded viral loads at delivery, 98 (77%) were undetectable and 118 (92%) were 1000 copies/mL or less. The presence of coinfections among our cohort is presented in Table 1.
A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women
Table 1. Presence of Co-Infections Among HIV-Positive Pregnant Women Infection
Table 2. Medical Comorbidities Among HIV-Positive Pregnant Women
n (%)
Medical Comorbidity
Syphilis
4 (3%)
Tuberculosis
Hepatitis B
8 (6%)
Asthma
6 (4%)
Hepatitis C
2 (1%)
Hypertension
6 (4%)
Gonorrhea/Chlamydia
3 (2%)
Malaria
3 (2%)
Rubella non-immune
12 (8%)
Anemia
2 (1%)
Pyelonephritis
2 (1%)
Other
Forty-one women (29%) had comorbidities, the most common being tuberculosis, asthma, and hypertension (Table 2). Alcohol and drug use was low in this cohort, with 80% (113/142) non-smokers; only three women (2%) admitted to alcohol use and five (4%) admitted to illicit drug use. Genetic screening by maternal serology was commonly performed in this cohort of women, with 104 (73%) completing testing and 4 (4%) had an abnormal result. One of these women chose to undergo amniocentesis after being given an estimated risk of trisomy 21 of 1:4. She was on cART and had an undetectable viral load at the time of amniocentesis. Amniocentesis revealed a normal karyotype. No genetic abnormalities occurred in the entire cohort, including among the women with abnormal serologic screens. The most common reason for not being tested was presenting to care too late. The mean gestational age at delivery was 38.1 weeks. The preterm birth rate was 19%, with no difference found in the rates of preterm birth between women on protease inhibitor (PI)-containing regimens compared to those without PIs (P > 0.05); 65% were late preterm births (more than 34 weeks’ gestational age), and only six births were less than 30 weeks. Of the total 27 preterm births, 17 resulted from spontaneous preterm labour, and 10 were induced. The most common reason for preterm induction of labour was preterm premature rupture of membranes (7/10). There was one induction for growth restriction at 36 weeks gestation, one for preeclampsia at 34 weeks gestation, and one for intrauterine fetal death at 25 weeks gestation. The incidence of gestational diabetes and any hypertension was low in this cohort of women. Nine women (6%) had gestational diabetes; five of these were controlled with diet alone and four required insulin. All of those with diet control were on a PI (lopinavir/ritonavir or nelfinavir) and only one requiring insulin was on a PI (nelfinavir). Seven women (5%) had hypertension as a complication in pregnancy; one had pre-existing hypertension and the remainder had gestational hypertension. Only one woman
n (%) 10 (7%)
12 (8%)
required pharmacologic treatment. Two of these women developed preeclampsia requiring induction of labour, one at 34 and the other at 38 weeks gestation. The incidence of ultrasound abnormalities was low, with fetal anatomic anomalies infrequently observed. There were four fetuses (3%) with echogenic intracardiac foci, three (2%) with pelviectasis, and one with a choroid plexus cyst. Three pregnancies (2%) had abnormal Doppler flow studies, and five (4%) had intrauterine growth restriction. Four of these had growth between the third and tenth percentile, and one case was below the third percentile. All of these women were on PIs (either lopinavir/ritonavir, nelfinavir, or atazanavir). In the entire cohort, 45 women (32%) were positive for GBS. Mode of delivery was vaginal in 87 (61%) and Caesarean section in 55 (39%) women. In our program, HIV-exposed infants are followed for five years after birth. HIV polymerase chain reaction (PCR) testing is performed at birth, one month, and two months of age. HIV serology is performed at 18 months of age to confirm clearance of maternal antibody. All infants remained HIV-negative. DISCUSSION
In this 10-year cohort of 142 pregnancies in well-controlled HIV-positive women, we found low rates of co-infection and serious comorbidities, abnormal genetic screening tests, and pregnancy complications. Positive GBS culture rates were higher than among the general population at the study institution. Studies addressing outcomes in pregnancies complicated by HIV have reported conflicting information, with some demonstrating higher risks for adverse outcomes, and others showing no difference in these risks between HIV-positive and HIV-negative women.10e19 Further, some antiretroviral drugs have been implicated more than others. These studies
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have been conducted in diverse global locations and with heterogeneous populations of HIV-positive women, with varying degrees of medication adherence and immune function. These factors and others, such as ethnicity, smoking, and alcohol and drug use, may be confounders and affect the degree of strength of the associations found between HIV status and adverse outcomes in pregnancy. Understanding these risks from these various studies is challenging. Most of the initial work demonstrating an increase in the risk of preterm birth among women on cART originated in Europe, with preterm delivery rates up to three times higher in women taking these medications.10e13 Some of these studies, as well as studies from Africa, implicated PIs as the drugs associated with the highest risks.14 Subsequent studies from North America did not show an increase in preterm birth risk among women on cART.15e17 A meta-analysis of studies published up until 2006 reported no association between cART and increased risk of preterm delivery overall (OR 1.01; 95% CI 0.8 to 1.3), although there was an increased risk seen among women on PI-containing regimens (OR 1.35; 95% CI 1.1 to 1.7).18 More recent work from France has also demonstrated an increase in the preterm birth rate among women on cART (OR 1.69; 95% CI 1.38 to 2.07), and particularly in women taking ritonavir-boosted PI therapy (adjusted hazard ratio 2.03; 95% CI 1.06 to 3.89).19 In our cohort, the preterm birth rate was 19%, higher than the national average; of approximately 8%.20 an increased risk for preterm delivery among women on PI-containing regimens was not demonstrated in the current study. The current study was not statistically powered to detect a difference in the risk for preterm birth, an outcome with a recognized multifactorial etiology. We are currently conducting a prospective study of matched cohorts of HIVpositive and HIV-negative women to better understand the preterm birth rates and risks in the HIV-positive population. The rates of both gestational diabetes and any hypertension were low in our cohort (5% each. The effect of antiretroviral drugs on glucose metabolism and insulin resistance among pregnant women remains poorly understood, and there have been conflicting results in the literature with respect to the risk of gestational diabetes in HIV-positive women.7,21,22 Gestational diabetes complicates 2% to 5% of pregnancies among women in North America,23 and the rate in our cohort (6%) was similar. Gonzalez-Tome et al. specifically implicated PIs as a risk for developing gestational diabetes,7 but others have concluded that PIs do not increase the risk.21,22 Six of the nine women who developed gestational diabetes in this cohort were on PIcontaining drug regimens. The association between cART and gestational diabetes remains unclear.
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Observational and cohort studies evaluating the risk for hypertension disorders in pregnancies complicated by HIV have suggested that the risk is increased,8 while matched cohort studies from Canada and the United States have not demonstrated this increase.9,24 In the current study, six women developed hypertension during pregnancy; two of these developed preeclampsia. Most women who were eligible for serologic genetic screening (and who presented for care early enough in pregnancy) accepted testing, and four women had positive screens. Multiple marker serum testing has been shown to be reliable in HIV-positive pregnant women with no difference in the likelihood of false positive tests, although multiples of the median levels of specific hormone markers may differ between HIV-positive and negative women.25,26 Genetic screening is an important issue for pregnant women, but the option of reliable serologic screening is important for HIVpositive women, as it may help to avoid the need for invasive testing such as amniocentesis or chorionic villus sampling. Lopez and Coll have suggested that the risk of HIV transmission due to invasive procedures such as amniocentesis is low, since they had no cases of transmission among 159 women on cART.27 National guidelines now state that amniocentesis performed in women on cART does not appear to increase the risk of transmission, especially if the viral load is undetectable, but that women should be counselled that data are limited. Prenatal risk assessment is recommended, using tests with high sensitivity and low falsepositive rates, such as serum screening combined (or not) with nuchal translucency, anatomic ultrasound, and noninvasive molecular prenatal testing.28 There was a low incidence of fetal ultrasonographic abnormalities in our cohort, and no serious fetal anomalies occurred. Antiretroviral drugs are not believed to be teratogenic; a recent meta-analysis of 21 studies showing no difference in the likelihood of birth defects between infants born to mothers on efavirenz-based and nonefavirenzbased regimens.29 Fetal growth restriction was also rare in the current study. The risk of fetal growth abnormalities has not been consistently reported, with some studies reporting an increased risk and others showing no increase in risk,30 and no association was observed in studies accounting for confounding variables. In a Canadian matched cohort study, there was no difference in the risk of growth restriction between HIV-positive women and an HIV-negative matched control group.9 In an American prospective observational study, HIV severity was associated with an increased risk of fetal growth abnormalities after adjusting for sociodemographic variables, medication use and disease severity; cART use was not associated.31
A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women
The rate of GBS positivity in this cohort was 32%, which is higher than the baseline population rate of 22% at our institution.32 In one study of 90 HIV-positive pregnant women, HIV status was not independently associated with GBS colonization,33 although the overall relationship remains unclear. Adverse maternal and perinatal outcomes may be associated with HIV-positivity, combination or specific antiretroviral drug use, or the presence of confounding factors. It has previously been hypothesized that one of the most important confounding variables in the association between adverse outcomes and HIV-positivity is disease severity.13,17,31 In the current study, most women had wellcontrolled HIV infection, adequate prenatal care, and low rates of substance use and co-morbidities; rates of antenatal complications were low, and pregnancy outcomes were favourable. Many studies to date have evaluated outcomes in HIVpositive women with poor access to care and with poorly controlled disease, and outcomes may differ between these populations. Retrospective studies are limited by their reliance on data extracted from chart review. The cohort in the present study was from a single centre and may not be fully representative of a more diverse population. Finally, there was no control group with which to compare outcomes. CONCLUSION
This important study evaluated pregnancy outcomes in HIVpositive women and demonstrated favourable outcomes in women with appropriate access to multidisciplinary prenatal and HIV care and with well-controlled disease. The study adds strength to the argument that good outcomes can be achieved for HIV-positive pregnant women with appropriate management and good access to both prenatal and HIV care. HIV-positive women should be optimally cared for in advance of and during pregnancy in order to maximize the likelihood of good pregnancy outcomes.
REFERENCES 1. UN AIDS. 2014 Global AIDS Response Progress Reporting Country Report- Canada. Available at: http://www.unaids.org/en/dataanalysis/ knowyourresponse/countryprogressreports/2014countries/. Accessed July 3, 2014. 2. Public Health Agency of Canada. Population Specific HIV/AIDS Status Report: Women. Available at: http://www.phac-aspc.gc.ca.html. Accessed July 3, 2014. 3. Caprara D, Shah R, MacGillivray SJ, Urquia M, Yudin MH. Demographic and management trends among HIV-positive pregnant women over 10 years at one Canadian urban hospital. J Obstet Gynaecol Can 2014;36:123e7.
4. Forbes JC, Alimenti AM, Singer J, Brophy JC, Bitnun A, Samson LM, et al. 21-year review of vertical HIV transmission in Canada (1990e2010). AIDS 2012;26:757e63. 5. Watts DH, Williams PL, Kacanek D, Griner R, Rich K, Hazra R, et al. Combination antiretroviral use and preterm birth. J Infect Dis 2013;207:612e21. 6. Chen JY, Ribaudo HJ, Souda S, Parekh N, Ogwu A, Lockman S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012;206:1695e705. 7. Gonzalez-Tome MI, Ramos Amador JT, Guillen S, Solis I, FernandezIbieta M, Munoz E, et al. Gestational diabetes mellitus in a cohort of HIV-1 infected women. HIV Med 2008;9:868e74. 8. Suy A, Martinez E, Coll O, Lonca M, Palacio M, de Lazzari E, et al. Increased risk of preeclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy. AIDS 2006;20:59e66. 9. Boyajian T, Shah PS, Murphy KE. Risk of preeclampsia in HIV-positive pregnant women receiving HAART: a matched cohort study. J Obstet Gynaecol Can 2012;34:136e41. 10. European Collaborative Study, Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000;14:2913e20. 11. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS 2004;18:2337e9. 12. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS 2007;21:1019e26. 13. Rudin C, Spaenhauer A, Keiser O, Rickenbach M, Kind C, Aebi-Popp K, et al. Antiretroviral therapy during pregnancy and premature birth: analysis of Swiss data. HIV Medicine 2011;12:228e35. 14. Powis KM, Kitch D, Ogwu A, Hughes MD, Lockman S, Leidner J, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitorbased HAART during pregnancy. J Infect Dis 2011;204:506e14. 15. Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002;346:1863e70. 16. Szyld EG, Warley EM, Freimanis L, Gonin R, Cahn PE, Galvet GA, et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS 2006;20:2345e53. 17. Patel K, Shapiro DE, Brogly SB, Livingston EG, Stek AM, Bardeguez AD, et al. Prenatal protease inhibitor use and risk of preterm birth among HIVinfected women initiating antiretroviral drugs during pregnancy. J Infect Dis 2010;201:1035e44. 18. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a metaanalysis. AIDS 2007;21:607e15. 19. Sibiude J, Warszawski J, Tubiana R, Dolfus C, Faye A, Rouzioux C, et al. Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir boost? Clin Inf Dis 2012;54:1348e60. 20. Statistics Canada. Health Statistics Division. Births 2005. Ottawa: Statistics Canada; 2007. Catalogue No.:84F0210XIE. 21. Tang JH, Sheffield JS, Grimes J, McElwee B, Roberts SW, Laibl V, et al. Effect of protease inhibitor therapy on glucose intolerance in pregnancy. Obstet Gynecol 2006;107:1115e9. 22. Hitti J, Andersen J, McComsey G, Liu T, Melvin A, Smith L, et al. Protease inhibitor-based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol 2007;196:331.e1e7. 23. Berger H, Crane J, Farine D, Armson A, de la Ronde S, Keenan-Lindsay L, et al. Screening for gestational diabetes mellitus, Society of Obstetricians and
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Gynaecologists of Canada Clinical Practice Guideline. J Obstet Gynaecol Can 2002;24:894e912. 24. Kourtis AP, Bansil P, McPheeters M, Meikle SF, Posner SF, Jamieson DJ. Hospitalizations of pregnant HIV-infected women in the USA prior to and during the era of HAART, 1994e2003. AIDS 2006;20: 1823e31. 25. Le Meaux J-P, Tsatsaris V, Schmitz T, Fulla Y, Launay O, Goffinet F, et al. Maternal biochemical serum screening for Down Syndrome in pregnancy with human immunodeficiency virus infection. Obstet Gynecol 2008;112:223e30.
and Gynaecologists of Canada Clinical Practice Guideline. J Obstet Gynaecol Can 2014;36:648e53. 29. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2011;25:2301e4. 30. Senise JF, Castelo A, Martinez M. Current treatment strategies, complications and considerations for the use of HIV antiretroviral therapy during pregnancy. AIDS Rev 2011;13:198e213.
26. Brossard P, Boulvain M, Coll O, Barlow P, Aebi-Popp K, Bischof P, et al. Is screening for fetal anomalies reliable in HIV-infected pregnant women? A multicentre study. AIDS 2008;22:2013e7.
31. Aaron E, Bonacquisti A, Mathew L, Alleyne G, Bamford LP, Culhane JF. Small-for-gestational-age births in pregnant women with HIV, due to severity of HIV disease, not antiretroviral therapy. Inf Dis Obstet Gynecol 2012; http://dx.doi.org/10.1155/2012/ 135030.
27. Lopez M, Coll O. Chronic viral infections and invasive procedures: risk of vertical transmission and current recommendations. Fetal Diagn Ther 2010;281:1e8.
32. Shore EM, Yudin MH. Choice of antibiotic for group B streptococcus in women in labour based on antibiotic sensitivity testing. J Obstet Gynaecol Can 2012;34:230e5.
28. Gagnon A, Davies G, Wilson RD, Audibert F, Brock J, Campagnolo C, et al. Prenatal invasive procedures in women with hepatitis B, hepatitis C, and/or human immunodeficiency virus infections, Society of Obstetricians
33. Shah M, Aziz N, Leva N, Cohan D. Group B streptococcus colonization by HIV status in pregnant women: prevalence and risk factors. J Women’s Health 2011;20:1737e41.
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A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women Mark H. Yudin, MD, MSc,1 Daniela Caprara, MD, MSc,1 S. Jay MacGillivray, RM,1 Marcelo Urquia, PhD,2 Rajiv R. Shah, MD, MSc1 1
Department of Obstetrics and Gynecology, St. Michael’s Hospital, University of Toronto, Toronto, ON
2
Keenan Research Centre, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON
Abstract Objective: To review the incidence of antenatal complications among a cohort of HIV-positive pregnant women over a 10-year period. Methods: A retrospective review was performed of all HIV-positive pregnant women receiving multidisciplinary prenatal care at an urban tertiary care centre from March 2000 to March 2010. Collected data included the presence of additional infectious or medical conditions, genetic screening information, and the presence or absence of antenatal complications. Results: One hundred and forty-two singleton pregnancies during the study period were identified. Almost 95% of women were taking combination antiretroviral therapy during pregnancy, and greater than 90% had viral loads less than 1000 copies/ml at delivery. The presence of co-infections was low. Forty-one women (29%) had other medical comorbidities. Genetic screening occurred in 104 pregnancies (73%); 4% were abnormal screens. Rates of any hypertension, gestational diabetes, and fetal growth restriction were all low. Thirty-two percent of women were colonized with group B streptococcus. Conclusion: This study adds strength to the argument that good outcomes can be achieved for HIV-positive pregnant women with good access to both prenatal and HIV care, and appropriate management. Women with HIV should be optimally cared for in
Key Words: HIV, pregnancy, pregnancy complications, pregnancy outcomes This work was presented in part or in whole at: The Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada (SOGC), June 24, 2011, Vancouver, British Columbia, Canada The Annual Meeting of the Canadian Conference on HIV/AIDS Research, April 20, 2012, Montreal, Quebec, Canada The Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada (SOGC), June 11, 2015 Competing Interests: None declared.
advance of and during pregnancy in order to maximize the likelihood of good pregnancy outcomes.
Résumé Objectif : Analyser l’incidence, sur une période de 10 ans, des complications prénatales chez une cohorte de femmes enceintes séropositives pour le VIH. Méthodes : Nous avons mené une analyse rétrospective portant sur toutes les femmes enceintes séropositives pour le VIH qui ont reçu des soins prénataux multidisciplinaires au sein d’un centre urbain de soins tertiaires entre mars 2000 et mars 2010. Parmi les données recueillies, on trouvait la présence de troubles infectieux ou médicaux additionnels, les résultats du dépistage génétique et la présence ou l’absence de complications prénatales. Résultats : Au cours de la période d’étude, nous avons identifié 142 grossesses monofœtales. Pratiquement 95 % des femmes avaient reçu un traitement par association d’antirétroviraux pendant la grossesse et plus de 90 % d’entre elles présentaient des charges virales inférieures à 1 000 copies/ml au moment de l’accouchement. La présence de co-infections était faible. Quarante et une femme (29 %) présentaient d’autres comorbidités médicales. Un dépistage génétique avait été mené dans le cadre de 104 grossesses (73 %); 4 % d’entre elles ont obtenu des résultats anormaux. Les taux d’hypertension (quelle qu’elle soit), de diabète gestationnel et de retard de croissance intra-utérin étaient tous faibles. Une colonisation par des streptocoques du groupe B a été constatée chez 32 % de ces femmes. Conclusion : Cette étude soutient l’hypothèse selon laquelle il est possible pour les femmes enceintes séropositives pour le VIH d’obtenir de bonnes issues lorsqu’elles disposent d’un bon accès à des soins prénataux et contre le VIH, et à des services de prise en charge adéquats. Pour maximiser la probabilité d’obtenir de bonnes issues de grossesse, les femmes enceintes séropositives pour le VIH devraient faire l’objet de soins optimaux avant et pendant la grossesse. Copyright ª 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
Received on April 2, 2015 Accepted on July 24, 2015 http://dx.doi.org/10.1016/j.jogc.2015.10.013
J Obstet Gynaecol Can 2016;38(1):35e40
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INTRODUCTION
T
here are more than 71 000 HIV-positive individuals currently living in Canada, and over the past decade the proportion of these who are female has remained stable at approximately one quarter of all cases.1 At least 75% of Canadian HIV-positive women are of child-bearing age, and HIV infection is diagnosed in Canadian women at a younger age than in Canadian men.2 Individuals who are currently HIV-positive are likely to live a healthy and productive life, leading to increasing numbers of pregnancies among HIV-positive women in developed countries such as Canada.3,4 There is an emerging body of literature reporting on maternal and perinatal outcomes among HIV-positive women. Much of this information is conflicting, with some studies reporting increased rates of adverse outcomes (such as preterm birth, growth restriction, preeclampsia and gestational diabetes) and others reporting no increase in this risk, compared to HIV-negative women.5e19 Further, these studies have been conducted in a variety of geographic locations and with heterogeneous populations, varying degrees of medication adherence and immune function. These factors and others have been suggested as confounders which may affect the associations between HIV-positivity and adverse outcomes. We recently reported on a cohort of HIV-positive pregnant women cared for in Toronto, Ontario over a 10-year period.3 The majority of these women had prenatal care throughout their pregnancy and had well-controlled HIV infection, with 94% being treated with combination antiretroviral therapy (cART) and more than 90% having viral loads less than 1000 copies/mL at the time of delivery. The primary objective of this study was to report the antenatal complications and pregnancy outcomes of this cohort of well-controlled HIV-positive women having multidisciplinary prenatal care in one major Canadian centre.
losses were excluded. All charts were reviewed by a single reviewer (D.C.) and data were collected using a standardized data sheet and transferred to a Microsoft Excel (Microsoft Corp., Redmond, WA) file. Both electronic and paper charts were used for data collection and all data were anonymized before analysis. Data collected have been previously described,3 but, for the present analysis, relevant data included the presence of additional infections or medical conditions, genetic screening information, and the presence or absence of antenatal and intrapartum complications such as preterm birth (defined as birth < 37 weeks’ gestation), gestational diabetes (diagnosed by having an abnormal result from a 2-hour glucose tolerance test), hypertension (diagnosed as blood pressure greater than 140/90 or requiring antihypertensive medication with pre-existing/chronic hypertension either predating pregnancy or occurring up to 20 weeks gestation, and gestational hypertension occurring at 20 weeks gestation or greater), preeclampsia (defined as pre-existing/chronic or gestational hypertension combined with new or worsening proteinuria or one/more adverse conditions or one/more severe complications), fetal growth abnormalities (defined as growth less than the 10th percentile growth for gestational age by ultrasound assessment), abnormal ultrasound findings, and group B streptococcus (GBS) status. The distribution of study variables was examined using frequencies, with categorical variables expressed as counts and percentages, and continuous or discrete variables expressed as means and ranges. Bivariate analyses included cross-tabulations. Associations between categorical variables were assessed with the chi-square test. Assessment of trends was performed using the Cochrane-Armitage test for binomial proportions. A P-value < 0.05 was used as the cutoff for statistical significance. All statistical tests were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC). Approval for the study was obtained from the St Michael’s Hospital Research Ethics Board.
METHODS
This study was a retrospective chart review of all HIVpositive pregnant women cared for at St. Michael’s Hospital in Toronto, Ontario from March 2000 to March 2010. Cases were identified using an internal hospital obstetric database and using chart codes with the aid of hospital decision support. In this way, we were able to perform two independent searches to confidently identify all eligible women during the study period. The final cohort included all singleton pregnancies; first trimester
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RESULTS
Between March 2000 and March 2010, 142 singleton pregnancies in HIV-positive women were identified at our institution. Two sets of twins and one early pregnancy loss were excluded. Almost 94% (133/142) of women were on cART during pregnancy. Of 128 with recorded viral loads at delivery, 98 (77%) were undetectable and 118 (92%) were 1000 copies/mL or less. The presence of coinfections among our cohort is presented in Table 1.
A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women
Table 1. Presence of Co-Infections Among HIV-Positive Pregnant Women Infection
Table 2. Medical Comorbidities Among HIV-Positive Pregnant Women
n (%)
Medical Comorbidity
Syphilis
4 (3%)
Tuberculosis
Hepatitis B
8 (6%)
Asthma
6 (4%)
Hepatitis C
2 (1%)
Hypertension
6 (4%)
Gonorrhea/Chlamydia
3 (2%)
Malaria
3 (2%)
Rubella non-immune
12 (8%)
Anemia
2 (1%)
Pyelonephritis
2 (1%)
Other
Forty-one women (29%) had comorbidities, the most common being tuberculosis, asthma, and hypertension (Table 2). Alcohol and drug use was low in this cohort, with 80% (113/142) non-smokers; only three women (2%) admitted to alcohol use and five (4%) admitted to illicit drug use. Genetic screening by maternal serology was commonly performed in this cohort of women, with 104 (73%) completing testing and 4 (4%) had an abnormal result. One of these women chose to undergo amniocentesis after being given an estimated risk of trisomy 21 of 1:4. She was on cART and had an undetectable viral load at the time of amniocentesis. Amniocentesis revealed a normal karyotype. No genetic abnormalities occurred in the entire cohort, including among the women with abnormal serologic screens. The most common reason for not being tested was presenting to care too late. The mean gestational age at delivery was 38.1 weeks. The preterm birth rate was 19%, with no difference found in the rates of preterm birth between women on protease inhibitor (PI)-containing regimens compared to those without PIs (P > 0.05); 65% were late preterm births (more than 34 weeks’ gestational age), and only six births were less than 30 weeks. Of the total 27 preterm births, 17 resulted from spontaneous preterm labour, and 10 were induced. The most common reason for preterm induction of labour was preterm premature rupture of membranes (7/10). There was one induction for growth restriction at 36 weeks gestation, one for preeclampsia at 34 weeks gestation, and one for intrauterine fetal death at 25 weeks gestation. The incidence of gestational diabetes and any hypertension was low in this cohort of women. Nine women (6%) had gestational diabetes; five of these were controlled with diet alone and four required insulin. All of those with diet control were on a PI (lopinavir/ritonavir or nelfinavir) and only one requiring insulin was on a PI (nelfinavir). Seven women (5%) had hypertension as a complication in pregnancy; one had pre-existing hypertension and the remainder had gestational hypertension. Only one woman
n (%) 10 (7%)
12 (8%)
required pharmacologic treatment. Two of these women developed preeclampsia requiring induction of labour, one at 34 and the other at 38 weeks gestation. The incidence of ultrasound abnormalities was low, with fetal anatomic anomalies infrequently observed. There were four fetuses (3%) with echogenic intracardiac foci, three (2%) with pelviectasis, and one with a choroid plexus cyst. Three pregnancies (2%) had abnormal Doppler flow studies, and five (4%) had intrauterine growth restriction. Four of these had growth between the third and tenth percentile, and one case was below the third percentile. All of these women were on PIs (either lopinavir/ritonavir, nelfinavir, or atazanavir). In the entire cohort, 45 women (32%) were positive for GBS. Mode of delivery was vaginal in 87 (61%) and Caesarean section in 55 (39%) women. In our program, HIV-exposed infants are followed for five years after birth. HIV polymerase chain reaction (PCR) testing is performed at birth, one month, and two months of age. HIV serology is performed at 18 months of age to confirm clearance of maternal antibody. All infants remained HIV-negative. DISCUSSION
In this 10-year cohort of 142 pregnancies in well-controlled HIV-positive women, we found low rates of co-infection and serious comorbidities, abnormal genetic screening tests, and pregnancy complications. Positive GBS culture rates were higher than among the general population at the study institution. Studies addressing outcomes in pregnancies complicated by HIV have reported conflicting information, with some demonstrating higher risks for adverse outcomes, and others showing no difference in these risks between HIV-positive and HIV-negative women.10e19 Further, some antiretroviral drugs have been implicated more than others. These studies
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have been conducted in diverse global locations and with heterogeneous populations of HIV-positive women, with varying degrees of medication adherence and immune function. These factors and others, such as ethnicity, smoking, and alcohol and drug use, may be confounders and affect the degree of strength of the associations found between HIV status and adverse outcomes in pregnancy. Understanding these risks from these various studies is challenging. Most of the initial work demonstrating an increase in the risk of preterm birth among women on cART originated in Europe, with preterm delivery rates up to three times higher in women taking these medications.10e13 Some of these studies, as well as studies from Africa, implicated PIs as the drugs associated with the highest risks.14 Subsequent studies from North America did not show an increase in preterm birth risk among women on cART.15e17 A meta-analysis of studies published up until 2006 reported no association between cART and increased risk of preterm delivery overall (OR 1.01; 95% CI 0.8 to 1.3), although there was an increased risk seen among women on PI-containing regimens (OR 1.35; 95% CI 1.1 to 1.7).18 More recent work from France has also demonstrated an increase in the preterm birth rate among women on cART (OR 1.69; 95% CI 1.38 to 2.07), and particularly in women taking ritonavir-boosted PI therapy (adjusted hazard ratio 2.03; 95% CI 1.06 to 3.89).19 In our cohort, the preterm birth rate was 19%, higher than the national average; of approximately 8%.20 an increased risk for preterm delivery among women on PI-containing regimens was not demonstrated in the current study. The current study was not statistically powered to detect a difference in the risk for preterm birth, an outcome with a recognized multifactorial etiology. We are currently conducting a prospective study of matched cohorts of HIVpositive and HIV-negative women to better understand the preterm birth rates and risks in the HIV-positive population. The rates of both gestational diabetes and any hypertension were low in our cohort (5% each. The effect of antiretroviral drugs on glucose metabolism and insulin resistance among pregnant women remains poorly understood, and there have been conflicting results in the literature with respect to the risk of gestational diabetes in HIV-positive women.7,21,22 Gestational diabetes complicates 2% to 5% of pregnancies among women in North America,23 and the rate in our cohort (6%) was similar. Gonzalez-Tome et al. specifically implicated PIs as a risk for developing gestational diabetes,7 but others have concluded that PIs do not increase the risk.21,22 Six of the nine women who developed gestational diabetes in this cohort were on PIcontaining drug regimens. The association between cART and gestational diabetes remains unclear.
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Observational and cohort studies evaluating the risk for hypertension disorders in pregnancies complicated by HIV have suggested that the risk is increased,8 while matched cohort studies from Canada and the United States have not demonstrated this increase.9,24 In the current study, six women developed hypertension during pregnancy; two of these developed preeclampsia. Most women who were eligible for serologic genetic screening (and who presented for care early enough in pregnancy) accepted testing, and four women had positive screens. Multiple marker serum testing has been shown to be reliable in HIV-positive pregnant women with no difference in the likelihood of false positive tests, although multiples of the median levels of specific hormone markers may differ between HIV-positive and negative women.25,26 Genetic screening is an important issue for pregnant women, but the option of reliable serologic screening is important for HIVpositive women, as it may help to avoid the need for invasive testing such as amniocentesis or chorionic villus sampling. Lopez and Coll have suggested that the risk of HIV transmission due to invasive procedures such as amniocentesis is low, since they had no cases of transmission among 159 women on cART.27 National guidelines now state that amniocentesis performed in women on cART does not appear to increase the risk of transmission, especially if the viral load is undetectable, but that women should be counselled that data are limited. Prenatal risk assessment is recommended, using tests with high sensitivity and low falsepositive rates, such as serum screening combined (or not) with nuchal translucency, anatomic ultrasound, and noninvasive molecular prenatal testing.28 There was a low incidence of fetal ultrasonographic abnormalities in our cohort, and no serious fetal anomalies occurred. Antiretroviral drugs are not believed to be teratogenic; a recent meta-analysis of 21 studies showing no difference in the likelihood of birth defects between infants born to mothers on efavirenz-based and nonefavirenzbased regimens.29 Fetal growth restriction was also rare in the current study. The risk of fetal growth abnormalities has not been consistently reported, with some studies reporting an increased risk and others showing no increase in risk,30 and no association was observed in studies accounting for confounding variables. In a Canadian matched cohort study, there was no difference in the risk of growth restriction between HIV-positive women and an HIV-negative matched control group.9 In an American prospective observational study, HIV severity was associated with an increased risk of fetal growth abnormalities after adjusting for sociodemographic variables, medication use and disease severity; cART use was not associated.31
A Ten-Year Review of Antenatal Complications and Pregnancy Outcomes Among HIV-Positive Pregnant Women
The rate of GBS positivity in this cohort was 32%, which is higher than the baseline population rate of 22% at our institution.32 In one study of 90 HIV-positive pregnant women, HIV status was not independently associated with GBS colonization,33 although the overall relationship remains unclear. Adverse maternal and perinatal outcomes may be associated with HIV-positivity, combination or specific antiretroviral drug use, or the presence of confounding factors. It has previously been hypothesized that one of the most important confounding variables in the association between adverse outcomes and HIV-positivity is disease severity.13,17,31 In the current study, most women had wellcontrolled HIV infection, adequate prenatal care, and low rates of substance use and co-morbidities; rates of antenatal complications were low, and pregnancy outcomes were favourable. Many studies to date have evaluated outcomes in HIVpositive women with poor access to care and with poorly controlled disease, and outcomes may differ between these populations. Retrospective studies are limited by their reliance on data extracted from chart review. The cohort in the present study was from a single centre and may not be fully representative of a more diverse population. Finally, there was no control group with which to compare outcomes. CONCLUSION
This important study evaluated pregnancy outcomes in HIVpositive women and demonstrated favourable outcomes in women with appropriate access to multidisciplinary prenatal and HIV care and with well-controlled disease. The study adds strength to the argument that good outcomes can be achieved for HIV-positive pregnant women with appropriate management and good access to both prenatal and HIV care. HIV-positive women should be optimally cared for in advance of and during pregnancy in order to maximize the likelihood of good pregnancy outcomes.
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