Elimination of perinatal human immunodeficiency virus (HIV) in the United States has been a goal set by the Centers for Disease Control and Prevention (CDC) since 2012.1 Although significant declines have occurred, the recent estimate of perinatal HIV transmission is still 1.75 times the elimination goal of 1 per 100,000 live births.2 Incident HIV infection during pregnancy and breastfeeding is associated with the highest perinatal HIV transmission risk.3–5 Biological and behavioral evidence about the increased risk for HIV during pregnancy remains conflicting,6 but studies show that women at risk for HIV have increased vulnerability during pregnancy.7,8
Few HIV prevention strategies besides HIV testing have been incorporated into routine U.S.-based antenatal care. Repeat HIV testing in the third trimester for at-risk women is recommended; however, in one observational study conducted in the same setting as the present study, less than one third of pregnant women were retested for HIV despite living in a high prevalence area.9 Little is done in counseling pregnant women about their risk for HIV,10 a risk that is increased in high burden areas.11 Despite safety data of effective biomedical interventions like HIV pre-exposure prophylaxis in pregnancy and breastfeeding,12–14 most U.S.-based pre-exposure prophylaxis awareness campaigns have not included at-risk pregnant women. The only U.S. Food and Drug Administration–approved form of pre-exposure prophylaxis is a daily oral fixed-dose combination of tenofovir disoproxil fumarate and emtricitabine for all people at substantial risk of acquiring HIV.15 Pre-exposure prophylaxis decreases HIV acquisition by 61% (95% CI 40–75%) among women with 75% adherence to daily dosing.16 Furthermore, a recent U.S. study showed that at-risk women frequently chose to use pre-exposure prophylaxis if offered during the periconceptional period or pregnancy.17
The continued, albeit decreased, HIV perinatal transmission cases reflect the need for targeted HIV prevention strategies to reach the elimination goal. However, studies targeting pregnant U.S. women at risk for HIV as potential pre-exposure prophylaxis candidates are lacking.18 The primary objective of this study was to estimate the proportion of U.S.-based pregnant women living in a high HIV incident area who were eligible for pre-exposure prophylaxis during pregnancy and identify associated correlates for eligibility.
MATERIALS AND METHODS
All women who delivered at the Johns Hopkins Hospital in Baltimore, Maryland, in 2012 were included in this retrospective cohort study. Women were excluded if they were living with HIV at the time of the first antenatal care visit, underwent elective termination of pregnancy, transferred prenatal care from an outside clinic, or did not have prenatal care records available. The Johns Hopkins University School of Medicine institutional review board approved the study.
Data were abstracted by doctoral-level clinicians and a postdoctoral trainee from the electronic medical record using a standardized data collection sheet with double data entry. At the first antenatal care visit, a skilled nurse systematically collected demographic information; insurance, medical, sexual, and social history; completed an HIV risk assessment; and performed routine prenatal blood tests and urine toxicology screening. At the second antenatal care visit, a health care provider confirmed the medical, sexual, and psychosocial history and performed a pelvic examination that included gonorrhea and chlamydia testing. Repeat testing for gonorrhea and chlamydia occurred if women reported genitourinary symptoms, during routine screening at 35–37 weeks of gestation, or both.
Pre-exposure prophylaxis eligibility was defined using the CDC's guidance for pre-exposure prophylaxis use based on the most common risk factors for HIV acquisition: HIV-negative heterosexual women with an HIV-positive partner, bacterial sexually transmitted infection (STI), a high number of sex partners, inconsistent or no condom use, practicing commercial sex work, or living in a high prevalence area or network.19 The primary outcome (ie, pre-exposure prophylaxis eligibility during pregnancy) was defined, on the basis of risk factors included in the CDC's guidance, as women with an HIV-positive partner or women with any positive gonorrhea or chlamydia test or diagnoses of genital herpes, syphilis, or trichomoniasis.20 Because of the study's location in Baltimore, all participants were living in the metropolitan area with the third highest HIV incidence in the United States21 and incidence rates of chlamydia, gonorrhea, and syphilis 2.5- to threefold higher than the national rates during the study year.22 The study therefore assessed factors other than location to determine the risk of HIV acquisition and pre-exposure prophylaxis eligibility. The secondary outcomes were pre-exposure prophylaxis eligibility at the first antenatal care visit and negative change in pre-exposure prophylaxis eligibility during pregnancy, for example, those who were considered ineligible for pre-exposure prophylaxis at the first antenatal care visit but acquired a new risk factor during the course of pregnancy. Specifically, change in pre-exposure prophylaxis eligibility was defined as an incident STI over the course of pregnancy and was examined among the subpopulation of women who were not eligible for pre-exposure prophylaxis at the first antenatal care visit. Incident STI cases included women who 1) initially tested negative for gonorrhea or chlamydia at the first antenatal care visit but tested positive at a later date or 2) reported genitourinary symptoms and were subsequently diagnosed with trichomoniasis or genital herpes after the first antenatal care visit. Correlates included age, parity, race, marital status, education level, insurance status, histories of mental illness, substance use, prior STIs, smoking status during pregnancy, and gestational age at the first antenatal care visit.
For the univariable analysis, Student t test or Wilcoxon rank-sum test (nonnormal distributions) were used to compare continuous variables and χ2 or Fisher exact tests were used for categorical variables. Multiple logistic regression models were used to identify correlates associated with pre-exposure prophylaxis eligibility. Results were reported as adjusted odds ratio (OR) with 95% CI. Statistical significance was defined by two-sided P<.05. Variables were included using forward and backward regressions and the most adequate models were selected on the basis of the Akaike information criteria to avoid overfitting, Hosmer-Lemeshow goodness-of-fit test, C-statistic, and mean variance inflation factor. Missing data were handled using listwise deletion because at most, they represented 1.5% of observations for the insurance status variable. Data analyses were performed with Stata 13.1.
Among the 1988 women who gave birth at the Johns Hopkins Hospital during the study year, we excluded 351 from our analysis: 36 living with HIV, 14 who underwent elective termination of pregnancy, 274 who transferred care from an outside clinic, and 27 who did not have prenatal care were excluded from the study. Thus, 1,637 women were included in this analysis of whom 10.1% (165) were eligible for pre-exposure prophylaxis at any time during pregnancy (Table 1). Three of these women (0.6%) reported having an HIV-positive partner and 163 (34.5%) were diagnosed with an STI during pregnancy. Compared with women ineligible for pre-exposure prophylaxis, these pre-exposure prophylaxis–eligible women were significantly more likely to be younger, African American, single or never married, and have less than a high school diploma (Table 1). Compared with women ineligible for pre-exposure prophylaxis, these pre-exposure prophylaxis–eligible women were also more likely to report prior STIs, substance abuse, and regularly smoking during pregnancy (Table 1). Pre-exposure prophylaxis–eligible women entered into antenatal care at a median gestational age of 13.6 weeks and 86.1% had public insurance. There were no statistically significant differences between women eligible for pre-exposure prophylaxis and those who were not in terms of parity or history of mental illness.
In the multivariable analysis, women eligible for pre-exposure prophylaxis at any time in pregnancy had smaller odds of being older (adjusted OR 0.9/1-year increase, 95% CI 0.8–0.9) and greater odds of having higher parity (adjusted OR 1.3/one-child increase, 95% CI 1.1–1.5), being African American (adjusted OR 3.3, 95% CI 1.6–6.7), single (adjusted OR 2.4, 95% CI 1.2–4.8), and smoking during pregnancy (adjusted OR 1.8, 95% CI 1.0–3.0) than women who were not eligible for pre-exposure prophylaxis (Table 2). However, education level, insurance type, history of mental illness, substance use, prior STIs, and gestational age at the first antenatal care visit did not differ significantly between women based on their pre-exposure prophylaxis eligibility at any time in pregnancy.
We sought to determine which pregnant woman might be eligible for pre-exposure prophylaxis at the first antenatal care visit. Among the 1,637 participants, 122 women (7.5%) were eligible for pre-exposure prophylaxis at their first antenatal care visit; two had HIV-positive partners, 119 were diagnosed with an STI at that first visit, and one woman had an HIV-positive partner and was diagnosed with an STI. These women were significantly more likely to be younger, African American, single, have greater parity, have public insurance, and have less than a high school diploma compared with women who were not pre-exposure prophylaxis–eligible (Table 1). Women eligible for pre-exposure prophylaxis at their first antenatal care visit were also significantly more likely to have a history of substance abuse and STIs and to report smoking regularly during their pregnancy compared with women who were not eligible. They also had greater gestational age at their first antenatal care visit. History of mental illness was not significantly associated with pre-exposure prophylaxis eligibility at the first antenatal care visit in the univariable analysis.
After adjusting for all correlates, women who were eligible for pre-exposure prophylaxis at their first antenatal care visit had smaller odds of being older (adjusted OR 0.9/1-year increase, 95% CI 0.8–0.9) and greater odds of having a higher parity (adjusted OR 1.2/one-child increase, 95% CI 1.0–1.5), being African American (adjusted OR 4.3, 95% CI 1.8–10.1), and smoking regularly during pregnancy (adjusted OR 2.1, 95% CI 1.2–3.6) compared with women not eligible for pre-exposure prophylaxis (Table 2). However, marital status, education level, insurance type, history of mental illness, substance use, prior STIs, and gestational age at the first antenatal care visit did not differ between women based on their pre-exposure prophylaxis eligibility at their first antenatal care visit.
We sought to determine whether a pregnant woman's risk for HIV acquisition changed during pregnancy. Of the pregnant women who were initially ineligible for pre-exposure prophylaxis at the first antenatal care visit (n=1,515), 44 women (2.7%) had an incident STI and thus became eligible for pre-exposure prophylaxis. Compared with women who did not become eligible for pre-exposure prophylaxis during pregnancy, newly eligible women were significantly more likely to be younger, African American, single, and not to have graduated from high school (Appendix 1, available online at http://links.lww.com/AOG/A990). Most had public insurance. History of mental illness, substance use, STIs, parity, and gestational age at the first antenatal care visit were not significantly different between the two groups in the univariable analysis.
Age was the only covariate that remained statistically significant for change in pre-exposure prophylaxis eligibility during pregnancy in the multivariable analysis. Older women (adjusted OR 0.8/1-year increase, 95% CI 0.7–0.9) had smaller odds of becoming eligible for pre-exposure prophylaxis during pregnancy compared with younger women (Appendix 2, available online at http://links.lww.com/AOG/A990).
Among this sample of urban pregnant women, 10% were eligible for pre-exposure prophylaxis; independent correlates for pre-exposure prophylaxis eligibility included young age, multiparity, African American race, being single, and smoking status. These demographic factors—and by extension risk factors for HIV acquisition—can be used to target subpopulations with HIV prevention messages. Pregnant women are more likely to believe their main sexual partner is monogamous compared with nonpregnant women23,24 and may not be aware of their male partner’s HIV status or risk behaviors such as injection drug use and having sex with men, yet less than 30% of pregnant women use condoms during sexual intercourse25 and safe sex practices may be even further limited for pregnant women who experience intimate partner violence.26
After examining HIV risk by timing of antenatal care clinical encounters, we found that a little more than 7% were eligible for pre-exposure prophylaxis during the first antenatal care visit, and 3% who were initially ineligible became eligible during antenatal care. After adjustment for correlates, the risk factors for pre-exposure prophylaxis eligibility were similar (age, race, and parity) with the exception of marital status comparing women eligible for pre-exposure prophylaxis at intake and at any time in pregnancy. Only younger age was found to be significantly associated with a negative change in pre-exposure prophylaxis eligibility. This change in risk is of particular importance given the high risk of perinatal HIV transmission after seroconversion during pregnancy.6 This change in women’s HIV risk also challenges the notion of static risk profiles in favor of fluid ones and pinpoints the importance of repeated risk assessment. Addressing HIV risk solely at intake would not reach all patients. In high prevalence areas, each health care encounter should include an HIV risk assessment, and clinicians can initiate or at least raise awareness of pre-exposure prophylaxis.
Preventive HIV biomedical interventions are underused during pregnancy. The CDC estimated that 0.6% or 468,000 heterosexual women in the United States had an indication for pre-exposure prophylaxis on the basis of risky sexual behaviors,18 but no study has estimated that proportion among pregnant women. However, differences in target populations may make comparison with this study focusing on pregnancy difficult. Estimates of the number of U.S. perinatal HIV cases during 2010–2013 showed that 56.4% of maternal HIV diagnoses occurred during pregnancy or postpartum.2 Although there were no data on timing of seroconversion, some of these perinatal transmission cases potentially could have been prevented through enhanced HIV counseling and testing for at-risk pregnant women and offering pre-exposure prophylaxis. Two U.S. medical centers identified only 27 women in or around pregnancy who chose to use pre-exposure prophylaxis (67% acceptance) over 5 years17; however, our study estimates that 10% of urban pregnant women would be pre-exposure prophylaxis–eligible.
Given at-risk women's high uptake of pre-exposure prophylaxis during pregnancy,17 health care providers should identify those with the highest risk to address this gap. Data suggest that pre-exposure prophylaxis is safe in pregnancy and breastfeeding27; the Antiretroviral Pregnancy Registry finds no increased risk of birth defects from pre-exposure prophylaxis exposure28; a substudy of women who became pregnant while on pre-exposure prophylaxis found no difference in pregnancy loss, preterm birth, birth defects, or 1-year growth anomalies29; and a pharmacokinetic study found that pre-exposure prophylaxis was undetectable or negligible in breastfed infants’ serum.13 These safety data should encourage health care providers to discuss and perhaps offer pre-exposure prophylaxis and other HIV prevention strategies during pregnancy with at-risk women who stand to reap tremendous benefits.
The study has several limitations. As a chart review from a single institution's obstetric population without a prospective design, some data elements (eg, condom use, number of sexual partners) were not collected, which might have identified additional pre-exposure prophylaxis–eligible women, making this study's findings conservative. However, condom use has been found to be an inaccurate measure that is susceptible to social desirability bias.30,31 Next, generalizability is limited given the primarily urban African American women engaged in antenatal care in a high HIV incidence setting. However, recent data show that the majority of perinatal HIV transmission occurs among African American patients living in specific locations.2 Hence, HIV prevention interventions should target populations most at risk.
In summary, this study underscores missed opportunities for HIV prevention throughout pregnancy. Determining which women are most at risk for HIV is necessary to target prevention messaging and interventions to ultimately eliminate perinatal transmission. The study highlights additional demographic factors that may be used to identify pre-exposure prophylaxis–eligible pregnant women in addition to CDC guidelines. It is critical to gain a better understanding of the role of these preventive interventions among pregnant women when the consequences of acute HIV can be devastating for not only the mother, but also the unborn child. Given these high stakes, additional demonstration projects in U.S. prenatal care delivery settings are needed to further assess risk of HIV acquisition and eligibility for pre-exposure prophylaxis among pregnant women.
1. Nesheim S, Taylor A, Lampe MA, Kilmarx PH, Fitz Harris L, Whitmore S, et al. A framework for elimination of perinatal transmission of HIV in the United States. Pediatrics 2012;130:738–44.
2. Taylor AW, Nesheim SR, Zhang X, Song R, FitzHarris LF, Lampe MA, et al. Estimated perinatal HIV infection among infants born in the United States, 2002–2013. JAMA Pediatr 2017;171:435–42.
3. Nesheim S, Harris LF, Lampe M. Elimination of perinatal HIV infection in the USA and other high-income countries: achievements and challenges. Curr Opin HIV AIDS 2013;8:447–56.
4. Birkhead GS, Pulver WP, Warren BL, Hackel S, Rodriguez D, Smith L. Acquiring human immunodeficiency virus during pregnancy and mother-to-child transmission in New York: 2002–2006. Obstet Gynecol 2010;115:1247–55.
5. Palasanthiran P, Ziegler JB, Stewart GJ, Stuckey M, Armstrong JA, Cooper DA, et al. Breast-feeding during primary maternal human immunodeficiency virus infection and risk of transmission from mother to infant. J Infect Dis 1993;167:441–4.
6. Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy and postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-analysis. PLoS Med 2014;11:e1001608.
7. Gray RH, Li X, Kigozi G, Serwadda D, Brahmbhatt H, Wabwire-Mangen F, et al. Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study. Lancet 2005;366:1182–8.
8. Mugo NR, Heffron R, Donnell D, Wald A, Were EO, Rees H, et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. AIDS 2011;25:1887–95.
9. Liao C, Golden WC, Anderson JR, Coleman JS. Missed opportunities for repeat HIV testing in pregnancy: implications for elimination of mother-to-child transmission in the United States. AIDS Patient Care STDS 2017;31:20–26.
10. Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during pregnancy: compelling reason for repeat HIV testing. AIDS 2009;23:1255–9.
11. Centers for Disease Control and Prevention (CDC). Characteristics associated with HIV infection among heterosexuals in urban areas with high AIDS prevalence—24 cities, United States, 2006–2007. MMWR Morb Mortal Wkly Rep 2011;60:1045–9.
12. Heffron R, Pintye J, Matthews LT, Weber S, Mugo N. PrEP as peri-conception HIV prevention for women and men. Curr HIV/AIDS Rep 2016;13:131–9.
13. Mofenson LM. Tenofovir pre-exposure prophylaxis for pregnant and breastfeeding women at risk of HIV infection: the time is now. PLoS Med 2016;13:e1002133.
14. Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, et al. Pre-exposure prophylaxis use by breastfeeding HIV-uninfected women: a prospective short-term study of antiretroviral excretion in breast milk and infant absorption. PLoS Med 2016;13:e1002132.
16. Hanscom B, Janes HE, Guarino PD, Huang Y, Brown ER, Chen YQ, et al. Brief report: preventing HIV-1 infection in women using oral preexposure prophylaxis: a meta-analysis of current evidence. J Acquir Immune Defic Syndr 2016;73:606–608.
17. Seidman DL, Weber S, Timoney MT, Oza KK, Mullins E, Cohan DL, et al. Use of HIV pre-exposure prophylaxis during the preconception, antepartum and postpartum periods at two United States medical centers. Am J Obstet Gynecol 2016;215:632.e1–632.e7.
18. Smith DK, Van Handel M, Wolitski RJ, Stryker JE, Hall HI, Prejean J, et al. Vital signs: estimated percentages and numbers of adults with indications for preexposure prophylaxis to prevent HIV acquisition—United States, 2015. MMWR Morb Mortal Wkly Rep;64:1291–5.
20. Tobian AA, Quinn TC. Herpes simplex virus type 2 and syphilis infections with HIV: an evolving synergy in transmission and prevention. Curr Opin HIV AIDS 2009;4:294–9.
22. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases—reported cases and rates of reported cases per 100,000 population, United States, 1941–2013. Available at: http://www.cdc.gov/std/stats13/tables/1.htm
. Retrieved August 14, 2016.
23. Wilson TE, Minkoff H, McCalla S, Petterkin C, Jaccard J, et al. The relationship between pregnancy and sexual risk taking. Am J Obstet Gynecol 1996;174:1033–6.
24. Friedman AL, Bloodgood B. ‘Something we'd rather not talk about’: findings from CDC exploratory research on sexually transmitted disease communication with girls and women. J Womens Health (Larchmt) 2010;19:1823–31.
25. Niccolai LM, Ethier KA, Kershaw TS, Lewis JB, Ickovics JR, et al. Pregnant adolescents at risk: sexual behaviors and sexually transmitted disease prevalence. Am J Obstet Gynecol 2003;188:63–70.
26. Maman S, Campbell J, Sweat MD, Gielen AC. The intersections of HIV and violence: directions for future research and interventions. Soc Sci Med 2000;50:459–78.
27. Seidman DL, Weber S, Cohan D. Offering pre-exposure prophylaxis for HIV prevention to pregnant and postpartum women: a clinical approach. J Int AIDS Soc 2017;20(suppl 1):24–30.
28. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989 through 31 July 2016. Wilmington (NC): Registry Coordinating Center; 2016.
29. Mugo NR, Hong T, Celum C, Donnell D, Bukusi EA, John-Stewart G, et al. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA 2014;312:362–71.
30. Evans JL, Couture MC, Stein ES, Sansothy N, Maher L, Page K, et al. Biomarker validation of recent unprotected sexual intercourse in a prospective study of young women engaged in sex work in Phnom Penh, Cambodia. Sex Transm Dis 2013;40:462–8.
31. Heffron R, Parikh UM, Penrose KJ, Mugo N, Donnell D, Celum C, et al. Objective measurement of inaccurate condom use reporting among women using depot medroxyprogesterone acetate for contraception. AIDS Behav 2017;21:2173–2179.