EPIDEMIOLOGY
AND
PREVENTION
Abacavir and Lamivudine Exposures During Pregnancy and Non-defect Adverse Pregnancy Outcomes: Data From the Antiretroviral Pregnancy Registry Vani Vannappagari, MBBS, MPH, PhD,*† Nana Koram, PhD, MPH,* Jessica Albano, PhD,‡ Hugh Tilson, MD, DrPH,† and Conway Gee, PhD§
Background: The antiretroviral (ARV) pregnancy registry, an international voluntary registry, provides information on teratogenicity and non-defect adverse pregnancy outcomes.
Methods: We analyzed ARV pregnancy registry prospective singleton pregnancies, estimating frequencies of and risk for nondefect adverse outcomes among HIV-infected women. Prenatal exposures to abacavir (ABC)-containing regimens vs. non-ABC ARV regimens, and lamivudine (3TC)-containing regimens vs. non3TC regimens were compared. Results: Of 2006 outcomes with prenatal ABC exposure, 95.6% were live births; 4.4% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had low birth weight (LBW); 11.9% were preterm births. Relative risks comparing exposure to ABC vs. non-ABC ARV regimens were spontaneous abortions 0.92 [95% confidence interval (CI): 0.66 to 1.27], induced abortions 0.84 (95% CI: 0.59 to 1.21), stillbirths 0.59 (95% CI: 0.35 to 1.00), preterm births 0.96 (95% CI: 0.84 to 1.09), and LBW 1.00 (95% CI: 0.90 to 1.13). Of 11,211 outcomes with prenatal 3TC exposure, 95.3% were live births; 4.7% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had LBW; 11.9% were preterm births. The relative risks comparing exposure to 3TC vs. non-3TC ARV regimens were spontaneous abortions 0.63 (95% CI: 0.50 to 0.80), induced abortions 0.54 (95% CI: 0.43 to 0.69), stillbirths 1.25 (95% CI: 0.86 to 1.80), preterm births 0.86 (95% CI: 0.77 to 0.95), and LBW 1.02 (95% CI: 0.93 to 1.12).
Received for publication April 29, 2014; accepted October 10, 2014. From the *Epidemiology and Real world Evidence, ViiV Healthcare, Research Triangle Park, NC; †Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; ‡INC Research, Post Approval and Strategic Services, Raleigh, NC; and §INC Research, Biostatistics, Wilmington, NC. Presented at the 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013, Atlanta, GA. V.V. is an employee of ViiV Healthcare, a joint venture between GlaxoSmithKline and Pfizer. N.K. is an employee of GlaxoSmithKline. V.V. owns GlaxoSmithKline stock. J.A. and C.G. are salaried employees of INC Research, the coordinating center for the Antiretroviral Pregnancy Registry. H.T. is a member of the Antiretroviral Pregnancy Registry Steering Committee and consults with individual sponsors, including GlaxoSmithKline. Correspondence to: Vani Vannappagari, MBBS, MPH, PhD, Epidemiology and Real world Evidence, ViiV Healthcare, 5 Moore Drive, Mail Stop: 5.4300.4B, PO Box 13398, Research Triangle Park, NC 27709-3398 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Conclusions: ABC-containing and non-ABC ARV regimens have similar risks for non–birth defect adverse pregnancy outcomes. 3TC-containing regimens have lower risk for spontaneous abortions, induced abortions, and preterm births compared with non-3TC ARV regimens, whereas both regimens had similar prevalence and risks for stillbirths and LBW. Key Words: abacavir, lamivudine, pregnancy outcomes, HIV, antiretroviral pregnancy registry (J Acquir Immune Defic Syndr 2015;68:359–364)
INTRODUCTION Current guidelines from the World Health Organization (WHO) suggest that all HIV-positive pregnant and breastfeeding women initiate antiretroviral therapy regardless of CD4 count.1 In the United States, guidelines from the National Institutes of Health recommend that all pregnant women receive combination antiretroviral therapy regardless of disease severity to prevent perinatal transmission of HIV. Both guidelines recommend 3TC as one of the preferred nucleoside reverse transcriptase inhibitors (NRTIs)1,2 and US guidelines recommend abacavir (ABC) as an alternative NRTI.2 Although HIV-positive nonpregnant women are prescribed antiretrovirals (ARVs) most appropriate for their treatment conditions, the decision to continue or switch them to other ARVs during pregnancy is based on the guidelines for ARV use. For providers treating women who are or become pregnant with ARV drugs, teratogenicity and their effect on pregnancy outcomes are the 2 main safety concerns. Results from studies on non–birth defect pregnancy outcomes and ARV use are mixed. Differing results may be attributable to the large number of potential confounding factors (eg, ethnicity, smoking, alcohol or illicit drug use, viral load, or CD4 count).3 There have been 11 recent studies (since 2004) that were summarized in a systematic review that found a reported risk for prematurity, low birth weight (LBW), and other outcomes after in utero exposure to ARV therapy.4 One of these studies was a randomized trial that found that protease inhibitor-based ARV therapy was associated with an increased risk for preterm delivery compared with NRTIbased ARV therapy [odds ratio: 2.0; 95% confidence interval (CI): 1.3 to 3.3].5 These results were supported by 3 prospective observational cohort studies; however, no association was found in 7 other cohort studies, whereas a larger
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
www.jaids.com |
359
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Vannappagari et al
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
cohort study (N = 4943) found that combination therapy regardless of protease inhibitor exposure to be associated with the risk of preterm and very preterm delivery compared with mono or dual therapy.4 In the Mma Bana Study, there was increased risk of prematurity among infants born to women receiving zidovudine/3TC/ritonavir-boosted lopinavir [relative risk (RR): 1.52; 95% CI: 1.07 to 2.17] compared with zidovudine/3TC/ABC.6 Ekouevi et al7 showed higher rates of infant LBW with prenatal exposure to zidovudine/3TC/ nevirapine started at 24 weeks compared with a short course regimen started between 32 and 36 weeks (RR: 1.81; 95% CI: 1.09 to 3.0). The Antiretroviral Pregnancy Registry (APR) has been monitoring birth defects in pregnant women with ARV exposure for over 20 years. According to its most recent interim report published in December 2013 for data through July 31, 2013, the overall prevalence of birth defects among women with first trimester exposure to any ARV monitored by the APR is 2.9 (95% CI: 2.5 to 3.3).8 This rate is comparable with the birth defect rates 2.72 per 100 live births (95% CI: 2.68 to 2.76; calculated by the APR) reported by the Centers for Disease Control and Prevention’s populationbased comparator, the Metropolitan Atlanta Congenital Defects Program.9 For ABC, sufficient numbers of first trimester exposures have been monitored through the APR to detect at least a 2-fold increase in risk of overall birth defects. No such increases have been detected to date and the prevalence of birth defects with first trimester exposure to ABC is estimated to be 3.0% (95% CI: 2.0 to 4.3).8 For 3TC, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No such increases have been detected to date and the prevalence of birth defects after first trimester exposure to 3TC is estimated to be 3.1% (95% CI: 2.6 to 3.7).8 Details of reported birth defects can be found in the interim report, published biannually, at http://www.apregistry.com/forms/interim_report.pdf. Although 3TC and ABC have been used commonly during pregnancy, and neither have been associated with increased risk for birth defects,8 their effect on non–birth defect pregnancy outcomes has not been well investigated. Since the primary remit of the APR is to monitor for teratogenic effects of the ARVs, the interim report does not include rates for non-defect adverse pregnancy outcomes such as LBW, prematurity, stillbirths, and spontaneous or induced abortions. In this analysis, we examine the risk of non-defect adverse pregnancy outcomes among pregnant women exposed to ABC- and 3TC-containing regimens.
rates with didanosine and nelfinavir compared with its population-based comparators, the Metropolitan Atlanta Congenital Defects Program and the Texas Birth Defects Registry. Although the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients. However, potential limitations of registries such as this should be recognized. The Registry is ongoing. Health care providers are encouraged to report eligible patients to the Registry at www.APRegistry.com.
METHODS
In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of ARV exposure, the Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause.8 The Registry notes modest but statistically significant elevations of overall defect
This is a secondary analysis of data from the APR. The APR is a prospective exposure-registration cohort study, established in January 1989 to detect early signs of major teratogenic effects after exposure to ARV drugs during pregnancy. Registration is voluntary and confidential. The majority of case reports received by the APR are from the United States and its territories (77.7%).8 From among the 66 other countries that the registry has received reports from, 4.3% are from Brazil, 3.8% are from the United Kingdom, 2.4% from Argentina, 3.2% from Uganda, 1.5% from South Africa, and 1.1% are from France.8 Each year the APR enrolls approximately 1300 pregnant women in the United States, representing approximately 15% of the HIV-positive women who give birth to live infants annually in the United States,10 and 200 pregnant women from other countries.8 Health care providers prospectively register pregnant women with prenatal exposures to any ARV before the pregnancy outcome is known. Patients are followed during pregnancy through health care providers who provide information on maternal risk factors and pregnancy outcome. An institutional review board approval was obtained from the Western institutional review board for the protocol to establish the APR and the approval is renewed annually. The APR was granted a waiver from obtaining patient informed consent. The outcome of pregnancy is defined at the time of delivery or fetal loss, or when a defect reported after enrollment is detected on a prenatal test. The registry also receives information on women enrolled in clinical trials and retrospective reports. However, this analysis is restricted to women who were registered prospectively, with singleton deliveries (twins and triplet births were excluded), from January 1, 1989, through July 31, 2013. Gestational weeks were calculated beginning from the first day of the last menstrual period. Where the date of the last menstrual period was not available, the estimated date of delivery was used. If the gestation week was inconsistent with the exposure dates and/or the date of outcome (outside 6 1 week for the first trimester, outside 6 2 weeks for the second and third trimesters), a corrected estimated date of delivery where ultrasound results were available was used. Non-defect adverse pregnancy outcomes included in the analyses are spontaneous abortions, induced abortions, stillbirths, preterm births (,37-week gestation), very preterm births (,32-week gestation), LBW (,2500 g), and very LBW (,1500 g). Spontaneous abortion as defined by the
360
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
The APR Consensus Statement
| www.jaids.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
registry is fetal death or expulsion of products of conception before 20-week gestation. Stillbirth is defined as a fetal death occurring 20-week gestation or greater, or if the gestational age is unknown, a fetus weighing 500 g or more.
Statistical Analysis For APR data through July 31, 2013, we estimated the prevalence of non-defect adverse pregnancy outcomes and calculated RRs and 95% CI for the following: (1) adverse birth outcome cases exposed to ABC-containing regimens compared with those exposed to non-ABC ARV regimens and (2) adverse outcome cases exposed to 3TC-containing regimens compared with those exposed to non-3TC ARV regimens. The analysis was limited to singleton pregnancies, and first trimester exposures were not considered since drug exposure at any point during pregnancy is more relevant. This analysis compared exposure to ABC- or 3TC-containing regimens at any time during pregnancy with exposure to non-ABC or non–3TC-containing regimens. Where appropriate, P values were estimated using either the independent t test or Fisher exact test for continuous and discrete variables, respectively. Unknown or missing values were excluded from the analysis. For spontaneous losses, induced abortions, and
ABC and 3TC Exposures and Birth Outcomes
stillbirths, prevalence was estimated based on the number of pregnancies, with the 95% CI based on the Clopper–Pearson exact binomial method.11,12 For preterm births and LBW, the estimated prevalence was based on the number of live singleton births, and excludes cases with birth defects, and all cases with unknown gestational age or unknown birth weight, respectively. The 95% CIs were also based on the Clopper–Pearson exact binomial method. RRs for ABC and 3TC were calculated for regimens containing ABC vs. regimens excluding ABC, and regimens containing 3TC vs. regimens excluding 3TC, respectively. The 95% CIs for the RRs were based on the normal asymptotic method.
RESULTS Maternal Demographics There were a total of 14,950 prospectively reported pregnancies from HIV-infected women for which outcome is known. Of these, 14,684 were singleton pregnancies and 266 were pregnancies with multiple outcomes that were excluded. Among the 14,684 singleton pregnancies, 2006 had prenatal exposure to ABC-containing regimens; 12,678 had prenatal exposure to non–ABC-containing regimens; 11,211
TABLE 1. Maternal Characteristics: Singleton Prospective Pregnancies by ABC Exposure During Pregnancy Among HIV-Infected Women Reported to the Antiretroviral Pregnancy Registry Through July 31, 2013 With Outcome
No. pregnancies Age, yrs* N Mean (SD) Median (interquartile range) Min–Max Missing Race, n (%)† White Black Hispanic Asian Other Missing CD4+ T-cell categories at start of pregnancy, n (%)† $500/mL 200–499/mL ,200/mL Unknown NA Missing Country of report origin, n (%)† United States Other Missing
Overall
ABC-Containing ARV Regimen
Non-ABC ARV Regimen
14,684
2006
12,678
P 0.2174
14,608 28.2 (6.04) 28.0 (9.0) 13–55 76 (0.5%)
1998 28.3 (6.15) 28.0 (9.0) 13–48 8 (0.4%)
12,610 28.1 (6.03) 28.0 (10.0) 13–55 68 (0.5%)
2272 8682 2915 128 402 285
(15.5) (59.1) (19.9) (0.9) (2.7) (1.9)
232 1400 319 20 21 14
(11.6) (69.8) (15.9) (1.0) (1.0) (0.7)
2040 7282 2596 108 381 271
(16.1) (57.4) (20.5) (0.9) (3.0) (2.1)
4561 6583 2407 77 24 1032
(31.1) (44.8) (16.4) (0.5) (0.2) (7.0)
745 949 251 9 11 41
(37.1) (47.3) (12.5) (0.4) (0.5) (2.0)
3816 5634 2156 68 13 991
(30.1) (44.4) (17.0) (0.5) (0.1) (7.8)
,0.0001
,0.0001
,0.0001 11,872 (80.8) 2808 (19.1) 4 (0.0)
1769 (88.2) 236 (11.8) 1 (0.0)
10,103 (79.7) 2572 (20.3) 3 (0.0)
Percentages are based on the number of pregnancies. *P value is based on the independent t test. †P value is based on the Fisher exact test (x2 test for Race). Analysis does not include NA, unknown, or missing values.
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jaids.com |
361
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Vannappagari et al
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
had prenatal exposure to 3TC-containing regimens; 3473 had prenatal exposure to non–3TC-containing regimens. Tables 1 and 2 describe the maternal characteristics of the ABC and 3TC analysis populations, respectively. Overall, 8.6% of term deliveries ($37 weeks) were LBW ,2500 g.
ABC vs. Non–ABC-Containing Regimens Of the 2006 singleton pregnancy outcomes with prenatal ABC exposure, 95.6% were live births and 4.4% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.2% of infants had LBW and 11.9% were preterm births. Of 12,678 outcomes with prenatal exposure to non-ABC ARV regimens, 94.6% were live births and 5.4% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.1% of infants had LBW and 12.4% were preterm births. Table 3 presents the frequencies of the pregnancy outcomes. Among pregnant women with exposure to ABC-containing regimens, 9.1% of term deliveries ($37 weeks) were LBW ,2500 g; among those with non-ABC ARV exposure, 8.5% of term deliveries were LBW. Table 4 presents the prevalence and 95% CI of spontaneous abortions, induced abortions, still births, preterm
births, and LBW for regimens containing ABC and for regimens excluding ABC. The RR of adverse pregnancy outcomes comparing prenatal exposure to ABC-containing vs. non-ABC ARV regimens were for spontaneous abortions 0.92 (95% CI: 0.66 to 1.27; P = 0.68), induced abortions 0.84 (95% CI: 0.59 to 1.21; P = 0.38), stillbirths 0.59 (95% CI: 0.35 to 1.00; P = 0.05), preterm births 0.96 (95% CI: 0.84 to 1.09; P = 0.57), and LBW 1.00 (95% CI: 0.90 to 1.13; P = 0.94) (Table 4). None of the RRs are statistically significantly different between the 2 groups.
3TC vs. Non–3TC-Containing Regimens Of the 11,211 singleton pregnancy outcomes with prenatal 3TC exposure, 95.3% were live births and 4.7% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.2% of infants had LBW and 11.9% were preterm births. Of 3473 outcomes with prenatal exposure to non-3TC ARV regimens, 93.1% were live births and 6.9% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 15.9% of infants had LBW and 13.8% were preterm births (Table 3). Among pregnant women with exposure to 3TC-containing regimens, 8.8% of term
TABLE 2. Maternal Characteristics: Singleton Prospective Pregnancies by 3TC Exposure During Pregnancy Among HIV-Infected Women Reported to the Antiretroviral Pregnancy Registry Through July 31, 2013 With Outcome
No. pregnancies Age, yrs* N Mean (SD) Median (interquartile range) Min–Max Missing Race, n (%)† White Black Hispanic Asian Other Missing CD4+ T-cell categories at start of pregnancy, n (%)† $500/mL 200–499/mL ,200/mL Unknown NA Missing Country of report origin, n (%)† United States Other Missing
Overall
3TC-Containing ARV Regimen
Non-3TC ARV Regimen
14,684
11,211
3473
14,608 28.2 (6.04) 28.0 (9.0) 13–55 76 (0.5%)
11,159 28.0 (6.03) 28.0 (10.0) 13–48 52 (0.5%)
3449 28.6 (6.08) 28.0 (9.0) 13–55 24 (0.7%)
2272 8682 2915 128 402 285
(15.5) (59.1) (19.9) (0.9) (2.7) (1.9)
1789 6775 2192 96 275 84
(16.0) (60.4) (19.6) (0.9) (2.5) (0.7)
483 1907 723 32 127 201
(13.9) (54.9) (20.8) (0.9) (3.7) (5.8)
4561 6583 2407 77 24 1032
(31.1) (44.8) (16.4) (0.5) (0.2) (7.0)
3488 5067 1655 51 20 930
(31.1) (45.2) (14.8) (0.5) (0.2) (8.3)
1073 1516 752 26 4 102
(30.9) (43.7) (21.7) (0.7) (0.1) (2.9)
P ,0.0001
,0.0001
,0.0001
,0.0001 11,872 (80.8) 2808 (19.1) 4 (0.0)
8880 (79.2) 2328 (20.8) 3 (0.0)
2992 (86.2) 480 (13.8) 1 (0.0)
Percentages are based on the number of pregnancies. *P value is based on the independent t test. †P value is based on the Fisher exact test (x2 test for Race). Analysis does not include NA, unknown, or missing values.
362
| www.jaids.com
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
ABC and 3TC Exposures and Birth Outcomes
TABLE 3. Pregnancy Outcomes: ABC vs. Non-ABC ARV and 3TC vs. Non-3TC ARV Exposed, Reported to the Antiretroviral Pregnancy Registry, Prospective Data Through July 31, 2013 Birth Outcomes Live births Spontaneous abortions Stillbirths Induced abortions Total adverse birth outcomes* Birth weight ,2500 g ,1500 g Unknown Gestational age ,37 wk ,32 wk Unknown
Regimens Containing ABC (%)
Regimens Excluding ABC (%)
Regimens Containing 3TC (%)
Regimens Excluding 3TC (%)
1918 (95.6) 40 (2.0) 15 (0.7) 33 (1.6) 88 (4.4) N = 1781† 288 (16.2) 28 (1.6) 84 N = 1860‡ 221 (11.9) 35 (1.9) 5
11,993 (94.6) 276 (2.2) 161 (1.3) 248 (2.0) 685 (5.4) N = 10,771† 1735 (16.1) 232 (2.2) 886 N = 11,634‡ 1442 (12.4) 256 (2.2) 23
10,679 (95.3) 212 (1.9) 141 (1.3) 179 (1.6) 532 (4.7) N = 9557† 1548 (16.2) 192 (2.0) 812 N = 10,351‡ 1228 (11.9) 206 (2.0) 18
3232 (93.1) 104 (3.0) 35 (1.0) 102 (2.9) 241 (6.9) N = 2995† 475 (15.9) 68 (2.3) 158 N = 3143‡ 435 (13.8) 85 (2.7) 10
Percentages are based on the total outcomes in the respective analysis. Bold values indicate the totals for overall adverse event. *Total adverse birth outcomes include still births, spontaneous, or induced abortions, and exclude birth defects in live births. †Excludes cases with unknown birth weight. ‡Excludes cases with unknown gestational age.
deliveries ($37 weeks) were LBW ,2500 g; among those with non-3TC ARV exposure, 7.9% of term deliveries were LBW. Table 4 presents the prevalence and 95% CI of spontaneous abortions, induced abortions, still births, preterm births, and LBW for regimens containing 3TC and for regimens excluding 3TC. Statistically significant lower risk
of adverse pregnancy outcomes was observed for prenatal exposure to 3TC-containing regimens compared with non-3TC ARV regimens for spontaneous abortions (RR: 0.63; 95% CI: 0.50 to 0.80; P , 0.01), induced abortions (RR: 0.54; 95% CI: 0.43 to 0.69; P , 0.01), and preterm births (RR: 0.86; 95% CI: 0.77 to 0.95; P , 0.01). The risk for stillbirths (RR: 1.25, 95% CI: 0.86 to 1.80; P = 0.28) and LBW (RR: 1.02; 95% CI:
TABLE 4. Prevalence and Relative Risk of Non-defect Adverse Birth Outcomes: ABC vs. Non-ABC ARV and 3TC vs. Non-3TC ARV, Reported to the Antiretroviral Pregnancy Registry, Prospective Data Through July 31, 2013 ABC vs. Non–ABC-Containing ARV Regimen ABC Spontaneous abortions* Prevalence (95% CI) RR (95% CI)† Induced abortions* Prevalence (95% CI) RR (95% CI)† Stillbirths* Prevalence (95% CI) RR (95% CI)† Preterm births (,37 wk)‡ Prevalence (95% CI) RR (95% CI)† LBW (,2500 g)§ Prevalence (95% CI) RR (95% CI)†
Non-ABC
3TC vs. Non–3TC-Containing ARV Regimen 3TC
Non-3TC
1.99% (1.43 to 2.71) 2.18% (1.93 to 2.45) 0.92 (0.66 to 1.27); P = 0.6787
1.89% (1.65 to 2.16) 2.99% (2.45 to 3.62) 0.63 (0.50 to 0.80); P = 0.0002
1.65% (1.14 to 2.30) 1.96% (1.72 to 2.21) 0.84 (0.59 to 1.21); P = 0.3809
1.60% (1.37 to 1.85) 2.94% (2.40 to 3.55) 0.54 (0.43 to 0.69); P # 0.0001
0.75% (0.42 to 1.23) 1.27% (1.08 to 1.48) 0.59 (0.35 to 1.00); P = 0.0464
1.26% (1.06 to 1.48) 1.01% (0.70 to 1.40) 1.25 (0.86 to 1.80); P = 0.2839
11.88% (10.45 to 13.44) 12.39% (11.80 to 13.01) 0.96 (0.84 to 1.09); P = 0.5688
11.86% (11.25 to 12.50) 13.84% (12.65 to 15.10) 0.86 (0.77 to 0.95); P = 0.0036
16.17% (14.49 to 17.96) 16.11% (15.42 to 16.82) 1.00 (0.90 to 1.13); P = 0.9445
16.20% (15.46 to 16.95) 15.86% (14.57 to 17.22) 1.02 (0.93 to 1.12); P = 0.6694
*Prevalence is based on the number of pregnancies. 95% CI is based on the exact binomial (Clopper–Pearson) method. †Relative risk—regimens containing ABC vs. regimens excluding ABC and regimens containing 3TC vs. regimens excluding 3TC. The 95% CI is based on the normal asymptotic method. P value is based on the Fisher exact test. ‡Prevalence is based on the number of live singleton births—excludes cases with defects and cases with unknown gestational age. 95% CI is based on the exact binomial (Clopper– Pearson) method. §Prevalence is based on the number of live singleton births—excludes cases with defects and cases with unknown birth weight. 95% CI is based on the exact binomial (Clopper– Pearson) method.
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jaids.com |
363
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
Vannappagari et al
0.93 to 1.12; P = 0.67) was not statistically significantly different between the 2 groups (Table 4).
DISCUSSION
CONCLUSIONS ABC and 3TC both currently have US Federal Drug Administration Pregnancy Category C status, that is, their use in pregnancy is recommended only if the potential benefits outweigh the potential risks. Our data found that there is no difference in the observed risk for non-defect adverse pregnancy outcomes after exposure to ABC compared with exposure to non-ABC regimens. In addition, 3TC-containing regimens seem to have lower risk for spontaneous abortions, induced abortions, and preterm births when compared with non–3TC-containing regimens. These findings may be helpful to physicians considering treatment in women at higher risk for these non-defect outcomes.
Data on the effect of specific ARV use on non-defect adverse birth outcomes are limited as most published literature in this area is focused on birth defects. These analyses show that ABC-containing regimens and non–ABCcontaining regimens have similar prevalence and risks for non-defect adverse pregnancy outcomes. 3TC-containing regimens were found to have lower prevalence and risk for spontaneous abortions, induced abortions, and preterm births compared with non–3TC-containing regimens, whereas both groups had similar prevalence and risks for stillbirths and LBW. A potential limitation of this study is that non–3TCcontaining regimens include emtricitabine, an ARV that is similar to 3TC; thus were there a class effect, those in the comparison group with emtricitabine exposures would cause regression to the mean, thus diminishing any difference that would be detected. Although the number of pregnancies included in the analyses is large, potential confounders like disease status (incompletely ascertained by the APR) and unmeasured confounders (non-ARV drug factors like concomitant drugs, illicit drug use, alcohol, and tobacco use) are not measured and adjusted for in the analyses. Unmeasured confounders could also include health-related behaviors such as maternal body mass index. Non–birth defect pregnancy outcomes are not the primary objective of the APR or interest of the reporting provider, resulting in potential underascertainment of the pregnancy outcomes investigated in these analyses. Differential ascertainment due to voluntary reporting and observational nature of the APR cannot be ruled out. Because of voluntary reporting, the pregnancy loss rate in the APR is difficult to interpret, and reporting of pregnancy losses, may be further subject to selection bias. This may account for the low rate of spontaneous and induced abortions and still births observed in this study. There is also the potential for reporting bias due to cultural or legal constraints in nations where induced abortions are illegal, and thus may be reported as spontaneous abortions. Although published literature on non-defect adverse birth outcomes is conflicting, the Mma Bana study6 conducted in Botswana comparing pregnant women on ABC/ 3TC/zidovudine to pregnant women on 3TC/zidovudine + lopinavir/ritonavir found that prematurity was less common among those on the ABC-containing regimen compared with those on the non–ABC-containing regimen. However, the proportion of infants with LBW did not differ significantly by group.6 These results are similar to those noted in this study for ABC. A secondary study based on the same population as that for the Mma Bana study comparing patients on ABC/ 3TC/zidovudine to those on lopinavir/ritonavir-containing regimens observed that premature delivery rates were higher among those with exposure to the latter non–ABC-containing regimen (21% vs. 11.8%; P = 0.004). In multivariate analysis, exposure to lopinavir/ritonavir-containing regimens was associated with a 2-fold higher rate of preterm delivery compared with exposure to ABC/3TC/zidovudine.5
1. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/hiv/pub/ guidelines/arv2013/download/en/. Accessed January 13, 2014. 2. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Bethesda, Maryland: National Institutes of Health. Available at: http:// aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. Accessed January 13, 2014. 3. Heidari S, Mofenson L, Cotton MF, et al. Antiretroviral drugs for preventing mother-to-child transmission of HIV: a review of potential effects on HIV-exposed but uninfected children. J Acquir Immune Defic Syndr. 2011;57:290–296. 4. Chou R, Cantor AG, Zakher B, et al. Screening for HIV in pregnant women: systematic review to update the 2005 U.S. Preventive Services Task Force Recommendation. Ann Intern Med. 2012;157: 719–728. 5. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. 2011;204:506–514. 6. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362: 2282–2294. 7. Ekouevi DK, Coffie PA, Ouattara E, et al. Pregnancy outcomes in women exposed to Efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS databases, Abidjan, Cote d’Ivoire. J Acquir Immune Defic Syndr. 2011;56:183–187. 8. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2013. Wilmington, NC: Registry Coordinating Center. p10; 17-20; 2728; 29-30; 49–50. Issued 12-1-2013. Available at www.apregistry.com. 9. Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program 40th Anniversary Edition Surveillance Report: Reporting Birth Defects Surveillance Data 1968-2003. Birth Defects Research (Part A) 79. 2007;65–93. Erratum: 2008; 82: 41–62. 10. Whitmore SK, Zhang X, Taylor AW, et al. Estimated number of infants born to HIV-infected women in the United States and five dependent areas, 2006. J Acquire Immune Defic Syndr. 2011;57: 218–222. 11. Schuette PH, Rochester GG. Confidence Intervals for Binomial Proportions with Applications to Product Safety Signaling in Drug Exposure Registries. Paper presented at: Joint Statistical Meetings; July 30-August 4, 2011; Miami, Florida. 12. Schuette PH, Jackson MT, Rochester GG. Power and Sample Size for Safety Registries: New Methods Using Confidence Intervals and Sawtooth Power Curves. Paper presented at: useR! The 8th International R User Conference; June 12-15, 2012; Nashville, Tennessee.
364
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
| www.jaids.com
REFERENCES
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
AND
PREVENTION
Abacavir and Lamivudine Exposures During Pregnancy and Non-defect Adverse Pregnancy Outcomes: Data From the Antiretroviral Pregnancy Registry Vani Vannappagari, MBBS, MPH, PhD,*† Nana Koram, PhD, MPH,* Jessica Albano, PhD,‡ Hugh Tilson, MD, DrPH,† and Conway Gee, PhD§
Background: The antiretroviral (ARV) pregnancy registry, an international voluntary registry, provides information on teratogenicity and non-defect adverse pregnancy outcomes.
Methods: We analyzed ARV pregnancy registry prospective singleton pregnancies, estimating frequencies of and risk for nondefect adverse outcomes among HIV-infected women. Prenatal exposures to abacavir (ABC)-containing regimens vs. non-ABC ARV regimens, and lamivudine (3TC)-containing regimens vs. non3TC regimens were compared. Results: Of 2006 outcomes with prenatal ABC exposure, 95.6% were live births; 4.4% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had low birth weight (LBW); 11.9% were preterm births. Relative risks comparing exposure to ABC vs. non-ABC ARV regimens were spontaneous abortions 0.92 [95% confidence interval (CI): 0.66 to 1.27], induced abortions 0.84 (95% CI: 0.59 to 1.21), stillbirths 0.59 (95% CI: 0.35 to 1.00), preterm births 0.96 (95% CI: 0.84 to 1.09), and LBW 1.00 (95% CI: 0.90 to 1.13). Of 11,211 outcomes with prenatal 3TC exposure, 95.3% were live births; 4.7% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had LBW; 11.9% were preterm births. The relative risks comparing exposure to 3TC vs. non-3TC ARV regimens were spontaneous abortions 0.63 (95% CI: 0.50 to 0.80), induced abortions 0.54 (95% CI: 0.43 to 0.69), stillbirths 1.25 (95% CI: 0.86 to 1.80), preterm births 0.86 (95% CI: 0.77 to 0.95), and LBW 1.02 (95% CI: 0.93 to 1.12).
Received for publication April 29, 2014; accepted October 10, 2014. From the *Epidemiology and Real world Evidence, ViiV Healthcare, Research Triangle Park, NC; †Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; ‡INC Research, Post Approval and Strategic Services, Raleigh, NC; and §INC Research, Biostatistics, Wilmington, NC. Presented at the 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013, Atlanta, GA. V.V. is an employee of ViiV Healthcare, a joint venture between GlaxoSmithKline and Pfizer. N.K. is an employee of GlaxoSmithKline. V.V. owns GlaxoSmithKline stock. J.A. and C.G. are salaried employees of INC Research, the coordinating center for the Antiretroviral Pregnancy Registry. H.T. is a member of the Antiretroviral Pregnancy Registry Steering Committee and consults with individual sponsors, including GlaxoSmithKline. Correspondence to: Vani Vannappagari, MBBS, MPH, PhD, Epidemiology and Real world Evidence, ViiV Healthcare, 5 Moore Drive, Mail Stop: 5.4300.4B, PO Box 13398, Research Triangle Park, NC 27709-3398 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Conclusions: ABC-containing and non-ABC ARV regimens have similar risks for non–birth defect adverse pregnancy outcomes. 3TC-containing regimens have lower risk for spontaneous abortions, induced abortions, and preterm births compared with non-3TC ARV regimens, whereas both regimens had similar prevalence and risks for stillbirths and LBW. Key Words: abacavir, lamivudine, pregnancy outcomes, HIV, antiretroviral pregnancy registry (J Acquir Immune Defic Syndr 2015;68:359–364)
INTRODUCTION Current guidelines from the World Health Organization (WHO) suggest that all HIV-positive pregnant and breastfeeding women initiate antiretroviral therapy regardless of CD4 count.1 In the United States, guidelines from the National Institutes of Health recommend that all pregnant women receive combination antiretroviral therapy regardless of disease severity to prevent perinatal transmission of HIV. Both guidelines recommend 3TC as one of the preferred nucleoside reverse transcriptase inhibitors (NRTIs)1,2 and US guidelines recommend abacavir (ABC) as an alternative NRTI.2 Although HIV-positive nonpregnant women are prescribed antiretrovirals (ARVs) most appropriate for their treatment conditions, the decision to continue or switch them to other ARVs during pregnancy is based on the guidelines for ARV use. For providers treating women who are or become pregnant with ARV drugs, teratogenicity and their effect on pregnancy outcomes are the 2 main safety concerns. Results from studies on non–birth defect pregnancy outcomes and ARV use are mixed. Differing results may be attributable to the large number of potential confounding factors (eg, ethnicity, smoking, alcohol or illicit drug use, viral load, or CD4 count).3 There have been 11 recent studies (since 2004) that were summarized in a systematic review that found a reported risk for prematurity, low birth weight (LBW), and other outcomes after in utero exposure to ARV therapy.4 One of these studies was a randomized trial that found that protease inhibitor-based ARV therapy was associated with an increased risk for preterm delivery compared with NRTIbased ARV therapy [odds ratio: 2.0; 95% confidence interval (CI): 1.3 to 3.3].5 These results were supported by 3 prospective observational cohort studies; however, no association was found in 7 other cohort studies, whereas a larger
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
www.jaids.com |
359
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Vannappagari et al
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
cohort study (N = 4943) found that combination therapy regardless of protease inhibitor exposure to be associated with the risk of preterm and very preterm delivery compared with mono or dual therapy.4 In the Mma Bana Study, there was increased risk of prematurity among infants born to women receiving zidovudine/3TC/ritonavir-boosted lopinavir [relative risk (RR): 1.52; 95% CI: 1.07 to 2.17] compared with zidovudine/3TC/ABC.6 Ekouevi et al7 showed higher rates of infant LBW with prenatal exposure to zidovudine/3TC/ nevirapine started at 24 weeks compared with a short course regimen started between 32 and 36 weeks (RR: 1.81; 95% CI: 1.09 to 3.0). The Antiretroviral Pregnancy Registry (APR) has been monitoring birth defects in pregnant women with ARV exposure for over 20 years. According to its most recent interim report published in December 2013 for data through July 31, 2013, the overall prevalence of birth defects among women with first trimester exposure to any ARV monitored by the APR is 2.9 (95% CI: 2.5 to 3.3).8 This rate is comparable with the birth defect rates 2.72 per 100 live births (95% CI: 2.68 to 2.76; calculated by the APR) reported by the Centers for Disease Control and Prevention’s populationbased comparator, the Metropolitan Atlanta Congenital Defects Program.9 For ABC, sufficient numbers of first trimester exposures have been monitored through the APR to detect at least a 2-fold increase in risk of overall birth defects. No such increases have been detected to date and the prevalence of birth defects with first trimester exposure to ABC is estimated to be 3.0% (95% CI: 2.0 to 4.3).8 For 3TC, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No such increases have been detected to date and the prevalence of birth defects after first trimester exposure to 3TC is estimated to be 3.1% (95% CI: 2.6 to 3.7).8 Details of reported birth defects can be found in the interim report, published biannually, at http://www.apregistry.com/forms/interim_report.pdf. Although 3TC and ABC have been used commonly during pregnancy, and neither have been associated with increased risk for birth defects,8 their effect on non–birth defect pregnancy outcomes has not been well investigated. Since the primary remit of the APR is to monitor for teratogenic effects of the ARVs, the interim report does not include rates for non-defect adverse pregnancy outcomes such as LBW, prematurity, stillbirths, and spontaneous or induced abortions. In this analysis, we examine the risk of non-defect adverse pregnancy outcomes among pregnant women exposed to ABC- and 3TC-containing regimens.
rates with didanosine and nelfinavir compared with its population-based comparators, the Metropolitan Atlanta Congenital Defects Program and the Texas Birth Defects Registry. Although the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients. However, potential limitations of registries such as this should be recognized. The Registry is ongoing. Health care providers are encouraged to report eligible patients to the Registry at www.APRegistry.com.
METHODS
In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of ARV exposure, the Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause.8 The Registry notes modest but statistically significant elevations of overall defect
This is a secondary analysis of data from the APR. The APR is a prospective exposure-registration cohort study, established in January 1989 to detect early signs of major teratogenic effects after exposure to ARV drugs during pregnancy. Registration is voluntary and confidential. The majority of case reports received by the APR are from the United States and its territories (77.7%).8 From among the 66 other countries that the registry has received reports from, 4.3% are from Brazil, 3.8% are from the United Kingdom, 2.4% from Argentina, 3.2% from Uganda, 1.5% from South Africa, and 1.1% are from France.8 Each year the APR enrolls approximately 1300 pregnant women in the United States, representing approximately 15% of the HIV-positive women who give birth to live infants annually in the United States,10 and 200 pregnant women from other countries.8 Health care providers prospectively register pregnant women with prenatal exposures to any ARV before the pregnancy outcome is known. Patients are followed during pregnancy through health care providers who provide information on maternal risk factors and pregnancy outcome. An institutional review board approval was obtained from the Western institutional review board for the protocol to establish the APR and the approval is renewed annually. The APR was granted a waiver from obtaining patient informed consent. The outcome of pregnancy is defined at the time of delivery or fetal loss, or when a defect reported after enrollment is detected on a prenatal test. The registry also receives information on women enrolled in clinical trials and retrospective reports. However, this analysis is restricted to women who were registered prospectively, with singleton deliveries (twins and triplet births were excluded), from January 1, 1989, through July 31, 2013. Gestational weeks were calculated beginning from the first day of the last menstrual period. Where the date of the last menstrual period was not available, the estimated date of delivery was used. If the gestation week was inconsistent with the exposure dates and/or the date of outcome (outside 6 1 week for the first trimester, outside 6 2 weeks for the second and third trimesters), a corrected estimated date of delivery where ultrasound results were available was used. Non-defect adverse pregnancy outcomes included in the analyses are spontaneous abortions, induced abortions, stillbirths, preterm births (,37-week gestation), very preterm births (,32-week gestation), LBW (,2500 g), and very LBW (,1500 g). Spontaneous abortion as defined by the
360
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
The APR Consensus Statement
| www.jaids.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
registry is fetal death or expulsion of products of conception before 20-week gestation. Stillbirth is defined as a fetal death occurring 20-week gestation or greater, or if the gestational age is unknown, a fetus weighing 500 g or more.
Statistical Analysis For APR data through July 31, 2013, we estimated the prevalence of non-defect adverse pregnancy outcomes and calculated RRs and 95% CI for the following: (1) adverse birth outcome cases exposed to ABC-containing regimens compared with those exposed to non-ABC ARV regimens and (2) adverse outcome cases exposed to 3TC-containing regimens compared with those exposed to non-3TC ARV regimens. The analysis was limited to singleton pregnancies, and first trimester exposures were not considered since drug exposure at any point during pregnancy is more relevant. This analysis compared exposure to ABC- or 3TC-containing regimens at any time during pregnancy with exposure to non-ABC or non–3TC-containing regimens. Where appropriate, P values were estimated using either the independent t test or Fisher exact test for continuous and discrete variables, respectively. Unknown or missing values were excluded from the analysis. For spontaneous losses, induced abortions, and
ABC and 3TC Exposures and Birth Outcomes
stillbirths, prevalence was estimated based on the number of pregnancies, with the 95% CI based on the Clopper–Pearson exact binomial method.11,12 For preterm births and LBW, the estimated prevalence was based on the number of live singleton births, and excludes cases with birth defects, and all cases with unknown gestational age or unknown birth weight, respectively. The 95% CIs were also based on the Clopper–Pearson exact binomial method. RRs for ABC and 3TC were calculated for regimens containing ABC vs. regimens excluding ABC, and regimens containing 3TC vs. regimens excluding 3TC, respectively. The 95% CIs for the RRs were based on the normal asymptotic method.
RESULTS Maternal Demographics There were a total of 14,950 prospectively reported pregnancies from HIV-infected women for which outcome is known. Of these, 14,684 were singleton pregnancies and 266 were pregnancies with multiple outcomes that were excluded. Among the 14,684 singleton pregnancies, 2006 had prenatal exposure to ABC-containing regimens; 12,678 had prenatal exposure to non–ABC-containing regimens; 11,211
TABLE 1. Maternal Characteristics: Singleton Prospective Pregnancies by ABC Exposure During Pregnancy Among HIV-Infected Women Reported to the Antiretroviral Pregnancy Registry Through July 31, 2013 With Outcome
No. pregnancies Age, yrs* N Mean (SD) Median (interquartile range) Min–Max Missing Race, n (%)† White Black Hispanic Asian Other Missing CD4+ T-cell categories at start of pregnancy, n (%)† $500/mL 200–499/mL ,200/mL Unknown NA Missing Country of report origin, n (%)† United States Other Missing
Overall
ABC-Containing ARV Regimen
Non-ABC ARV Regimen
14,684
2006
12,678
P 0.2174
14,608 28.2 (6.04) 28.0 (9.0) 13–55 76 (0.5%)
1998 28.3 (6.15) 28.0 (9.0) 13–48 8 (0.4%)
12,610 28.1 (6.03) 28.0 (10.0) 13–55 68 (0.5%)
2272 8682 2915 128 402 285
(15.5) (59.1) (19.9) (0.9) (2.7) (1.9)
232 1400 319 20 21 14
(11.6) (69.8) (15.9) (1.0) (1.0) (0.7)
2040 7282 2596 108 381 271
(16.1) (57.4) (20.5) (0.9) (3.0) (2.1)
4561 6583 2407 77 24 1032
(31.1) (44.8) (16.4) (0.5) (0.2) (7.0)
745 949 251 9 11 41
(37.1) (47.3) (12.5) (0.4) (0.5) (2.0)
3816 5634 2156 68 13 991
(30.1) (44.4) (17.0) (0.5) (0.1) (7.8)
,0.0001
,0.0001
,0.0001 11,872 (80.8) 2808 (19.1) 4 (0.0)
1769 (88.2) 236 (11.8) 1 (0.0)
10,103 (79.7) 2572 (20.3) 3 (0.0)
Percentages are based on the number of pregnancies. *P value is based on the independent t test. †P value is based on the Fisher exact test (x2 test for Race). Analysis does not include NA, unknown, or missing values.
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jaids.com |
361
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Vannappagari et al
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
had prenatal exposure to 3TC-containing regimens; 3473 had prenatal exposure to non–3TC-containing regimens. Tables 1 and 2 describe the maternal characteristics of the ABC and 3TC analysis populations, respectively. Overall, 8.6% of term deliveries ($37 weeks) were LBW ,2500 g.
ABC vs. Non–ABC-Containing Regimens Of the 2006 singleton pregnancy outcomes with prenatal ABC exposure, 95.6% were live births and 4.4% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.2% of infants had LBW and 11.9% were preterm births. Of 12,678 outcomes with prenatal exposure to non-ABC ARV regimens, 94.6% were live births and 5.4% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.1% of infants had LBW and 12.4% were preterm births. Table 3 presents the frequencies of the pregnancy outcomes. Among pregnant women with exposure to ABC-containing regimens, 9.1% of term deliveries ($37 weeks) were LBW ,2500 g; among those with non-ABC ARV exposure, 8.5% of term deliveries were LBW. Table 4 presents the prevalence and 95% CI of spontaneous abortions, induced abortions, still births, preterm
births, and LBW for regimens containing ABC and for regimens excluding ABC. The RR of adverse pregnancy outcomes comparing prenatal exposure to ABC-containing vs. non-ABC ARV regimens were for spontaneous abortions 0.92 (95% CI: 0.66 to 1.27; P = 0.68), induced abortions 0.84 (95% CI: 0.59 to 1.21; P = 0.38), stillbirths 0.59 (95% CI: 0.35 to 1.00; P = 0.05), preterm births 0.96 (95% CI: 0.84 to 1.09; P = 0.57), and LBW 1.00 (95% CI: 0.90 to 1.13; P = 0.94) (Table 4). None of the RRs are statistically significantly different between the 2 groups.
3TC vs. Non–3TC-Containing Regimens Of the 11,211 singleton pregnancy outcomes with prenatal 3TC exposure, 95.3% were live births and 4.7% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 16.2% of infants had LBW and 11.9% were preterm births. Of 3473 outcomes with prenatal exposure to non-3TC ARV regimens, 93.1% were live births and 6.9% resulted in spontaneous abortion, induced abortion, or stillbirth. Among live births without a birth defect, 15.9% of infants had LBW and 13.8% were preterm births (Table 3). Among pregnant women with exposure to 3TC-containing regimens, 8.8% of term
TABLE 2. Maternal Characteristics: Singleton Prospective Pregnancies by 3TC Exposure During Pregnancy Among HIV-Infected Women Reported to the Antiretroviral Pregnancy Registry Through July 31, 2013 With Outcome
No. pregnancies Age, yrs* N Mean (SD) Median (interquartile range) Min–Max Missing Race, n (%)† White Black Hispanic Asian Other Missing CD4+ T-cell categories at start of pregnancy, n (%)† $500/mL 200–499/mL ,200/mL Unknown NA Missing Country of report origin, n (%)† United States Other Missing
Overall
3TC-Containing ARV Regimen
Non-3TC ARV Regimen
14,684
11,211
3473
14,608 28.2 (6.04) 28.0 (9.0) 13–55 76 (0.5%)
11,159 28.0 (6.03) 28.0 (10.0) 13–48 52 (0.5%)
3449 28.6 (6.08) 28.0 (9.0) 13–55 24 (0.7%)
2272 8682 2915 128 402 285
(15.5) (59.1) (19.9) (0.9) (2.7) (1.9)
1789 6775 2192 96 275 84
(16.0) (60.4) (19.6) (0.9) (2.5) (0.7)
483 1907 723 32 127 201
(13.9) (54.9) (20.8) (0.9) (3.7) (5.8)
4561 6583 2407 77 24 1032
(31.1) (44.8) (16.4) (0.5) (0.2) (7.0)
3488 5067 1655 51 20 930
(31.1) (45.2) (14.8) (0.5) (0.2) (8.3)
1073 1516 752 26 4 102
(30.9) (43.7) (21.7) (0.7) (0.1) (2.9)
P ,0.0001
,0.0001
,0.0001
,0.0001 11,872 (80.8) 2808 (19.1) 4 (0.0)
8880 (79.2) 2328 (20.8) 3 (0.0)
2992 (86.2) 480 (13.8) 1 (0.0)
Percentages are based on the number of pregnancies. *P value is based on the independent t test. †P value is based on the Fisher exact test (x2 test for Race). Analysis does not include NA, unknown, or missing values.
362
| www.jaids.com
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
ABC and 3TC Exposures and Birth Outcomes
TABLE 3. Pregnancy Outcomes: ABC vs. Non-ABC ARV and 3TC vs. Non-3TC ARV Exposed, Reported to the Antiretroviral Pregnancy Registry, Prospective Data Through July 31, 2013 Birth Outcomes Live births Spontaneous abortions Stillbirths Induced abortions Total adverse birth outcomes* Birth weight ,2500 g ,1500 g Unknown Gestational age ,37 wk ,32 wk Unknown
Regimens Containing ABC (%)
Regimens Excluding ABC (%)
Regimens Containing 3TC (%)
Regimens Excluding 3TC (%)
1918 (95.6) 40 (2.0) 15 (0.7) 33 (1.6) 88 (4.4) N = 1781† 288 (16.2) 28 (1.6) 84 N = 1860‡ 221 (11.9) 35 (1.9) 5
11,993 (94.6) 276 (2.2) 161 (1.3) 248 (2.0) 685 (5.4) N = 10,771† 1735 (16.1) 232 (2.2) 886 N = 11,634‡ 1442 (12.4) 256 (2.2) 23
10,679 (95.3) 212 (1.9) 141 (1.3) 179 (1.6) 532 (4.7) N = 9557† 1548 (16.2) 192 (2.0) 812 N = 10,351‡ 1228 (11.9) 206 (2.0) 18
3232 (93.1) 104 (3.0) 35 (1.0) 102 (2.9) 241 (6.9) N = 2995† 475 (15.9) 68 (2.3) 158 N = 3143‡ 435 (13.8) 85 (2.7) 10
Percentages are based on the total outcomes in the respective analysis. Bold values indicate the totals for overall adverse event. *Total adverse birth outcomes include still births, spontaneous, or induced abortions, and exclude birth defects in live births. †Excludes cases with unknown birth weight. ‡Excludes cases with unknown gestational age.
deliveries ($37 weeks) were LBW ,2500 g; among those with non-3TC ARV exposure, 7.9% of term deliveries were LBW. Table 4 presents the prevalence and 95% CI of spontaneous abortions, induced abortions, still births, preterm births, and LBW for regimens containing 3TC and for regimens excluding 3TC. Statistically significant lower risk
of adverse pregnancy outcomes was observed for prenatal exposure to 3TC-containing regimens compared with non-3TC ARV regimens for spontaneous abortions (RR: 0.63; 95% CI: 0.50 to 0.80; P , 0.01), induced abortions (RR: 0.54; 95% CI: 0.43 to 0.69; P , 0.01), and preterm births (RR: 0.86; 95% CI: 0.77 to 0.95; P , 0.01). The risk for stillbirths (RR: 1.25, 95% CI: 0.86 to 1.80; P = 0.28) and LBW (RR: 1.02; 95% CI:
TABLE 4. Prevalence and Relative Risk of Non-defect Adverse Birth Outcomes: ABC vs. Non-ABC ARV and 3TC vs. Non-3TC ARV, Reported to the Antiretroviral Pregnancy Registry, Prospective Data Through July 31, 2013 ABC vs. Non–ABC-Containing ARV Regimen ABC Spontaneous abortions* Prevalence (95% CI) RR (95% CI)† Induced abortions* Prevalence (95% CI) RR (95% CI)† Stillbirths* Prevalence (95% CI) RR (95% CI)† Preterm births (,37 wk)‡ Prevalence (95% CI) RR (95% CI)† LBW (,2500 g)§ Prevalence (95% CI) RR (95% CI)†
Non-ABC
3TC vs. Non–3TC-Containing ARV Regimen 3TC
Non-3TC
1.99% (1.43 to 2.71) 2.18% (1.93 to 2.45) 0.92 (0.66 to 1.27); P = 0.6787
1.89% (1.65 to 2.16) 2.99% (2.45 to 3.62) 0.63 (0.50 to 0.80); P = 0.0002
1.65% (1.14 to 2.30) 1.96% (1.72 to 2.21) 0.84 (0.59 to 1.21); P = 0.3809
1.60% (1.37 to 1.85) 2.94% (2.40 to 3.55) 0.54 (0.43 to 0.69); P # 0.0001
0.75% (0.42 to 1.23) 1.27% (1.08 to 1.48) 0.59 (0.35 to 1.00); P = 0.0464
1.26% (1.06 to 1.48) 1.01% (0.70 to 1.40) 1.25 (0.86 to 1.80); P = 0.2839
11.88% (10.45 to 13.44) 12.39% (11.80 to 13.01) 0.96 (0.84 to 1.09); P = 0.5688
11.86% (11.25 to 12.50) 13.84% (12.65 to 15.10) 0.86 (0.77 to 0.95); P = 0.0036
16.17% (14.49 to 17.96) 16.11% (15.42 to 16.82) 1.00 (0.90 to 1.13); P = 0.9445
16.20% (15.46 to 16.95) 15.86% (14.57 to 17.22) 1.02 (0.93 to 1.12); P = 0.6694
*Prevalence is based on the number of pregnancies. 95% CI is based on the exact binomial (Clopper–Pearson) method. †Relative risk—regimens containing ABC vs. regimens excluding ABC and regimens containing 3TC vs. regimens excluding 3TC. The 95% CI is based on the normal asymptotic method. P value is based on the Fisher exact test. ‡Prevalence is based on the number of live singleton births—excludes cases with defects and cases with unknown gestational age. 95% CI is based on the exact binomial (Clopper– Pearson) method. §Prevalence is based on the number of live singleton births—excludes cases with defects and cases with unknown birth weight. 95% CI is based on the exact binomial (Clopper– Pearson) method.
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jaids.com |
363
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 68, Number 3, March 1, 2015
Vannappagari et al
0.93 to 1.12; P = 0.67) was not statistically significantly different between the 2 groups (Table 4).
DISCUSSION
CONCLUSIONS ABC and 3TC both currently have US Federal Drug Administration Pregnancy Category C status, that is, their use in pregnancy is recommended only if the potential benefits outweigh the potential risks. Our data found that there is no difference in the observed risk for non-defect adverse pregnancy outcomes after exposure to ABC compared with exposure to non-ABC regimens. In addition, 3TC-containing regimens seem to have lower risk for spontaneous abortions, induced abortions, and preterm births when compared with non–3TC-containing regimens. These findings may be helpful to physicians considering treatment in women at higher risk for these non-defect outcomes.
Data on the effect of specific ARV use on non-defect adverse birth outcomes are limited as most published literature in this area is focused on birth defects. These analyses show that ABC-containing regimens and non–ABCcontaining regimens have similar prevalence and risks for non-defect adverse pregnancy outcomes. 3TC-containing regimens were found to have lower prevalence and risk for spontaneous abortions, induced abortions, and preterm births compared with non–3TC-containing regimens, whereas both groups had similar prevalence and risks for stillbirths and LBW. A potential limitation of this study is that non–3TCcontaining regimens include emtricitabine, an ARV that is similar to 3TC; thus were there a class effect, those in the comparison group with emtricitabine exposures would cause regression to the mean, thus diminishing any difference that would be detected. Although the number of pregnancies included in the analyses is large, potential confounders like disease status (incompletely ascertained by the APR) and unmeasured confounders (non-ARV drug factors like concomitant drugs, illicit drug use, alcohol, and tobacco use) are not measured and adjusted for in the analyses. Unmeasured confounders could also include health-related behaviors such as maternal body mass index. Non–birth defect pregnancy outcomes are not the primary objective of the APR or interest of the reporting provider, resulting in potential underascertainment of the pregnancy outcomes investigated in these analyses. Differential ascertainment due to voluntary reporting and observational nature of the APR cannot be ruled out. Because of voluntary reporting, the pregnancy loss rate in the APR is difficult to interpret, and reporting of pregnancy losses, may be further subject to selection bias. This may account for the low rate of spontaneous and induced abortions and still births observed in this study. There is also the potential for reporting bias due to cultural or legal constraints in nations where induced abortions are illegal, and thus may be reported as spontaneous abortions. Although published literature on non-defect adverse birth outcomes is conflicting, the Mma Bana study6 conducted in Botswana comparing pregnant women on ABC/ 3TC/zidovudine to pregnant women on 3TC/zidovudine + lopinavir/ritonavir found that prematurity was less common among those on the ABC-containing regimen compared with those on the non–ABC-containing regimen. However, the proportion of infants with LBW did not differ significantly by group.6 These results are similar to those noted in this study for ABC. A secondary study based on the same population as that for the Mma Bana study comparing patients on ABC/ 3TC/zidovudine to those on lopinavir/ritonavir-containing regimens observed that premature delivery rates were higher among those with exposure to the latter non–ABC-containing regimen (21% vs. 11.8%; P = 0.004). In multivariate analysis, exposure to lopinavir/ritonavir-containing regimens was associated with a 2-fold higher rate of preterm delivery compared with exposure to ABC/3TC/zidovudine.5
1. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/hiv/pub/ guidelines/arv2013/download/en/. Accessed January 13, 2014. 2. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Bethesda, Maryland: National Institutes of Health. Available at: http:// aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. Accessed January 13, 2014. 3. Heidari S, Mofenson L, Cotton MF, et al. Antiretroviral drugs for preventing mother-to-child transmission of HIV: a review of potential effects on HIV-exposed but uninfected children. J Acquir Immune Defic Syndr. 2011;57:290–296. 4. Chou R, Cantor AG, Zakher B, et al. Screening for HIV in pregnant women: systematic review to update the 2005 U.S. Preventive Services Task Force Recommendation. Ann Intern Med. 2012;157: 719–728. 5. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. 2011;204:506–514. 6. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362: 2282–2294. 7. Ekouevi DK, Coffie PA, Ouattara E, et al. Pregnancy outcomes in women exposed to Efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS databases, Abidjan, Cote d’Ivoire. J Acquir Immune Defic Syndr. 2011;56:183–187. 8. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2013. Wilmington, NC: Registry Coordinating Center. p10; 17-20; 2728; 29-30; 49–50. Issued 12-1-2013. Available at www.apregistry.com. 9. Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program 40th Anniversary Edition Surveillance Report: Reporting Birth Defects Surveillance Data 1968-2003. Birth Defects Research (Part A) 79. 2007;65–93. Erratum: 2008; 82: 41–62. 10. Whitmore SK, Zhang X, Taylor AW, et al. Estimated number of infants born to HIV-infected women in the United States and five dependent areas, 2006. J Acquire Immune Defic Syndr. 2011;57: 218–222. 11. Schuette PH, Rochester GG. Confidence Intervals for Binomial Proportions with Applications to Product Safety Signaling in Drug Exposure Registries. Paper presented at: Joint Statistical Meetings; July 30-August 4, 2011; Miami, Florida. 12. Schuette PH, Jackson MT, Rochester GG. Power and Sample Size for Safety Registries: New Methods Using Confidence Intervals and Sawtooth Power Curves. Paper presented at: useR! The 8th International R User Conference; June 12-15, 2012; Nashville, Tennessee.
364
Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
| www.jaids.com
REFERENCES
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
