Birth Defects among Children Born to Human Immunodeficiency Virus-infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

Susan B. Brogly, PhD; Mark J. Abzug, MD; D. Heather Watts, MD; Coleen K. Cunningham, MD; Paige L. Williams, PhD; James Oleske, MD; Daniel Conway, MD; Rhoda S. Sperling, MD; Hans Spiegel, MD; Russell B. Van Dyke, MD

Disclosures

Pediatr Infect Dis J. 2010;28(8):721-727.

Results

Of 5931 children in protocols 219 and 219C, 2202 enrolled by 1 year of age and constituted the study population. Following clinical review of birth defects according to MACDP guidelines, 117 children had at least 1 defect, 103 with at least 1 major defect, and 14 with 2 or more conditional defects but no major defect. Among these 117 children, 77 had 1 birth defect, 30 had 2 birth defects, 6 had 3 birth defects, and 4 had 4 birth defects. Overall defect prevalence was 5.3% (95% CI: 4.4, 6.3) including all 117 cases, and was 4.7% (95% CI: 3.8, 5.6) including 103 cases with major defects. Prevalence was 4.9% (95% CI: 2.6, 8.2) and 5.4% (95% CI: 4.4, 6.5) in HIV-infected and HIV-uninfected/indeterminate children (Table 1), respectively, and was 4.8% (95% CI: 3.7, 6.1) in first trimester unexposed children, and 5.8% (95% CI: 4.2, 7.8) in first trimester ARV exposed children (Table 2).

The majority of defects occurred in the heart and musculoskeletal system (Table, Supplemental Digital Content 1, https://links.lww.com/INF/A514). Prevalence was significantly higher among children whose mother had participated in a PACTG study during pregnancy and increased with increasing maternal age (Table 1). Prevalence also was higher among males and children with first trimester folate antagonist exposure (ie, trimethoprim/sulfamethoxazole), although these differences were not statistically significant, and folate antagonist exposure was unavailable for over half of the children. There was no difference in defect prevalence by highest log₁₀ median maternal HIV viral load (3.4 copies/mL [children with defects] vs. 3.5 copies/mL [children without defects]), or lowest median maternal CD4 count (360 cell/mL [children with defects] vs. 372 cells/mL [children without defects]) during pregnancy. Defect prevalence significantly differed by protocol: rates were 6.8% (95% CI: 5.2, 8.7) and 4.4 (95% CI: 3.3, 5.6) for children enrolled in protocol 219 (whether or not in 219C) and in 219C alone. Figure, Supplemental Digital Content 2, https://links.lww.com/INF/A513, shows the prevalence of birth defects by year of birth; 1992 and 2006 were excluded because of the small number of children born in these years. No overall difference in prevalence by year of birth was identified.

The unadjusted and adjusted estimates between first trimester in utero ARV exposure and birth defects are shown in Table 2. In unadjusted analyses, there was no significant association with overall first trimester ARV exposure or first trimester exposure to specific drug classes. However, significantly more children with birth defects were exposed to efavirenz in the first trimester. The mothers of all 5 cases were taking efavirenz at the time of conception and 3 stopped efavirenz around the time pregnancy would have been identified; the other 2 mothers stopped efavirenz in the second trimester. All mothers of the 5 efavirenz-exposed children with defects also were receiving lamivudine plus other ARV. The defects of these efavirenz exposed children included laryngomalacia (N = 1), meningomyelocele with Arnold-Chiari Malformation Type II (N = 1), hypospadias (N = 1), varus feet and hypertonicity of extremities (N = 1), and cleft palate (N = 1).

The rate of birth defects also was higher in children exposed to lopinavir/ritonavir in the first trimester than in children unexposed to lopinavir/ritonavir in the first trimester. The defects of the 6 lopinavir/ritonavir exposed children included hydronephrosis (N = 1), supernumerary nipple and umbilical hernia (N = 1), atrial septal defect (N = 1), pyloric stenosis (N = 2), and ventricular septal defect and hemangioma (N = 1). None of the children with defects were exposed to both efavirenz and lopinavir/ritonavir in the first trimester.

In models adjusted for first trimester folate antagonist exposure, year of birth, and perinatal study participation, the association with efavirenz persisted while the association with lopinavir/ritonavir was marginally significant (P = 0.07). To further explore possible confounding, we examined maternal and infant characteristics by perinatal protocol participation (data not shown). In models adjusted for year of birth, participation in a perinatal protocol was higher among infants with first trimester exposure to any ARV (Odd ratio [OR] = 1.47, 95% CI: 1.21, 1.79) and to any nucleoside analogue (OR = 1.48, 95% CI: 1.22, 1.80), and was lower among infants with first trimester exposure to any non-nucleoside analogue (OR = 0.57, 95% CI:0.38, 0.85). However, other characteristics generally were in the direction of a higher possible risk of defects in those who did not participate in a perinatal protocol (eg, more mothers <20 and >30 years of age, more maternal cocaine use, lower infant birth weights, more preterm births, and more HIV-infected infants) except for maternal alcohol use, which was higher among perinatal study participants.

We also examined associations between in utero ARV exposure and the most common categories of specific defects: musculoskeletal and heart (Table, Supplemental Digital Content 1, https://links.lww.com/INF/A514). Because of the lower number of cases (N = 36 and 34, respectively),^[2] these models were only adjusted for perinatal protocol participation and first trimester folate antagonist exposure. Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected in unadjusted (OR = 0.30, 95% CI: 0.10, 0.84) and adjusted models (OR = 0.24, 95% CI: 0.08, 0.69). Protective effects on musculoskeletal defects also were found with overall first trimester ARV exposure and any first trimester nucleoside analogue exposure in adjusted models. These latter findings appeared to be driven by zidovudine exposure; the frequency of exposure was similar for any ARV, for any nucleoside analogue, and for zidovudine. In contrast, significantly more children with heart defects—MACDP category of heart, other, which excludes conotruncal and obstructive defects (Table, Supplemental Digital Content 1, https://links.lww.com/INF/A514) were exposed to zidovudine in the first trimester in unadjusted (OR = 2.11, 95% CI: 1.07, 4.16) and adjusted models (OR = 2.04, 95% CI: 1.03, 4.05). This association was marginally significant when conotruncal and obstructive defects were included (OR = 1.78, 95% CI: 0.93, 3.40, P = 0.08).

To examine possible selection bias, we assessed enrollment into 219 and 219C of children who participated in PACTG 076, 316 or IMPAACT P1025 by defect status and in utero ARV exposure. These latter 3 studies were examined because birth defect information was collected and reviewed in these studies by the 076, 316, and P1025 investigators. It should be noted that 74% of children in 219 and 219C who participated in a perinatal protocol were in one of these studies. Among children who participated in PACTG 076, 316 or IMPAACT P1025, more children with defects (31.2%) than without defects (24.8%) enrolled in protocols 219 and 219C (P = 0.054). However, the only important differences in enrollment by defect status and in utero ARV exposure were among children without defects: enrollment was higher among children unexposed to abacavir (17.0% exposed vs. 25.2% unexposed enrolled, P = 0.048), and exposed to saquinavir (44.4% exposed vs. 24.6% unexposed enrolled, P = 0.018). This differential enrollment among children without defects would increase and decrease estimated associations with abacavir and saquinavir exposure, respectively. No other evidence of selection bias was identified.

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Table 1. Prevalence of at Least One Major or at Least 2 Conditional Birth Defects by Infant Characteristic of Children in PACTG Protocols 219 and 219C
Characteristic	Birth Defect (N = 117)		No Defect (N = 2085)		P*
Characteristic	N	%	N	%	P*
HIV infection status
Infected	13	4.9	254	95.1	0.58
Uninfected	104	5.4	1814	94.6
Indeterminate	0	0	17	100
Sex
Female	50	4.5	1061	95.5	0.09
Male	67	6.1	1024	93.9
Race/ethnicity
Non-Hispanic white	17	7.5	209	92.5	0.30
Non-Hispanic black	58	4.6	1199	95.4
Hispanic	38	5.7	633	94.3
Other	1	4.0	24	96.0
Unknown	3	13.0	20	87.0
Year of birth
1992–1996	26	5.4	454	94.6	0.24
1997–2001	54	6.2	820	93.8
2002–2006	37	4.4	811	95.6
Protocol
219 ± 219C	58	6.8	794	93.2	0.013
219C only	59	4.4	1291	95.6
Earliest year of enrollment in 219 or 219C
1993–1996	23	5.5	394	94.5	0.037
1997–2000	40	7.3	507	92.7
2001–2006	54	4.4	1184	95.6
Enrolled in perinatal study during gestation
Yes	76	8.3	838	91.7	<0.0001
No	41	3.2	1247	96.8
Maternal age at birth (yr)
<20	5	3.5	138	96.5	0.049
20–<25	23	4.6	474	95.4
25–<30	32	5.7	534	94.4
30–<35	27	5.4	472	94.6
≥35	21	7.1	274	92.9
Unknown	9	4.5	193	95.5
Gestational age at birth (wk)
<32	6	12.0	44	88.0	0.33
32–<37	18	6.3	268	93.7
≥37	65	6.8	892	93.2
Unknown	28	3.1	881	96.9
Birth weight (g)
<2500	28	7.0	370	93.0	0.10
≥2500	89	5.0	1706	95.0
Unknown	0	0	9	100
First trimester in utero folate antagonist exposure
Unexposed	68	8.0	785	92.0	0.08
Exposed	7	16.3	36	83.7
Unknown	42	3.2	1264	96.8
In utero alcohol exposure
Unexposed	41	5.3	732	94.7	0.25
Exposed	16	7.4	201	92.6
Unknown	60	5.0	1152	95.0
In utero tobacco exposure
Unexposed	35	5.3	621	94.7	0.44
Exposed	20	6.6	284	93.4
Unknown	62	5.0	1180	95.0
In utero marijuana exposure
Unexposed	49	6.1	760	93.9	0.18
Exposed	5	3.3	145	96.7
Unknown	63	5.1	1180	94.9
In utero cocaine exposure
Unexposed	47	5.9	754	94.1	0.38
Exposed	8	4.2	181	95.8
Unknown	62	5.1	1150	94.9
In utero heroin exposure
Unexposed	51	5.6	852	94.4	1.00
Exposed	3	5.0	57	95.0
Unknown	63	5.1	1176	94.9
In utero methadone exposure
Unexposed	54	5.7	890	94.3	0.43
Exposed	4	8.5	43	91.5
Unknown	59	4.9	1152	95.1

*P value from χ² test, Fisher exact test (in utero heroin exposure), or Cohrane-Armitage trend test (maternal age); subjects with unknown data excluded.
PACTG indicates Pediatric AIDS Clinical Trials Group.

Table 2. Prevalence and Odds Ratio of at Least 1 Major or at Least 2 Conditional Birth Defects According to First Trimester in Utero ARV Exposure Among Children in Protocols 219 and 219C*
First Trimester in Utero Exposure	Birth Defect (N = 105)		No Defect (N = 1928)		Unadjusted OR (95% CI)	Adjusted OR (95% CI)†
First Trimester in Utero Exposure	N	%	N	%	Unadjusted OR (95% CI)	Adjusted OR (95% CI)†
Any antiretroviral
Unexposed‡	61	4.8	1209	95.2	Ref.	Ref.
Exposed	44	5.8	719	94.2	1.21 (0.81, 1.81)	1.10 (0.72, 1.67)
Nucleoside/nucleotide analogues
Unexposed	61	4.8	1218	95.2	Ref.	Ref.
Exposed	44	5.8	710	94.2	1.24 (0.83, 1.84)	1.12 (0.73, 1.69)
Abacavir
Unexposed	100	5.1	1854	94.9	Ref.	Ref.
Exposed	5	6.3	74	93.7	1.25 (0.50, 3.17)	1.50 (0.57, 3.96)
Didanosine
Unexposed	104	5.2	1882	94.8	Ref.	Ref.
Exposed	1	2.1	46	97.9	0.39 (0.05, 2.88)	0.34 (0.05, 2.57)
Lamivudine
Unexposed	69	4.7	1394	95.3	Ref.	Ref.
Exposed	36	6.3	534	93.7	1.36 (0.90, 2.06)	1.37 (0.87, 2.16)
Stavudine
Unexposed	95	5	1814	95	Ref.	Ref.
Exposed	10	8.1	114	91.9	1.68 (0.85, 3.30)	1.53 (0.76, 3.09)
Tenofovir
Unexposed	101	5.1	1887	94.9	Ref.	Ref.
Exposed	4	8.9	41	91.1	1.82 (0.64, 5.19)	1.39 (0.45, 4.34)
Zidovudine
Unexposed	72	5	1356	95	Ref.	Ref.
Exposed	33	5.5	572	94.5	1.09 (0.71, 1.66)	0.98 (0.64, 1.52)
Non nucleoside analogues
Unexposed	97	5.1	1794	94.9	Ref.	Ref.
Exposed	8	5.6	134	94.4	1.10 (0.53, 2.32)	1.46 (0.67, 3.16)
Efavirenz
Unexposed	100	5	1901	95	Ref.	Ref.
Exposed	5	15.6	27	84.4	3.52 (1.33, 9.34)	4.31 (1.56, 11.86)
Nevirapine
Unexposed	100	5.2	1815	94.8	Ref.	Ref.
Exposed	5	4.2	113	95.8	0.80 (0.32, 2.01)	1.05 (0.41, 2.70)
Protease inhibitors
Unexposed	82	4.9	1598	95.1	Ref.	Ref.
Exposed	23	6.5	330	93.5	1.36 (0.84, 2.19)	1.36 (0.81, 2.28)
Indinavir
Unexposed	101	5.1	1879	94.9	Ref.	Ref.
Exposed	4	7.5	49	92.5	1.52 (0.54, 4.29)	1.50 (0.51, 4.35)
Lopinavir/ritonavir
Unexposed	99	5	1886	95	Ref.	Ref.
Exposed	6	12.5	42	87.5	2.72 (1.13, 6.55)	2.46 (0.93, 6.52)
Nelfinavir
Unexposed	92	5.1	1719	94.9	Ref.	Ref.
Exposed	13	5.9	209	94.1	1.16 (0.64, 2.11)	1.23 (0.66, 2.30)
Saquinavir
Unexposed	104	5.2	1899	94.8	Ref.	Ref.
Exposed	1	3.3	29	96.7	0.63 (0.09, 4.67)	0.46 (0.06, 3.49)

*Four children with trisomy 21 and 1 child with congenital toxoplasmosis excluded; 7 and 157 children with and without birth defects excluded due to unknown timing of in utero antiretroviral exposure.
^†Adjusted for participation in a PACTG perinatal study, first trimester folate antagonist exposure and year of birth.
^‡Includes children unexposed to any ARV during gestation (14 children with defects and 272 children without defects) and children exposed to ARV in the second and/or third trimester only.
ARV indicates antiretroviral therapy; OR, Odds Ratio; 95% CI, 95% confidence interval; PACTG, Pediatric AIDS Clinical Trials Group.

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