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.

Methods

Study Population

The source population was children enrolled in PACTG protocols 219 and 219C, a multisite US cohort of children born to HIV-infected women initiated to study the long-term effects of in utero ARV exposure and complications of pediatric HIV infection.^[14] Protocol 219 followed HIV-infected and HIV-uninfected perinatally exposed children at clinics across the United States from May 1993 through August 2000. Children currently or previously enrolled in another PACTG protocol and children whose mothers were enrolled in a PACTG perinatal protocol during pregnancy were eligible. In September 2000, a revised protocol was initiated, PACTG 219C, and the eligibility criterion mandating enrollment in another PACTG protocol was removed. The present study was restricted to children enrolled in 219 or 219C before 1 year of age to improve the accuracy of birth defect information recorded on protocol case report forms. The study was approved by site institutional review boards, and parents or guardians provided informed consent.

Data Collection

Study visits, which included physical examinations, were scheduled every 3 months for HIV-infected children, and every 6 months until 2 years of age (protocol 219), or every 3 months through 1 year of age (protocol 219C) and annually thereafter for HIV-uninfected children. Protocol 219 did not include a direct question regarding the presence of defects, but birth defects were a primary outcome and were recorded on diagnosis case report forms. Protocol 219C included a direct question regarding birth defects. Detailed data on birth defects also were collected in PACTG perinatal protocols 076, 185, 249, 250, 316, 332, 353, 354, 358, and 386 and the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) protocol P1025. Forty-two percent of mother-infant pairs in protocol 219 and 219C participated in one of these perinatal protocols during pregnancy-gestation; these data were used to supplement 219 and 219C data.

Exposure

Gestational age at birth was estimated from the date of last menstrual period, ultrasound measurement before 22 weeks gestation, or newborn examination. Trimesters were defined as first trimester, conception to <14 weeks gestation; second trimester, 14 weeks to <28 weeks gestation; and third trimester, 28 weeks to delivery. The primary determinant was first trimester in utero ARV exposure. We considered overall ARV exposure, ARV classes, and specific ARV agents to which at least 1 child with a birth defect was exposed in the first trimester. The reference group consisted of children unexposed to the particular ARV drug (or class) during the first trimester, and thus included ARV unexposed children, children exposed to ARV in labor only, children unexposed to the particular ARV drug but to other ARV, and children exposed to the particular ARV drug in the second and/or third trimester only.^[15] We also examined ARV exposure by trimester of first exposure (unexposed, first trimester, second or third trimester); however, since the first trimester estimates were substantially unchanged in this model from the former classification, results from the more parsimonious models were presented.

Outcome

The outcome was the presence of a birth defect documented within the first year of life. Clinicians blinded to ARV exposure reviewed and classified the reported defects according to the MACDP guidelines as major defects or conditional defects.^[16] To further prevent misclassification, we followed a modified version of MACDP guidelines employed by the APR,^[13] in which children with 2 or more conditional defects in the absence of a major defect were considered a case. Therefore, a child with at least 1 major defect or at least 2 conditional defects in the absence of a major defect was considered a case. Children classified as having birth defects solely based on conditional MACDP defects were categorized separately from those with major defects.

Statistical Analysis

The prevalence and exact 95% CI of birth defects per 100 live births was estimated overall, by cohort (219 vs. 219C), and infant HIV-infection status. Differences in birth defect prevalence across these and other characteristics were assessed using the χ² test, Fisher exact test, and Cochran-Armitage trend test for categorical variables, and the Wilcoxon rank sum test for continuous variables. Logistic regression models were used to estimate associations between first trimester in utero ARV exposure of any drug and of specific drugs and the most common categories of birth defects (all birth defects, musculoskeletal defects, and heart defects), including both HIV-infected and uninfected children. Potential confounders with a P < 0.25 in univariate analysis were initially included in adjusted models, but only those that produced at least a 10% change in the estimated odds ratio were retained in final models. Children with recognized chromosomal abnormalities or congenital infections such as toxoplasmosis were excluded from regression analyses.

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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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