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.

Abstract and Introduction

Abstract

Background: Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive.
Methods: A total of 2202 human immunodeficiency virus (HIV)-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219 C protocols before 1 year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects.
Results: A total of 117 live-born children had birth defects for a prevalence of 5.3% (95% confidence interval [CI]: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure (adjusted odds ratio [aOR] = 4.31 [95% CI: 1.56, 11.86]). Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected (aOR = 0.24 [95% CI: 0.08, 0.69]), while a higher risk of heart defects was found (aOR = 2.04 [95% CI: 1.03, 4.05]).
Conclusions: The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents, including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents.

Introduction

Since 1998, the US Public Health Service has recommended the use of combination antiretroviral therapy (ARV) to prevent mother-to-child human immunodeficiency virus (HIV) transmission.^[1] Because zidovudine and other nucleoside analogues can affect nuclear and mitochondrial deoxyribonucleic acid replication, the safety of in utero exposure to these drugs is of concern.^[2] In addition, there is inadequate fetal and neonatal safety data for non-nucleoside analogues and protease inhibitors. Efavirenz, a non-nucleoside analogue, is considered a potential teratogen on the basis of animal data and case reports.^[1,3–6]

While existing data on in utero ARV exposure and birth defects have been mostly reassuring,^[7–9] some studies have reported elevated risks with specific exposures;^[10,11] others have been limited by small sample size or possible confounding. The US Woman and Infants Transmission Study documented a birth defect rate of 3.56 per 100 live births in 2527 infants born to HIV-infected women from 1990 through 2000,^[12] which was not significantly different than the rate major of defects of 2.76 per 100 live births in the general pediatric population estimated by the Metropolitan Atlanta Congenital Defects Program (MACDP).^[11] However, first trimester zidovudine exposure was significantly associated with an increased risk of hypospadias among male infants. The US Antiretroviral Pregnancy Registry (APR) estimated an overall prevalence of defects of 2.9% (95% confidence interval [CI]: 2.4, 3.5) among greater than 4300 first trimester ARV exposed children, which did not differ from the rate among children exposed in later trimesters.^[13] The Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C provided an opportunity to further estimate the independent association between in utero ARV exposure, including newer agents, and birth defects.

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Abstract and Introduction
Methods
Results
Discussion
References

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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