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.

Discussion

In HIV-uninfected and HIV-infected children enrolled in protocols 219 and 219C by 1 year of age, we documented a birth defect prevalence of 5.3% including all 117 cases, and 4.7% including 103 major cases only. No differences were found according to infant HIV infection status. While we did not detect an association between overall in utero ARV exposure and defects, associations with particular ARV drugs were identified.

Our study is the first to provide evidence of an association between efavirenz and birth defects in a population-based investigation, although the small number of infants with first trimester efavirenz exposure must be considered. Of the 5 children in our study with birth defects and first trimester efavirenz exposure, only 1 had a neural tube defect and has previously been described^[5] and retrospectively reported to the APR. In prospectively reported APR cases, defects were detected in 13 (3.2%) of 407 live births with first trimester efavirenz exposure, which was similar to the overall APR rate; no specific pattern of defects was observed (1 case of meningomyelocele and 1 case of facial cleft with anophthalmia).^[13] However, 3 (15%) of 20 infant cynomolgus monkeys with first trimester efavirenz exposure at levels similar to human exposure had defects (anencephaly and unilateral anophthalmia, micro-ophthalmia, and cleft palate).^[6] We also detected associations between first trimester lopinavir/ritonavir exposure and defects, but this did not remain significant after adjustment for other covariates, perhaps because of low power. Animal studies have not demonstrated teratogenic effects, but have shown delayed skeletal ossification and skeletal variation at maternally toxic doses.^[1]

The rate of birth defects in our cohort was higher than the 2.9% prevalence reported by the APR.^[13] Other US^[12] and European^[8] studies of children born to HIV-infected women have not reported an elevated defect prevalence of birth defects, excluding the PACTG 076 randomized trial in which a rate of major defects of 8% was detected, and all ARV exposure occurred after the first trimester.^[17] It is possible that differential ascertainment across studies could account for the differences. A total of 636 children in our study population had echocardiograms, most per study protocol, and more children with (41%) than without defects (28%) had echocardiograms. Early screening echocardiography can detect important subclinical malformations and produce rates of cardiac defects of 5% to 10% higher than expected.^[18,19] Additionally, children whose mother had participated in a perinatal protocol were more likely to have a birth defect, possibly suggesting differential ascertainment.

To investigate potential selection bias, we examined enrollment into 219 and 219C among children who had participated in perinatal protocols PACTG 076, 316 and IMPAACT P1025. Despite the higher enrollment of children with defects into our cohort, it was nondifferential with respect to most in utero ARV exposures, and importantly, those with which we detected notable associations. Selection bias of our estimated associations between defects and ARV exposure is not of major concern. It should also be noted that IMPAACT P1025 is a cohort study and no ARV was given as part of the protocol;^[20] likewise, in PACTG 316, all women were on clinically indicated ARV and the only randomized component was single-dose nevirapine at labor and delivery.^[21]

To control for possible confounding, models were adjusted for perinatal protocol participation, exposure to folate antagonists, and year of birth. We examined other potential confounders of the association between in utero ARV exposure and birth defects, including maternal drug use, but had incomplete information. Some residual confounding may persist. Finally, because of the large number of ARVs available for use during pregnancy, it is impossible to adjust for all other ARVs when estimating effects of a particular ARV, and this should be considered in weighing the evidence from our study as well as other studies.

It is possible that some associations might have been attenuated if particular defects result from exposure to a particular ARV. We attempted to look at more refined categories of birth defects where power was sufficient. A lower risk of musculoskeletal defects and a higher risk of heart defects were found with first trimester zidovudine exposure. These findings were based on a small number of cases and require confirmation in other studies. An association between first trimester zidovudine exposure and septal heart defects was noted in PACTG protocol 185 and in a German study, although selection bias could not be ruled out.^[13]

A potential limitation of our study is that children, not pregnant women, enrolled in protocols 219 and 219C. Therefore, birth defects resulting in fetal loss were not included. Birth defects in stillbirths occurring after 20 weeks gestation were included in the Women and Infants Transmission Study^[12] and the APR.^[13] If defects caused by a specific exposure resulted in an increase in stillbirths then our estimates would likely be attenuated.

In this US cohort of children born to HIV-infected women, we identified a higher prevalence of birth defects than other studies. Overall, first trimester in utero ARV exposure was not associated with an increased risk of defects. However, some associations with first trimester in utero exposure to particular ARVs were identified. Further study is needed to rule out possible confounding, and to examine associations between ARV exposure and specific birth defects. Practitioners are urged to report all pregnant women receiving ARV during pregnancy to the APR (https://www.APRegistry.com) as early as possible and preferably before the pregnancy outcome is known.

1 2 3 4

Next Section

Supported by the National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632) (to the International Maternal Pediatric Adolescent AIDS Clinical Trials Group [IMPAACT]). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement 5 U01 AI41110 with the PACTG and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID (NIAID) the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9–001/HHSN267200800001C).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Acknowledgments
The following institutions and individuals participated in PACTG Protocols 219 and/or 219C: Baylor Texas Children's Hospital: F. Minglana, M. E. Paul, C. D. Jackson; University of Florida, Jacksonville: M. H. Rathore, A. Khayat, K. Champion, S. Cusic; Chicago Children's Memorial Hospital: R. Yogev, E. Chadwick; University of Puerto Rico, University Children's Hospital AIDS Program: I. Febo-Rodriguez, S. Nieves; Bronx Lebanon Hospital Center; M. Purswani, S. Baksi, E. Stuard, M. Dummit; San Juan Hospital: M. Acevedo, M. Gonzalez, L. Fabregas, M. E. Texidor; University of Miami: G. B. Scott, C. D. Mitchell, L. Taybo, S. Willumsen; University of Medicine & Dentistry of New Jersey: L. Bettica, J. Amour, B. Dashefsky, J. Oleske; Charity Hospital of New Orleans and Earl K. Long Early Intervention Clinic: M. Silio, T. Alchediak, C. Boe, M. Cowie; UCSD Mother, Child & Adolescent HIV Program: S. A. Spector, R. Viani, M. Caffery, L. Proctor; Howard University: S. Rana, D. Darbari, J. C. Roa, P. H. Yu; Jacobi Medical Center: M. Donovan, R. Serrano, M. Burey, R. Auguste; St. Christopher's Hospital for Children, Philadelphia: J. Chen, J. Foster; Baystate Medical Center Children's Hospital: B. W. Stechenberg, D. J. Fisher, A. M. Johnston, M. Toye; Los Angeles County Medical Center/USC: J. Homans, M. Neely, L. S. Spencer, A. Kovacs; Children's Hospital Boston: S. Burchett, N. Karthas; Children's Hospital of Michigan: E. Moore, C. Cromer; St. Jude Children's Research Hospital, Memphis: P. M. Flynn, N. Patel, M. Donohoe, S. Jones; New York University School of Medicine/Bellevue Hospital: W. Borkowsky, S. Chandwani, N. Deygoo, S. Akleh; The Children's Hospital at Downstate: E. Handelsman, H. J. Moallem, D. M. Swindell, J. M. Kaye; The Columbia Presbyterian Medical Center and Cornell University New York Presbyterian Hospital: A. Higgins, M. Foca, P. LaRussa, A. Gershon; The Children's Hospital of Philadelphia: R. M. Rutstein, C. A. Vincent, S. D. Douglas, G. A. Koutsoubis; Children's Hospital of Oakland: A. Petru, T. Courville; UCSF, Moffitt Hospital: D. Wara, D. Trevithick; Children's Hospital, University of Colorado, Denver: E. McFarland, C. Salbenblatt; Johns Hopkins University Pediatrics: N. Hutton, B. Griffith, M. Joyner, C. Kiefner; Children's Hospital and Regional Medical Center, Washington: M. Acker, R. Croteau, C. McLellan, K. Mohan; Metropolitan Hospital Center: M. Bamji, I. Pathak, S. Manwani, E. Patel; Children's National Medical Center: H. Spiegel, V. Amos; University of Massachusetts Medical School: K. Luzuriaga; University of Alabama at Birmingham: R. Pass, M. Crain; University of Maryland Medical Center: J. Farley, K. Klipner; Schneider Children's Hospital: V. R. Bonagura, S. J. Schuval, C. Colter, L. Campbell; Boston Medical Center: S. I. Pelton, A. M. Reagan; University of Illinois: K. C. Rich, K. Hayani, M. Bicchinella; SUNY Stony Brook: S. Nachman, D. Ferraro, S. Madjar; North Broward Hospital District: A. Puga; Duke University: F. Wiley, K. Whitfield, O. Johnson, R. Dizney; Harlem Hospital: S. Champion, M. Frere, M. DiGrado, E. J. Abrams; Cook County Hospital: J. Martinez; University of South Alabama: M. Mancao; Connecticut Children's Medical Center: J. Salazar, G. Karas; University of North Carolina at Chapel Hill: T. Belho, B. Pitkin, J. Eddleman; Ruiz Arnau University Hospital: W. Figueroa, E. Reyes; SUNY Upstate Medical University: L. B. Weiner, K. A. Contello, W. A. Holz, M. J. Famiglietti; Children's Medical Center of Dallas; University of Florida at Gainesville: R. Lawrence, J. Lew, C. Delany, C. Duff; Children's Hospital at Albany Medical Center: A. D. Fernandez, P. A. Hughes, N. Wade, M. E. Adams; Lincoln Medical & Mental Health Center; Phoenix Children's Hospital: J. P. Piatt, J. Foti, L. Clarke-Steffen; Public Health Unit of Palm Beach County: J. Sleasman, C. Delaney; Medical College of Georgia: C. S. Mani; Yale University School of Medicine: W. A. Andiman, S. Romano, L. Hurst, J. de Jesus; Vanderbilt University Medical Center: G. Wilson; University of Rochester Medical Center: G. A. Weinberg, F. Gigliotti, B. Murante, S. Laverty; St. Josephs Hospital and Medical Center, New Jersey: N. Hutchcon, A. Townley; Emory University Hospital: S. Nesheim, R. Dennis; University of South Florida: P. Emmanuel, J. Lujan-Zilberman, C. Graisberry, S. Moore; Children's Hospital of the King's Daughters: R. G. Fisher, K. M. Cunnion, T. T. Rubio, D. Sandifer; Medical University of South Carolina: G. M. Johnson; University of Mississippi Medical Center: H. Gay, S. Sadler; Harbor-UCLA Medical Center: M. Keller, J. Hayes, A. Gagajena, C. Mink; Mount Sinai Medical Center: D. Johnson; Children's Hospital of Los Angeles: J. Church, T. Dunaway, C. Salata; Long Beach Memorial: A. Deveikis, L. Melton; Robert Wood Johnson Medical School: S. Gaur, P. Whitley-Williams, A. Malhotra, L. Cerracchio; Sinai Children's Hospital: M. Dolan, J. D'Agostino, R. Posada; The Medical Center, Pediatric Columbus, Georgia: C. Mani, S. Cobb; Medical College of Virginia: S. R. Lavoie, T. Y. Smith; Cooper Hospital, University Medical Center: A. Feingold, S. Burrows-Clark; University of Cincinnati: J. Mrus, R. Beiting; Columbus Children's Hospital: M. Brady, J. Hunkler, K. Koranyi; Sacred Heart Children's CMS of Florida: W. Albritton; St. Luke's/Roosevelt Hospital Center: R. Warford, S. Arpadi; Incarnation Children's Center, New York: A. Gershon, P. Miller; Montefiore Medical—AECOM: A. Rubinstein, G. Krienik; Children's Hospital of Los Angeles: A. Kovacs and E. Operskalski; San Francisco General Hospital: D. Wara, A. Kamrin, S. Farrales; Cornell University New York Presbyterian: R. Johan-Liang, K. O'Keefe; St. Louis Children's Hospital: K. A. McGann, L. Pickering, G. A. Storch; North Shore University Hospital: S. Pahwa, L. Rodriquez; Oregon Health and Science University: P. Lewis, R. Croteau.

Cite this: Birth Defects among Children Born to Human Immunodeficiency Virus-infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C - Medscape - Aug 01, 2010.

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.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.