Male/Female Differences in Indomethacin Effects in Preterm Infants

MALE/FEMALE DIFFERENCES IN INDOMETHACIN EFFECTS IN PRETERM INFANTS ARNE OHLSSON, MD, ROBIN S. ROBERTS, MSC, BARBARA SCHMIDT, MD, PETER DAVIS, MD, DIANE MODDEMAN, MD, SAROJ SAIGAL, MD, ALFONSO SOLIMANO, MD, MICHAEL VINCER, MD, LINDA WRIGHT, MD, AND THE TRIAL OF INDOMETHACIN PROPHYLAXIS IN PRETERMS (TIPP) INVESTIGATORS

To test whether indomethacin prophylaxis has sex-mediated effects on severe intraventricular hemorrhage (grade III and IV) and on long-term outcomes in extremely-low-birth-weight infants. A secondary analysis was performed in the entire ‘‘Trial of Indomethacin Prophylaxis in Preterms study’’ cohort. The results suggest a weak differential treatment effect of indomethacin by sex. (J Pediatr 2005;147:860-2)

eurologic and developmental disability at 6 years of age after preterm birth before 26 weeks gestation is more common in boys than in girls.1 Sex differences in cerebral volumes of 8-year-olds born preterm indicate that the sex of the very preterm newborn influences the mechanisms by which the developing brain is affected.2 Indomethacin may have sexspecific effects on cerebrovascular reactivity in rats.3 Ment et al4 recently reported a secondary analysis by sex of infants enrolled in a randomized controlled trial of indomethacin to prevent intraventricular hemorrhage (IVH). Indomethacin halved the incidence of IVH, eliminated parenchymal hemorrhage, and was associated with higher verbal scores at 3 to 8 years of age in boys but not girls.4 Edwards5 called for a review of the TIPP (Trial of Indomethacin Prophylaxis in Preterms) data set to confirm or refute these findings.6

N

OBJECTIVE To test whether indomethacin prophylaxis has sex-mediated effects on severe IVH (grade III and IV) and on long-term outcomes in extremely-low-birth-weight infants.

POPULATION The TIPP randomized controlled trial was undertaken to determine whether the prophylactic administration of indomethacin improves survival without neurosensory impairment in extremely-low-birth-weight infants (those with birth weights below 1000 g).6 The primary outcome was death before a corrected age of 18 months or documentation in survivors of one or more of the following: cerebral palsy, cognitive delay, hearing loss requiring amplification, and bilateral blindness. [For definitions, see the original publication.6] Infants with birth weights ranging from 500 to 999 g were considered for enrollment when they were 2 hours old. A history, a physical examination, and a platelet count were the only screening tests prescribed by the protocol. The research ethics boards of all 32 participating clinical centers approved the protocol, and written informed consent was obtained from a parent or guardian of each infant. Infants were recruited between January 1996 and March 1998. A total of 1202 infants were randomized; 601 to the indomethacin group and 601 to the placebo group. Adequate data for the composite primary outcome were available for 574 (95.5%) and 569 (94.7%) infants, respectively.6 Two hundred seventy-one infants

IVH

860

Intraventricular hemorrhage

TIPP

Trial of Indomethacin Prophylaxis in Preterms

From the University of Toronto, Toronto, McMaster University, Hamilton, Ontario, the University of Manitoba, Winnipeg, Manitoba, the University of British Columbia, Vancouver, British Columbia, Dalhousie University, Halifax, Nova Scotia, Canada, the Royal Women’s Hospital, Melbourne, Australia, and the National Institute of Child Health and Development, Bethesda, Md. Supported by a grant from the Medical Research Council of Canada (MT-13288) and by grants from the National Institute of Child Health and Human Development to participating centers in the United States (U10 HD21364, U10 HD27851, U10 HD21373, U10 HD27881, M01 RR 00997, U10 HD27880, M01 RR 00070, U10 HD21385, U10 HD27904, and U10 HD34216). Indocid P.D.A. was donated by Merck Frosst and Merck. Submitted for publication May 31, 2005; accepted Jul 20, 2005. Reprint requests: No reprints will be made available. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.07.032

Table. Sex-mediated effects on long-term outcomes and severe intraventricular hemorrhage (IVH) in extremely-low-birth-weight infants Outcome

Sex

1. Primary composite (includes 2-6 below)

F M F M F M F M F M F M F M

2. Death 3. Cerebral palsy 4. Cognitive delay 5. Blindness 6. Deafness 7. Severe IVH

Indomethacin (n; %) 123/280; 148/294; 60/289; 65/306; 24/228; 34/239; 48/219; 70/225; 4/227; 5/238; 5/221; 5/235; 27/277; 25/292;

43.9 50.3 20.8 21.2 10.5 14.2 21.9 31.1 1.8 2.1 2.3 2.1 9.8 8.6

Placebo (n; %)

Odds ratio (95% CI)*

P value (for interaction)**

102/278; 36.7 159/291; 54.6 41/290; 14.1 70/304; 23.0 30/246; 12.2 25/231; 10.8 44/235; 18.7 73/222; 32.9 3/243; 1.2 4/229; 1.8 2/242; 0.8 8/224; 3.6 33/282; 11.7 42/285; 14.7

1.35 (0.95,1.93) 0.84 (0.60,1.18) 1.59 (1.01,2.52) 0.90 (0.60,1.35) 0.85 (0.46,1.55) 1.37 (0.76,2.46) 1.22 (0.75,1.98) 0.92 (0.61,1.40) 1.44 (0.27,8.16) 1.21 (0.28,5.42) 2.78 (0.47,20.9) 0.59 (0.16,2.01) 0.82 (0.46,1.44) 0.54 (0.31,0.94)

.048 .054 .24 .37 .87 .11 .29

*CI, Confidence interval. **Breslow-Day test for homogeneity (female versus male).

died or survived with impairments in the indomethacin group (47%) and 261 (46%) in the placebo group [odds ratio (OR) 1.1; 95% confidence interval, 0.8 to 1.4; P = .61].6

DESIGN/METHODS To investigate infant sex as a potential effect modifier for indomethacin, we computed the indomethacin odds ratio for various study outcomes separately for boys and girls in the entire TIPP Cohort [Indomethacin, n = 574 (female n = 280, male n = 294); Placebo, n = 569 (female n = 278, male n = 291)]. The analysis was based on the TIPP primary outcome, a composite of death or survival to 18 months corrected age with one or more of cerebral palsy, cognitive delay, blindness, or deafness. We analyzed the composite outcome, the individual components, and the occurrence of severe IVH during the neonatal period [indomethacin group 52/569 (9%) and placebo group 75/567 (13%); P = .02]. This latter outcome reflects a putative mechanism by which indomethacin could influence longer-term outcome. The data for each outcome were tabulated by treatment group separately for male and female infants, forming two 2 3 2 tables. The treatment effect (odds ratio) of indomethacin was calculated for males and females and the 2 odds ratios compared via a Breslow-Day test. A significant Breslow-Day test result would indicate that the effect of indomethacin is different for males and females.

RESULTS Results are summarized in the Table. The Breslow-Day test reached borderline statistical significance for the primary composite outcome (P = .048) and for death (P = .054). Statistical significance was not reached for any of the other individual components of the composite outcome (cerebral palsy, cognitive delay, blindness or deafness) or for severe IVH. Male/Female Differences In Indomethacin Effects In Preterm Infants

The primary composite outcome was less common in girls than in boys. In the placebo group 36.7% of the girls versus 54.6% of the boys died or survived with impairment. In the indomethacin group the corresponding rates were 43.9% for girls versus 50.3% for boys.

DISCUSSION 4

Ment et al suggested that indomethacin reduces white matter damage through an anti-inflammatory effect that is more pronounced in the more vulnerable male cells. This reduction in white matter damage would translate into fewer ultrasonographically detected lesions and improved neurodevelopmental outcomes. The study by Ment et al4 included 196 females and 235 males for a total of 432 infants. Our treatment effect estimates for the primary TIPP outcome, based on a much larger sample size of 558 females and 585 males for a total of 1143 slightly more immature infants, suggest only a weak differential treatment effect of indomethacin by sex. However, in this large cohort of extremely-low-birth-weight infants, adverse indomethacin effects in girls contribute importantly to the interaction. Although we used the same statistical techniques as Ment et al4 we could not confirm a preferential treatment benefit of prophylactic indomethacin for boys. Our results confirm previous studies1,2 of better neurodevelopmental outcomes in girls born preterm compared with boys. It is conceivable that drugs may act on the preterm female and male brains differently.

CONCLUSIONS Our data suggest a weak differential treatment effect of indomethacin by sex. However, the nature of the interaction was qualitatively different than that observed by Ment et al.4 In 861

the TIPP study a negative effect of indomethacin in females was a more prominent observation than a positive effect in males.

REFERENCES 1. Marlow N, Wolke D, Bracewell MA, Samara M, for the EPICure Study Group Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19. 2. Reiss AL, Kesler SR, Vohr B, Duncan CC, Katz KH, Pajot S, et al. Sex differences in cerebral volumes of 8-year olds born preterm. J Pediatr 2004;145:242-9.

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3. Geary GG, Krause DN, Duckles SP. Gonadal hormones affect diameter of male rat cerebral arteries through endothelium-dependent mechanisms. Am J Physiol Heart Circ Physiol 2000;279:H610-8. 4. Ment LR, Vohr BR, Makuch RW, Westerveld M, Katz KH, Schneider KC, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr 2004;145:832-4. 5. Edwards D. Brain protection for boys and girls. J Pediatr 2004;145: 723-4. 6. Schmidt B, Davis P, Moddeman D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely lowbirth-weight infants. N Engl J Med 2001;344:1966-72.

The Journal of Pediatrics  December 2005