Download PDF
Am J Perinatol
DOI: 10.1055/s-0044-1788717
Original Article

Sex-Related Differences in the Severity of Neonatal Opioid Withdrawal Syndrome: A Single-Center, Retrospective Cohort Study

Victoria A. Anderson 
1   Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
,
Saminathan Anbalagan 
2   Department of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, Pennsylvania
3   Department of Pediatrics/Neonatology, University of South Alabama, Mobile, Alabama
,
Michael T. Favara
4   Department of Pediatrics/Neonatology, ChristianaCare Hospital, Newark, Delaware
,
Daniela Stark
5   Department of Pediatrics, NYU Grossman School of Medicine, New York, New York
,
David Carola
2   Department of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, Pennsylvania
,
Kolawole O. Solarin
2   Department of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, Pennsylvania
,
Susan Adeniyi-Jones
2   Department of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, Pennsylvania
,
Zubair H. Aghai
2   Department of Pediatrics/Neonatology, Thomas Jefferson University/Nemours, Philadelphia, Pennsylvania
› Author Affiliations Funding None.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective Factors associated with the development and expression of Neonatal Opioid Withdrawal Syndrome (NOWS) are poorly understood. There are conflicting data on the role of infant sex in NOWS. Some studies have suggested that infant sex predicts NOWS severity and adverse outcomes, with male infants being more vulnerable. This study aimed to analyze if infant sex is associated with the severity of NOWS among those who require pharmacologic treatment.

Study Design This is a retrospective cohort study of term and late-preterm infants (≥35 weeks gestation) exposed to in utero opioids, born between September 2006 and August 2022, and required pharmacologic treatment for NOWS. Maternal and infant demographics were collected. Indicators of the severity of NOWS (duration of medical treatment (DOT), duration of hospitalization, maximum dose of opioid treatment, and use of secondary medications) were compared between male and female infants. Standard statistical tests and regression analysis were used to establish the differences in outcomes after accounting for confounders and baseline differences.

Results Out of the 1,074 infants included in the study, 47.9% were female, and 52.1% were male. There was no significant difference in demographic and baseline clinical characteristics between groups except for anthropometry (birth weight, head circumference, and length) and Apgar score at 5 minutes. The median DOT (25 days [14, 39] vs. 23 days [13, 39], p = 0.57), length of hospital stay (31.5 days [20, 44] vs. 28 days [20, 44], p = 0.35), treatment with phenobarbital (24.7 vs. 26.3%, p = 0.56), and clonidine (3.9 vs. 3.8%, p = 0.9) were similar in both groups. The differences remained nonsignificant after adjusting for birth anthropometric measurements, gestational age, 5-minute Apgar score, small for gestational age status, and maternal exposure to benzodiazepines.

Conclusion In this cohort of neonates, sex-related differences were not identified to influence the severity of NOWS among those who required pharmacological treatment.

Key Points

  • Vulnerability to NOWS is multifactorial.

  • The role of infant sex in the severity of NOWS is not concrete.

  • We noted that sex did not impact NOWS severity in those treated.

Keywords

NOWS - sex - gender - neonate - NAS - risk factors


Publication History

Received: 17 February 2024

Accepted: 08 July 2024

Article published online:
29 July 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Lyden J, Binswanger IA. The United States opioid epidemic. Semin Perinatol 2019; 43 (03) 123-131
    CrossrefPubMedGoogle Scholar
  • 2 Bruneau J, Ahamad K, Goyer MÈ. et al; CIHR Canadian Research Initiative in Substance Misuse. Management of opioid use disorders: a national clinical practice guideline. CMAJ 2018; 190 (09) E247-E257
    CrossrefPubMedGoogle Scholar
  • 3 Reddy UM, Davis JM, Ren Z, Greene MF. Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes Workshop Invited Speakers. Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: Executive Summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, Society for Maternal-Fetal Medicine, Centers for Disease Control and Prevention, and the March of Dimes Foundation. Obstet Gynecol 2017; 130 (01) 10-28
    CrossrefPubMedGoogle Scholar
  • 4 Towers CV, Terry P, Rackley B, Hennessy M, Visconti K. Fetal outcomes with detoxification from opioid drugs during pregnancy: a systematic review. Am J Perinatol 2020; 37 (07) 679-688
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Center for Substance Abuse Treatment. Medication-assisted Treatment for Opioid Addiction in Opioid Treatment Programs. Rockville (MD):: Substance Abuse and Mental Health Services Administration (US);; 2005
    Google Scholar
  • 6 Kelty E, Preen DB. Risk factors associated with the occurrence of neonatal opioid withdrawal syndrome: a review. CNS Drugs 2019; 33 (11) 1113-1120
    CrossrefPubMedGoogle Scholar
  • 7 Johnson K, Greenough A, Gerada C. Maternal drug use and length of neonatal unit stay. Addiction 2003; 98 (06) 785-789
    CrossrefPubMedGoogle Scholar
  • 8 Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG 2009; 116 (05) 665-671
    CrossrefPubMedGoogle Scholar
  • 9 Berghella V, Lim PJ, Hill MK, Cherpes J, Chennat J, Kaltenbach K. Maternal methadone dose and neonatal withdrawal. Am J Obstet Gynecol 2003; 189 (02) 312-317
    CrossrefPubMedGoogle Scholar
  • 10 Seligman NS, Salva N, Hayes EJ, Dysart KC, Pequignot EC, Baxter JK. Predicting length of treatment for neonatal abstinence syndrome in methadone-exposed neonates. Am J Obstet Gynecol 2008; 199 (04) 396.e1-396.e7
    CrossrefPubMedGoogle Scholar
  • 11 Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatr 1991; 118 (06) 933-937
    CrossrefPubMedGoogle Scholar
  • 12 Brown HL, Britton KA, Mahaffey D, Brizendine E, Hiett AK, Turnquest MA. Methadone maintenance in pregnancy: a reappraisal. Am J Obstet Gynecol 1998; 179 (02) 459-463
    CrossrefPubMedGoogle Scholar
  • 13 Dysart K, Hsieh HC, Kaltenbach K, Greenspan JS. Sequela of preterm versus term infants born to mothers on a methadone maintenance program: differential course of neonatal abstinence syndrome. J Perinat Med 2007; 35 (04) 344-346
    CrossrefPubMedGoogle Scholar
  • 14 Pourcyrous M, Elabiad MT, Rana D, Gaston KP, DeBaer L, Dhanireddy R. Racial differences in opioid withdrawal syndrome among neonates with intrauterine opioid exposure. Pediatr Res 2021; 90 (02) 459-463
    CrossrefPubMedGoogle Scholar
  • 15 Anbalagan S, Mendez MD. Neonatal Abstinence Syndrome. StatPearls; 2023
    Google Scholar
  • 16 Townsel C, Covault JM, Hussain N, Oncken C, Nold C, Campbell WA. Placental aromatase expression decreased in severe neonatal opioid withdrawal syndrome. J Matern Fetal Neonatal Med 2021; 34 (05) 670-676
    CrossrefPubMedGoogle Scholar
  • 17 O'Connor AB, O'Brien L, Alto WA. Are there gender related differences in neonatal abstinence syndrome following exposure to buprenorphine during pregnancy?. J Perinat Med 2013; 41 (05) 621-623
    CrossrefPubMedGoogle Scholar
  • 18 Jansson LM, Dipietro JA, Elko A, Velez M. Infant autonomic functioning and neonatal abstinence syndrome. Drug Alcohol Depend 2010; 109 (1–3): 198-204
    CrossrefPubMedGoogle Scholar
  • 19 Smith BL, Guzman TA, Brendle AH. et al. Perinatal morphine exposure leads to sex-dependent executive function deficits and microglial changes in mice. eNeuro 2022; 9 (05) ENEURO.0238–22
    CrossrefPubMedGoogle Scholar
  • 20 Skumlien M, Ibsen IO, Kesmodel US, Nygaard E. Sex differences in early cognitive development after prenatal exposure to opioids. J Pediatr Psychol 2020; 45 (05) 475-485
    CrossrefPubMedGoogle Scholar
  • 21 Unger A, Jagsch R, Bäwert A. et al. Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates?. Gend Med 2011; 8 (06) 355-364
    CrossrefPubMedGoogle Scholar
  • 22 Holbrook A, Kaltenbach K. Gender and NAS: does sex matter?. Drug Alcohol Depend 2010; 112 (1-2): 156-159
    CrossrefPubMedGoogle Scholar
  • 23 Charles MK, Cooper WO, Jansson LM, Dudley J, Slaughter JC, Patrick SW. Male sex associated with increased risk of neonatal abstinence syndrome. Hosp Pediatr 2017; 7 (06) 328-334
    CrossrefPubMedGoogle Scholar
  • 24 Alaedini K, Haddadi K, Asadian L. A review of neurobehavioral challenges in children exposed prenatally to intrauterine opioid. J Pediatr Rev 2017; 5: e9234
    CrossrefPubMedGoogle Scholar
  • 25 Nygaard E, Moe V, Slinning K, Walhovd KB. Longitudinal cognitive development of children born to mothers with opioid and polysubstance use. Pediatr Res 2015; 78 (03) 330-335
    CrossrefPubMedGoogle Scholar
  • 26 Weinberg MK, Tronick EZ, Cohn JF, Olson KL. Gender differences in emotional expressivity and self-regulation during early infancy. Dev Psychol 1999; 35 (01) 175-188
    CrossrefPubMedGoogle Scholar
  • 27 Townsel CD, Emmer SF, Campbell WA, Hussain N. Gender differences in respiratory morbidity and mortality of preterm neonates. Front Pediatr 2017; 5: 6
    CrossrefPubMedGoogle Scholar
  • 28 Wakschlag LS, Pickett KE, Cook Jr. E, Benowitz NL, Leventhal BL. Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 2002; 92 (06) 966-974
    CrossrefPubMedGoogle Scholar
  • 29 Massaro D, Massaro GD. Estrogen receptor regulation of pulmonary alveolar dimensions: alveolar sexual dimorphism in mice. Am J Physiol Lung Cell Mol Physiol 2006; 290 (05) L866-L870
    CrossrefPubMedGoogle Scholar
  • 30 Carey MA, Card JW, Voltz JW. et al. It's all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 2007; 18 (08) 308-313
    CrossrefPubMedGoogle Scholar
  • 31 Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. Wizemann TM, Pardue ML. eds. Exploring the Biological Contributions to Human Health: Does Sex Matter?. Washington (DC):: National Academies Press (US);; 2001. DOI: 10.17226/10028
    CrossrefGoogle Scholar
  • 32 Kaplan HC, Kuhnell P, Walsh MC. et al; OHIO PERINATAL QUALITY COLLABORATIVE. Orchestrated testing of formula type to reduce length of stay in neonatal abstinence syndrome. Pediatrics 2020; 146 (04) e20190914
    CrossrefPubMedGoogle Scholar