Sex Differences in Early Cognitive Development After Prenatal Exposure to Opioids

Martine Skumlien, MRES; Inge Olga Ibsen, MD; Ulrik Schiøler Kesmodel, PHD; Egil Nygaard, PHD


J Pediatr Psychol. 2020;45(5):475-485. 

In This Article

Abstract and Introduction


Objective: Prenatal opioid exposure has been linked with impaired cognitive development, with boys potentially at elevated risk. In the present study, we examined cognitive and language development of children prenatally exposed to opioids, with an additional focus on sex differences.

Methods: A sample of 378 children (n = 194 girls and n = 184 boys) aged 1.2–42.8 months was drawn from the Danish Family Outpatient Clinic database. Developmental outcomes were assessed using the Bayley-III cognitive and language scales, and substance exposure was determined with urine screening and/or verbal report. Children exposed to opioids (n = 94) were compared to children with no prenatal substance exposure (n = 38), and children exposed to alcohol (n = 131) or tobacco (n = 115). Group and sex differences were investigated with separate linear mixed models for each Bayley scale, controlling for concurrent cannabis exposure.

Results: There were significantly reduced scores in opioid-exposed boys compared to boys with no prenatal substance exposure, but no difference between opioid-exposed and nonexposed girls. Additionally, alcohol-exposed boys had lower cognitive scores than nonexposed boys, and alcohol-exposed girls had lower scores on both scales compared to opioid-exposed girls. There were otherwise no significant differences according to group, sex, or scale.

Conclusions: The present findings indicate poorer cognitive and language development in boys after prenatal opioid exposure. As academic performance is rooted in cognitive functioning, long-term follow-up might be necessary for exposed children.


Opioid maintenance treatment (OMT) has played a large part in improving outcomes for opioid-dependent patients, and current guidelines recommend maintenance treatment with methadone or buprenorphine for pregnant opioid-dependent women (World Health Organization, 2014). Yet, there is increasing evidence of poorer health and development in children prenatally exposed to opioids. Opioids cross the placenta and the blood–brain barrier of the developing fetus (Rosen & Pippenger, 1975; Syme, Paxton, & Keelan, 2004). In the neonate, prenatal methadone or buprenorphine exposure is associated with lower birth weight (e.g., Nørgaard, Nielsson, & Heide-Jørgensen, 2015; Patrick et al., 2015), lower average gestational age at birth (e.g., Nørgaard et al., 2015; Sarfi, Martinsen, Bakstad, Røislien, & Waal, 2009), and smaller head circumference (e.g., Chasnoff, Hatcher, & Burns, 1980; Lifschitz, Wilson, Smith, & Desmond, 1985) compared to nonexposed groups. Neonatal abstinence syndrome (NAS) occurs in around 50% of exposed infants (Reddy, Davis, Ren, & Greene, 2017), although the reported prevalence varies between studies.

Children exposed to illicit opioids and polysubstances in utero also demonstrate lower levels of general cognitive (Baar & Graaff, 1994; Nygaard, Moe, Slinning, & Walhovd, 2015) and fine-motor functioning (Bunikowski et al., 1998; Nygaard, Slinning, Moe, & Walhovd, 2017) throughout childhood and adolescence, as well as regulatory problems (Nygaard, Slinning, Moe, & Walhovd, 2016; Ornoy, Segal, Bar-Hamburger, & Greenbaum, 2001). Existing evidence suggests that toddlers prenatally exposed to methadone or buprenorphine are at risk for some of the same neurodevelopmental impairments, including poorer gross and fine-motor functioning (Hans & Jeremy, 2001; Strauss, Starr, Ostrea, Chavez, & Stryker, 1976), language abilities (Baar & Graaff, 1994; Beckwith & Burke, 2015; Salo et al., 2009), and cognitive functioning (Baar & Graaff, 1994; Bauman & Levine, 1986; Beckwith & Burke, 2015; Hans & Jeremy, 2001; Salo et al., 2010). In spite of these differences, opioid-exposed children usually score within the range of age-appropriate norms (Nygaard et al., 2017; Strauss et al., 1976). Moreover, in utero exposure to opioids is associated with less severe outcomes compared to in utero exposure to alcohol, which has been consistently linked with impaired cognitive functioning (Behnke, Smith, Committee on Substance Abuse, & Committee on Fetus and Newborn, 2013; Mattson & Riley, 1998). Prenatal tobacco exposure may also have detrimental effects on development, though to a lesser extent than alcohol (Behnke et al., 2013), thus the high prevalence of cigarette smoking reported for women in OMT (e.g., Mactier, Shipton, Dryden, & Tappin, 2014) may confound outcomes associated with in utero opioid exposure.

Prenatal opioid exposure may affect boys and girls differently (Alaedini, Haddadi, & Asadian, 2017). One early study of children exposed to methadone in utero showed that boys scored significantly lower than girls on the Bayley-II mental development index, which assesses early cognitive and language development jointly, at 1 and 2 years of age (Suffet & Brotman, 1984). In a more recent article (Nygaard et al., 2015), differences in cognitive abilities between opioid-exposed and nonexposed children (lower in exposed children) were substantially larger for boys than for girls the first few years of life, but group differences increased over time for girls, while they remained relatively stable for boys. Boys also appear to be more adversely impacted than girls after prenatal exposure to cocaine (Kestler, Bennett, Carmody, & Lewis, 2012). Thus, boys could be at greater risk after in utero opioid exposure during the first few years of life, although further evidence is needed to evaluate this claim.

Prescription opioid abuse among pregnant women is on the rise (Krans & Dunn, 2014; Reddy et al., 2017), with rates as high as 29% in some populations (Epstein et al., 2013). This is particularly the case for pain-management opioids, though these are seldom included in studies of the effects of prenatal exposure. Therefore, the aim of the present study was to compare the performance of children exposed to opioid analgesics and/or maintenance medication in utero to that of comparison groups with other or no in utero substance exposure on the Bayley-III cognitive and language scales. Children with additional exposure to heroin were also included, but constituted a very small minority of the sample. We hypothesized that opioid-exposed children would perform worse than children with no prenatal substance exposure, as well as tobacco-exposed children, but better than alcohol-exposed children. Group differences between opioid-exposed and nonexposed children were expected to be larger for boys than girls. The current study adds to the literature on cognitive outcomes after prenatal opioid exposure by including opioid analgesics, in addition to maintenance medication and heroin. Moreover, our sample size exceeds that of most previous studies, increasing our power to detect small group differences. Our results will thus aid our understanding of sex differences in cognitive and language development after prenatal opioid exposure.