After removal of duplicates, 15940 records were identified. Of these, 1179 studies investigated the relationship between childhood adversities and biological health outcomes, of which 380 (32%) reported outcomes in children. A majority of the studies with outcomes in children used a cross-sectional study design (241 studies, 63%). We identified 97 longitudinal cohort studies in children, and 24 met our final criteria (see flow diagram in Fig. 1 for the exclusion criteria). In addition, we identified 11 studies that met all inclusion criteria from the references section of the selected studies, for a total of 35 studies (Fig. 1).
Bias assessment
The bias assessment synthesis is displayed in Fig. 2. In 77% of the studies, exposed and unexposed participants were drawn from similar populations, suggesting a low risk of bias. In regard to adequate follow-up, 68% of the studies were assessed to have a low or moderately low risk of bias. The assessments of the exposure and the outcome were rated as having a low or moderately low risk of bias in 94% of the studies. In regard to confounders and covariates, 92% of the studies received a rating of low or moderately low risk of bias (Fig. 2). In addition, we observed that the majority of the studies examining maltreatment and intimate partner violence did not take into consideration the possible effect of social services for abused and neglected individuals on the outcome.
Study characteristics
Of the 35 studies published between 2001 and 2015, 20 were published in 2010 and later. Thirty-three were prospective cohort studies and 2 were retrospective cohort studies. Half of the studies were conducted in the United States, and the remaining ones were conducted in 4 other countries. Sample size ranged from 18 to 13907 participants. Six studies examined developmental outcomes (Table 2) and 29 examined clinical outcomes (Table 3).
Developmental outcomes
Six studies investigated developmental outcomes including physical, reproductive, and cognitive development. Studies found that adversity was associated with differences in height, age at menarche, and cognitive ability (Table 3).
Physical and reproductive development
Studies on physical development showed a weak association between parental divorce or separation and shorter height, but the association was not always statistically significant. Li et al found that for males whose parents divorced or separated, height was significantly lower at ages 7 and 11 years, but not at age 16 years. For females whose parents divorced or separated, height was lower on average at ages 7, 11, and 16 years, but not significantly lower [24]. Li and Power compared 2 generations of participants and found that cohort members whose parents divorced or separated were shorter on average, and offspring were taller on average, but these associations were not statistically significant [25]. Boynton-Jarrett and Harville examined children who were raised in a neglectful environment (e.g. physical neglect, bullying) and found that 1 form of neglectful environment (OR = 1.21, 95% CI: 1.03–1.43) and 2 or more forms (OR = 1.76, 95% CI: 1.41–2.20) were both significantly associated with late menarche [26].
Cognitive development
The reviewed studies reported an association between early adversity and significant delays in cognitive development. Enlow et al found that interpersonal trauma exposure during age 0–24 months, but not during age 24–64 months, was significantly associated with decreased cognitive scores at 24 to 96 months of age [27]. Similarly, Strathearn et al found a significant association between maltreatment and cognitive delay at age 4 years [28]. Richards and Wadsworth found that children who experienced parental death or divorce had lower cognitive ability scores at ages 8 and 15 years [29].
Clinical outcomes
Of the 29 selected studies investigating clinical outcomes, 14 focused on biological markers. Of these studies, 7 examined markers of endocrine function (cortisol), 4 examined markers of inflammation and immune function, 2 examined markers of autonomic nervous function, and 1 examined telomere length. Other clinical outcomes reported included obesity (6 studies), asthma (3 studies), infections and illnesses (3 studies), somatic complaints (3 studies), and sleep (3 studies).
Biological markers of endocrine function
Studies on cortisol, a stress hormone with a diurnal pattern of secretion, give insight to the dysregulation of the stress response in children exposed to adversity. Of the 7 selected studies that examined cortisol, 4 investigated the effect of maternal mental health on cortisol secretion and showed that results varied with age of exposure. Dreger et al found that maternal postnatal and recurrent distress were significantly associated with higher midday serum cortisol levels in 7–10-year-olds [30]. Essex et al assessed children’s afternoon or evening salivary cortisol levels and found that those who were exposed to maternal depression both in infancy and at age 4.5 years had marginally significant, higher cortisol levels at age 4.5 years than did children never exposed or exposed only at age 4.5 years. In addition, children exposed to maternal depression only in infancy did not have significantly higher cortisol levels [31]. Halligan et al found that maternal postnatal depression was associated with higher, more variable morning salivary cortisol in 13-year-old children [32]. Ashman et al compared 7–8-year-old children of depressed and nondepressed mothers and found no effect of maternal depression on salivary cortisol levels or diurnal rhythm of cortisol [33].
In contrast, the 3 studies examining the effect of maltreatment on children’s cortisol production reported lower cortisol levels in maltreated children. Peckins et al found that maltreated children were more likely than nonmaltreated children to have a blunted cortisol profile rather than a moderate or an elevated profile, but by late adolescence there was no longer a difference [34]. Two studies on cortisol response to a psychosocial stress test in 12-year-old twins indicated that maltreated or frequently bullied children did not exhibit the expected increase in cortisol following the stress test [35, 36].
Biological markers of inflammation and immune function
The reviewed studies indicated alterations of immune and inflammatory response in children exposed to adversity. In a sample of children exposed to their parents’ psychiatric symptoms, Wyman et al [37] and Caserta et al [38] found that higher levels of symptoms were associated with enhanced natural killer cell response in children, suggesting that chronic stress may exert effects of cytotoxicity on the developing immune system. Wolf et al found that greater parental depressive symptoms at baseline predicted increases in children's profiles of asthma-relevant inflammatory markers (i.e. eosinophil cationic protein and interleukin-4), in both children with asthma and controls [39]. In 3 cohorts of children, Copeland et al did not find an association between bullying or teasing and C-reactive protein levels (a marker of inflammation in the body) [40].
Biological markers of autonomic nervous function
Lynch et al found that the interaction between exposure to neighborhood crime, exposure to maltreatment, and children’s genotype was associated with different patterns of respiratory sinus arrhythmia reactivity, a measure of the vagal tone indicating the physiological response of the autonomic nervous system to stress [41]. Rigterink et al found that exposure to domestic violence was associated with differences in the physiological regulation of emotion—measured as vagal tone—between exposed and nonexposed children, with smaller increases in baseline vagal tone in exposed children, suggesting a less adaptive development of regulatory functioning over time among these children [42].
Telomere length
One study investigated the relationship between violence exposure and telomere length, a marker of cellular age that also correlates with disease morbidity and mortality. Shalev et al observed stress-related accelerated telomere erosion in children who experienced 2 or more types of violence exposure, providing support for a mechanism linking cumulative childhood stress to potential lifelong and transgenerational health impacts [43].
Obesity
Evidence for early adversity influencing weight or body mass index (BMI) in childhood was mixed, with different types of adversity resulting in varying outcomes at different ages. Schmeer found that children whose mothers dissolved a union had an 80% higher risk of becoming overweight or obese between ages 3 and 5 years, as compared with children of stable married mothers [44]. Morris et al found that children whose parents had separated had a BMI 1.1% (95% CI: 0.2–2.0) higher at age 4 years in comparison with children whose parents remained together, but this diminished to 0.5% (95% CI: -1.3–2.2) by age 17 years [45]. Boynton-Jarrett et al found that children whose mothers reported chronic intimate partner violence (IPV) were more likely to be obese at age 5 years than were children whose mothers reported no IPV (OR = 1.80, 95% CI: 1.24–2.61), whereas children who were exposed to either early (up to age 12 months) or late (at age 3 and/or 5 years) maternal IPV did not have a significant increase in risk. Analyses stratified by sex indicated an increased risk for obesity only among females exposed to maternal chronic IPV (OR = 2.21, 95% CI: 1.30–3.75), as compared with males (OR = 1.66, 95% CI: 0.94–2.93) [46].
Studies on household dysfunction showed an effect on weight during early childhood, whereas studies on abuse and neglect reported an effect on weight during adolescence. Shenk et al found that maltreatment significantly increased the risk for obesity among female adolescents (RR = 1.47, 95% CI: 1.03–2.08, P = .034) [47]. Noll et al found a borderline, nonsignificant increase in risk for obesity during middle/late adolescence (age 15–19 years) for females who had been sexually abused (OR = 2.03, 95% CI: 0.54–4.60, P = .09); the relationship was not significant during childhood/early adolescence (age 6–14 years) [48].
Childhood adversity also showed an effect on children’s ability to manage their weight. Frohlich et al examined weight change among overweight and obese 7–15-year-olds participating in a weight reduction intervention. They found that psychosocial variables—family adversity, maternal depression, and maternal attachment style—were significantly predictive of long-term success in weight reduction [49].
Asthma
Studies reported that children exposed to childhood adversity had an increased risk for asthma. Lanier et al found that maltreatment significantly increased the risk for first hospital treatment for asthma (HR = 1.73, 95% CI: 1.47–2.04, P < .001) [50]. Lange et al found that paternal posttraumatic stress disorder (PTSD; OR = 1.08, 95% CI: 1.03–1.14, P = .003), paternal major depressive episode (OR = 9.95, 95% CI: 1.38–71.59, P = .02), and paternal antisocial behavior (OR = 1.09, 95% CI: 1.04–1.15, P < .001), as well as maternal depressive symptoms (OR = 1.13, 95% CI: 1.02–1.25, P = .02) and parental depression (OR = 1.70, 95% CI: 1.14–2.53, P = .01) were associated with recent asthma symptoms at age 1 year. At age 3 years, maternal depressive symptoms showed a significant association with asthma diagnosis (OR = 1.13, 95% CI: 1.01–1.27, P = .03) and a borderline, significant association with hospitalizations for asthma (OR = 1.16, 95% CI: 1.00–1.36, P = .05). Paternal major depressive episode and parental depression had a borderline, nonsignificant association with oral steroid treatment (OR = 3.03, 95% CI: 0.84–10.97, P = .09) and hospitalizations for asthma (OR = 1.86, 95% CI: 0.98–3.56, P = .06) [51]. In addition, Kozyrskyj et al found that maternal long-term distress was significantly associated with an increased risk of asthma at age 7 years (OR = 1.25, 95% CI: 1.01–1.55), but postpartum distress and short-term distress were not [52].
Infections and illnesses
An increased risk for infection was also reported to be associated with childhood adversity. Lanier et al found that maltreatment increased the risk for first hospital treatment for non-asthma-related cardiorespiratory disease (e.g. acute respiratory infection; HR = 2.07, 95% CI: 1.87–2.29, P < .001) as well as other infections (e.g. mycoses; HR = 2.09, 95% CI: 1.85-2.36, P < .001) [50]. Wyman et al studied a sample of children 5–10 years of age and found that after 18 months of follow-up, children of parents reporting higher levels of psychiatric symptoms had more illnesses (RR = 1.49, 95% CI: 1.12–1.97, P = .01), but not more febrile illnesses (RR = 1.60, 95% CI: 0.94–2.73, P = .08) [37]. At the 3-year follow-up, Caserta et al found that children of parents reporting higher levels of psychiatric symptoms continued to experience more illnesses (RR = 1.40, 95% CI: 1.06–1.85, P = .02), but they also experienced more febrile illnesses (RR = 1.77, 95% CI: 1.00–3.13, P = .05) [38].
Somatic complaints
The relationship between childhood adversity and somatic complaints (i.e. common physical complaints of uncertain origin such as headaches and nausea) varied by number and types of adversities. Flaherty et al found that experiencing 5 or more adversities during childhood was not associated with child somatic complaints reported by the child at age 12 years, but was associated with child somatic complaints reported by the caregiver (OR = 4.26, 95% CI: 1.17–15.5, P = .03) [53]. In a subsequent study, Flaherty et al examined somatic concerns reported at age 14 years and found a graded relationship between exposure to adversity across all ages and child somatic concerns reported by the caregiver; ORs (95% CI) for somatic concerns were 4.19 (0.50–34.90), 8.91 (1.15–68.83), and 9.25 (1.25–68.23) for 1, 2, and ≥3 adversities, respectively [54]. Margolin et al found that parent-to-youth aggression was significantly associated with a slightly increased risk of experiencing somatic symptoms (RR = 1.03, 95% CI: 1.01–1.05, P < .05), whereas marital physical aggression and community violence were not (RR = 1.01, 95% CI: 0.99–1.03 and RR = 1.03, 95% CI: 0.99–1.08, respectively) [55].
Sleep
Childhood adversity was also shown to affect children’s sleep. In a study on the effect of maternal depression on infant sleep, Armitage et al found that average sleep time in 24 hours did not differ between children of depressed and nondepressed mothers at 2 or 24 weeks, but nocturnal sleep was 97 min longer among children of nondepressed mothers at both 2 and 24 weeks, and these children had fewer awakenings during the night than did children of depressed mothers [56]. In examining the effect of maternal PTSD on infant sleep, Hairston et al. found a marginally significant association for infant waking after sleep onset and a nonsignificant association for amount of time awake during the night [57]. Wolke and Lereya found that bullying victimization at both ages 8 and 10 years was associated with nightmares (OR = 1.82, 95% CI: 1.46–2.27), night terrors (OR = 2.01, 95% CI: 1.48–2.74), sleepwalking (OR = 1.71, 95% CI: 1.31–2.25), and any type of parasomnia (OR = 2.10, 95% CI: 1.72–2.58) at age 12 years [58].