Pre- and postnatal stress and asthma in children: Temporal- and sex-specific associations

Abstract

BACKGROUND

Temporal- and sex-specific effects of perinatal stress have not been examined for childhood asthma.

OBJECTIVES

We examined associations between pre- and/or postnatal stress and children's asthma (n=765) and effect modification by sex in a prospective cohort study.

METHODS

Maternal negative life events (NLEs) were ascertained prenatally and postpartum. NLEs scores were categorized as 0, 1-2, 3-4, or ≥5 to assess exposure-response relationships. We examined effects of pre- and postnatal stress on children's asthma by age 6 years modeling each as independent predictors; mutually adjusting for prenatal and postnatal stress; and finally considering interactions between pre- and postnatal stress. Effect modification by sex was examined in stratified analyses and by fitting interaction terms.

RESULTS

When considering stress in each period independently, among boys a dose-response relationship was evident for each level increase on the ordinal scale prenatally (OR=1.38, 95% CI 1.06, 1.79; p-for-trend=0.03) and postnatally (OR=1.53, 95% CI 1.16, 2.01; p-for-trend=0.001); among girls only the postnatal trend was significant (OR=1.60, 95% CI 1.14, 2.22; p-for-trend=0.005). Higher stress in both the pre- and postnatal periods was associated with increased odds of being diagnosed with asthma in girls [OR=1.37, 95% CI 0.98, 1.91 (p_interaction=0.07)] but not boys [OR=1.08, 95% CI 0.82, 1.42 (p_interaction=0.61)].

CONCLUSIONS

While boys were more vulnerable to stress during the prenatal period, girls were more impacted by postnatal stress and cumulative stress across both periods in relation to asthma. Understanding sex and temporal differences in response to early life stress may provide unique insight into asthma etiology and natural history.

INTRODUCTION

A growing number of prospective epidemiological studies demonstrate associations between increased prenatal maternal stress and early asthma phenotypes(1–5). While the magnitude of the association varies across studies, likely due to differences in study design, timing of exposure, and differences in the stress measure used, a recent meta-analysis substantiated a significant relationship between prenatal stress and childhood asthma(6). Similarly, increased postnatal caregiver perceived stress(7), adverse life events(1), and persistent depressive symptoms in mothers(8, 9) have all been prospectively linked with wheeze and asthma in pre-school aged children. Although studies to date have assessed the impact of either pre- or postnatal stress exposure, the relative importance of either exposure window is not well understood.

Exposure to psychological stress in critical developmental windows, including pregnancy and early childhood, may result in permanently altered changes in stress response systems (e.g., immune, autonomic, neuroendocrine, oxidation)(10–12) thought to play a role in the programming of respiratory disorders including asthma(13–16). The fetus is particularly vulnerable to stress due to immature immune, neuroendocrine and antioxidant defenses(17, 18). In addition, infants continue to be vulnerable as these systems are still developing and remain highly reactive and labile in response to environmental stressors in early life, particularly in the first two years(19, 20).

Pioneering studies performed largely in animals demonstrate that effects of prenatal stress and/or hormonal correlates on offspring development may be different from those related to postnatal stress(21) and may differ based on offspring sex. Sex-specific placental responsiveness to prenatal maternal stress and fetal sex hormones may contribute to differential effects of in utero stress on developmental outcomes(22, 23). Potential mechanisms may include differential placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity and/or sensitivity(24, 25); stress-induced oxidation in utero(26); and/or prenatal stress effects on inflammatory disorders due to interactions of sex hormones and immune-inflammatory pathways(27).

Prenatal stress may also result in the altered programming of stress response systems with enhanced vulnerability to subsequent stressful events such that those exposed in both time periods may be at greatest risk (i.e. a “two hit” model of disease(28)). Evidence demonstrates that an adverse postnatal environment modulates developmental consequences of prenatal stress in a sex-specific manner as well, with females generally being more adversely impacted(29).

Human studies examining sex-specific effects of early life stress on childhood asthma are sparse with conflicting results. An analysis using hospital contact data (N>400,000) found that prenatal exposure to maternal bereavement (proxy for maternal prenatal stress) was associated with a faster time to first asthma event between ages 1–4 years and having a documented asthma attack at 7–12 years in boys but not girls(30). A study of 68 children born to mothers exposed prenatally to disaster-related stress (i.e., the 1998 Quebec Ice Storm) showed increased physician-diagnosed asthma in girls but not in boys(31). While these findings suggest differential effects of prenatal stress on asthma development based on fetal sex, the studies were limited by the indirect measurement of prenatal stress and a lack of postnatal stress assessment so that the relative importance of exposure timing could not be examined. Understanding temporal- and sex-specific perinatal stress effects on asthma may help elucidate programming mechanisms and better identify those at heightened risk so that interventions may be applied at the correct life stage in order to promote optimal development.

In this study we leveraged a prospective pregnancy cohort to examine the relative importance of exposure to pre- and/or postnatal stress in association with children's asthma onset by age six years. Specifically, we first examined effects of pre- and postnatal stress in independent models, then mutually adjusted for pre-/postnatal stress, and finally examined joint effects of exposure to increased stress in both pregnancy and the first two years of life. We also examined whether temporal effects of perinatal stress differed relative to the child's sex. We hypothesized that among boys, increased prenatal stress would be more strongly associated with asthma development while among girls, elevated exposure to stress in the postnatal period and/or joint exposure to increased pre- and postnatal stress would be associated with a greater likelihood of developing asthma.

METHODS

Study Participants

The Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a pregnancy cohort designed to examine the effects of perinatal stress and other environmental factors on urban childhood asthma risk, has been described(32). Briefly, English or Spanish-speaking women receiving prenatal care at two Boston hospitals and affiliated community health centers were recruited from August 2002 to September 2009; 989 (78.1%) eligible women approached between 28.4±7.9 weeks gestation agreed to enroll. There were no significant differences for race/ethnicity, education, and income between eligible participants who enrolled compared to those who declined. These analyses include 765 mother-infant dyads with data on prenatal and postnatal stress followed up to age six years. Procedures were approved by human studies committees at the Brigham and Women's Hospital and Boston Medical Center; written consent was obtained in the participant's primary language.

Negative Life Events

Pre- and postnatal maternal stress were measured using the Crisis in Family Systems-Revised (CRISYS-R) survey, validated in English and Spanish(33, 34) administered within two weeks of enrollment and between 12 and 18 months postnatally. Mothers were asked to endorse life events experienced in the past six months across 11 domains (e.g., financial, legal, career, relationships, safety in the home, safety in the community, medical issues pertaining to self, medical issues pertaining to others, home issues, authority, and prejudice) and to rate each as positive, negative, or neutral. Stress theory centers around the notion that when we experience environmental demands that rise to the level of overwhelming our existing coping resources, we experience distress/stress with a concomitant physiological disruption that may impact health(35, 36). Research suggests increased vulnerability when experiencing events across multiple domains as this circumstance is more likely to overwhelm coping resources; therefore, the number of domains with one or more negative event were summed to create a negative life events (NLEs) domain score, with higher scores indicating greater stress(37).

Asthma onset

Telephone and face-to-face interviews at approximately 3-month intervals for the first 24 months of life then annually thereafter up to age 6 years were used to determine maternal-reported clinician diagnosed asthma. Mothers were asked, “Has a doctor or nurse ever said that your child had asthma?”. The majority of children received a diagnosis of asthma after age 3 years (78.7%) (Figure E1, online supplement).

Covariates

Potential confounders and pathway variables were considered. Questionnaires ascertained maternal age, education, race/ethnicity, atopic history (ever having clinician-diagnosed asthma, eczema, and/or hay fever), pre-pregnancy height and weight as well as child's sex, season of birth, and birth weight. Gestational age was based on reported last menstrual period and obstetrical estimates upon medical record review(38). Birth weight for gestational age (BWGA) z-scores were calculated based on normative U.S. data(39). Mothers who reported smoking at baseline and/or in the third trimester were classified as prenatal smokers; postnatal smoke exposure was documented based on maternal report of smoking and/or whether others smoked in the home at each postpartum interview. Maternal body mass index (BMI) was calculated by dividing weight by height squared (kg/m²). An internal validation analysis showed good agreement comparing height and weight measured early in pregnancy (<10 weeks) to self reported values(40).

Urban residents experiencing a greater number of negative life events may be more likely exposed to other environmental conditions that contribute to asthma expression(41, 42). Prenatal exposure to traffic-related air pollution, specifically black carbon (BC), was estimated by a validated spatio-temporal land use regression model that used maternal residential address over the entire pregnancy as detailed previously(43). Lower-SES populations exposed to higher stress may also be exposed to increased household allergens(44). Settled dust collected within 2 weeks of enrollment from the mother's bedroom using a standardized protocol(45) was assayed for cockroach allergen (Blatella Germanica, Bla g 1 and 2) using a monoclonal antibody-based Enzyme-Linked Immunosorbent Assay (Indoor Biotechnologies, Charlottesville, VA). Social resources that may influence stress experiences and asthma among residents may also vary by neighborhood characteristics or quality(41). A measure of neighborhood disadvantage was derived by linking enrollment addresses with aggregated data (census tract) from the 2000 U.S. Census indexed as an average z-score for percentages of: residents living below poverty, unemployed, non-U.S. citizens, and nonwhites in the neighborhood(46). Higher z-scores indicated greater disadvantage.

Analysis

The NLEs score was categorized a priori as 0, 1-2, 3-4, or ≥5 in order to assess exposure-response relationships. We used multivariable logistic regression to examine associations between pre- and postnatal maternal stress and children's diagnosed asthma. Trend tests were conducted treating the NLEs categories as an ordinal variable using the median value of each category. Spearman correlations between NLEs scores and other environmental factors were low to moderate (Table 1), therefore all were included in the analyses. Only prenatal BC was considered in analyses as prenatal and postnatal BC were highly correlated (r=0.94, p<.0001). Models were then sequentially adjusted for: standard controls, including infant sex and season of birth; covariates linked to stress and asthma in previous research, including maternal age, race, educational level, and atopy; and finally traffic-related air pollution, household cockroach exposures and the neighborhood disadvantage index. Effect modification by sex was examined in stratified analyses and by fitting interaction terms. Variables that may be in the pathway between maternal stress and asthma onset in the index children including pre-pregnancy BMI, pre/postnatal smoking, and child's BWGA(39), were considered in sensitivity analyses.

Table 1.

Spearman correlations between maternal NLEs, housing- and neighborhood-level environmental factors

	Prenatal NLEs		Postnatal NLEs		Prenatal BC Level		Prenatal Household Bla g 1		Prenatal Household Bla g 2
	R	P	r	P	r	P	r	P	r	P
Postnatal NLEs	0.59	<.0001	--	--	--	--	--	--	--	--
Prenatal BC Level	0.19	<.0001	0.21	<.0001	--	--	--	--	--	--
Prenatal Household Bla g 1	0.09	0.05	0.04	0.44	0.17	0.0002	--	--	--	--
Prenatal Household Bla g 2	0.03	0.54	0.03	0.64	0.15	0.0010	0.79	<.0001	--	--
Neighborhood disadvantage, z score	0.12	0.002	0.16	<.0001	0.55	<.0001	0.21	<.0001	0.18	<.0001

Definition of abbreviations: BC = black carbon; Bla g = Blatella germanica; NLEs = negative life events.

Using this approach, we first considered associations between child asthma and the pre- or postnatal NLEs score in separate models. Models were run for the entire sample and then stratified by sex. Next we ran models mutually adjusting for pre- and postnatal maternal stress, including sex-stratified models. As pre- and postnatal NLEs were moderately correlated (Spearman r = 0.59, p<.0001), collinearity was assessed using standard collinearity diagnostics for logistic regression (the condition index defined as the square root of the ratio of the largest singular value to each smallest singular value of the X'WX matrix, where X is the covariate matrix used in the regression model and W is the weight matrix in the logistic regression). The index was 21 showing that effect estimates were stable when both were included in the models (i.e., a condition index of 20–30 suggests moderate collinearity among exposures that does not severely affect model estimates(47, 48)). Finally, in order to examine the joint effects of pre- and postnatal stress, we included an interaction term using the continuous NLEs score in the two time periods in the overall model as well as within each sex strata. Main effects were considered statistically significant for p-value < 0.05. In the subgroup analyses, a p-value of 0.10 was taken to represent evidence of interaction. Analyses were performed using Statistical Analysis Software (SAS) version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

Sample characteristics are summarized in Table 2. There were no significant differences for covariates among subjects included in analyses compared to the entire cohort (online supplement, Table E1). Mothers were primarily ethnic minority (54% Hispanic, 29% African American) and had lower socioeconomic status (SES) (67% reported ≤12 years of education). The majority of children were not exposed to tobacco smoke in either the pre- or postnatal period (67%); 138 (18%) children were diagnosed with asthma by age 6 years with higher incidence in boys (21.0%) versus girls (14.9%) (Table 2).

Table 2.

ACCESS participant characteristics

	All (n=765)		Girls (n=375)		Boys(n=390)
Categorical Variables	n	%	n	%	n	%
Asthma by age 6 years *
No	627	82.0	319	85.1	308	79.0
Yes	138	18.0	56	14.9	82	21.0
Season of birth
Winter	205	26.8	114	30.4	91	23.3
Spring	179	23.4	75	20.0	104	26.7
Summer	164	21.4	71	18.9	93	23.9
Fall	217	28.4	115	30.7	102	26.2
Maternal Race
Hispanic	412	53.9	216	57.6	196	50.3
Black	221	28.9	100	26.7	121	31.0
White/Other	132	17.3	59	15.7	73	18.7
Maternal education
>12 yrs	252	32.9	121	32.3	131	33.6
≤12 yrs	513	67.1	254	67.7	259	66.4
Maternal atopy †	275	36.0	136	36.3	139	35.6
Tobacco Smoke Exposure
Never smoke exposed	512	66.9	250	66.7	262	67.2
Pre- and/or postnatal exposure ∫	253	33.1	125	33.3	128	32.8
Continuous Variables
Prenatal NLEs (range 0–11; median, IQR) ‡	2	1–4	2	1–4	2	1–4
Postnatal NLEs (range 0–11; median, IQR) ‡	2	1–3	2	1–3	2	1–3
Maternal age at enrollment (years; mean, SD)	26.8	5.9	26.8	5.8	26.8	6.0
Maternal body mass index (BMI) (kg/m2; mean, SD)	28.9	6.6	29.3	6.9	28.6	6.3
Neighborhood disadvantage; z-score (median, IQR)	0.25	−0.50–0.54	0.32	−0.30–0.55	0.15	−0.60–0.52
Prenatal black carbon (BC) level (μg/m3; median, IQR)	0.37	0.29–0.49	0.39	0.30–0.50	0.35	0.29–0.47
Bla g 1 (U/g; median, IQR)	0.20	0.2–0.4	0.20	0.2–0.4	0.20	0.2–0.4
Bla g 2 (U/g; median, IQR)	0.50	0.5–0.95	0.50	0.5–0.75	0.50	0.5–1.0
Gestational age at birth (weeks; mean, SD)	39.1	2.9	39.2	3.5	38.9	2.2
Birthweight percentile for gestational age (mean, SD)	46.0	30.0	43.8	29.8	48.1	30.2

^*Clinician diagnosed asthma

^†Maternal-reported doctor-diagnosed asthma, eczema, and/or hay fever,

^‡Negative life events assessed using the Crisis in Family Systems-Revised (CRISYS-R) survey³⁴, a multi-item survey summarized into a continuous score,

^∫Denotes prenatal maternal smoking or postnatal smoking in household by mother and/or others

Independent Relationships of Pre- and Postnatal Maternal NLEs with Asthma

Table 3 presents results considering pre- and postnatal NLEs in separate models. In the sample as a whole, there was a clear increase in the odds of being diagnosed with asthma for each increase in maternal stress category even after adjusting for sociodemographic factors, maternal atopy, and housing-/ neighborhood-level social and physical environmental factors (Model 3). When treating the NLEs categories as an ordinal variable, there was a significant exposure-response relationship both prenatally (OR=1.31, 95% CI 1.07, 1.60, for each level increase in prenatal stress category; p-for-trend=0.009) and postnatally (OR=1.53, 95% CI 1.25, 1.88 for each level increase in postnatal stress category; p-for-trend<0.0001).

Table 3.

Logistic regression models independently examining pre- and postnatal maternal NLEs in relation to asthma by age 6 years

NLEs domain score (range 0–10)			Univariable Model			Multivariable-adjusted Models*
		No. with Asthma (%)				Model 1			Model 2			Model 3
	n		OR	95%CI		OR	95%CI		OR	95%CI		OR	95%CI
Prenatal NLEs model
0	144	20 (13.9%)	Ref	--	--	Ref	--	--	Ref	--	--	Ref	--	--
1–2	300	43 (14.3%)	1.04	0.59	1.84	1.08	0.61	1.93	1.06	0.59	1.89	1.05	0.59	1.89
3–4	196	43 (21.9%)	1.74	0.98	3.12	1.80	1.00	3.25	1.62	0.89	2.94	1.60	0.88	2.92
≥5	125	32 (25.6%)	2.13	1.15	3.97	2.28	1.21	4.27	2.06	1.08	3.92	2.02	1.05	3.87
Postnatal NLEs model
0	152	18 (11.8%)	Ref	--	--	Ref	--	--	Ref	--	--	Ref	--	--
1–2	321	47 (14.6%)	1.28	0.71	2.28	1.31	0.73	2.35	1.26	0.70	2.27	1.30	0.72	2.37
3–4	187	39 (20.9%)	1.96	1.07	3.59	2.01	1.09	3.69	1.87	1.01	3.47	1.92	1.03	3.57
≥5	105	34 (32.4%)	3.56	1.88	6.76	3.68	1.93	7.02	3.43	1.77	6.62	3.52	1.79	6.93

^*Multivariable-adjusted logistic regressions (Models 1–3) predicting asthma (dependent variable) considering pre- and postnatal stress in separate models.

Model 1 included standard control variables (child's sex, season of birth).

Model 2 additionally included demographic variables (race/ethnicity, maternal education, maternal age and maternal atopy).

Model 3 additionally included physical and social environmental exposures [BC, household cockroach allergen, neighborhood disadvantage index].

Figure 1 shows the relationship between maternal stress and children's asthma in sex-stratified analyses considering pre- and postnatal stress separately. When stratified by sex, the OR for each level increase in stress category was significant for boys pre- (OR=1.38, 95% CI 1.06, 1.79; p-for-trend=0.03) and postnatally (OR=1.53, 95% CI 1.16, 2.01; p-for-trend=0.001); among girls the trend test was significant only in the postnatal (OR=1.60, 95% CI 1.14, 2.22; p-for-trend=0.005) period and not in the prenatal (OR=1.17, 95% CI 0.84, 1.63; p-for-trend=0.24) period. Interactions were not significant (sex x continuous prenatal NLEs, p=0.38; sex x continuous postnatal NLEs, p=0.81).

Figure 1. Sex-stratified associations between maternal stress and children's asthma.

Odds ratios (95% CIs) from multivariable logistic regression models demonstrating the relationship of (A) prenatal and (B) postnatal maternal stress with children's asthma diagnosis by age 6 years. Pre-and postnatal stress were considered in separate sex-stratified models adjusted for season of birth, maternal race/ethnicity, maternal age, maternal education, maternal atopy, BC, household cockroach allergen and the neighborhood disadvantage index.

Mutual adjustment for prenatal and postnatal maternal stress

For analyses mutually adjusted for pre- and postnatal maternal stress (Table 4), the two highest exposure categories were collapsed together in order to maintain adequate cell sizes. In the overall sample, when indicators for both pre- and postnatal stress were included in the model, only the effect of the highest category of postnatal stress remained significant (OR=2.18, 95% CI 1.12, 4.22). When stratified by sex, effects were only evident in girls. Girls born to mothers in the highest postnatal NLEs group had 4-fold increased odds of asthma compared to those born to women in the lowest postnatal NLEs category (OR=4.02, 95% CI 1.3, 12.7).

Table 4.

Logistic regression models mutually adjusted for pre- and postnatal NLEs in relation to asthma by age 6 years^*

NLEs domain score (range 0–10)	All				Girls				Boys
	n	OR	95% CI		n	OR	95%CI		N	OR	95%CI
Prenatal NLEs
0	144	Ref	--	--	63	Ref	--	--	81	Ref	--	--
1–2	300	0.89	0.48	1.66	160	0.54	0.21	1.41	140	1.29	0.55	2.99
≥3	321	1.15	0.60	2.19	152	0.60	0.22	1.66	169	1.63	0.67	3.99
Postnatal NLEs
0	152	Ref	--	--	72	Ref	--	--	80	Ref	--	--
1–2	321	1.30	0.69	2.43	163	2.57	0.86	7.66	158	0.94	0.41	2.14
≥3	292	2.18	1.12	4.22	140	4.02	1.27	12.69	152	1.68	0.70	4.04

^*Additionally adjusted for season of birth, maternal race/ethnicity, maternal education, maternal age, maternal atopy, BC, household cockroach allergen, the neighborhood disadvantage index, and child's sex in the unstratified model.

Joint Effects of Pre- and Postnatal Stress

In fully adjusted models including an interaction for prenatal × postnatal NLEs continuous scores, there was evidence of interaction in the sample as a whole (OR=1.19, 95% CI 0.97, 1.47; p=0.09). In stratified analysis, there was evidence of an interaction between increased pre- and postnatal stress in girls (OR=1.37 95% CI, 0.98, 1.91; p=0.07) but not in boys (OR= 1.08, 95% CI 0.82, 1.42; p=0.61). A three-way interaction between prenatal × postnatal stress × sex was not significant (p=0.56).

Sensitivity Analyses

Additional adjustment of these models for variables that may be in the pathway between maternal stress and offspring respiratory illness including pre-pregnancy BMI, pre/postnatal tobacco smoke exposure, and child's BWGA z-score, did not substantively change the reported findings (Table E2).

DISCUSSION

These analyses add to the stress and asthma literature in two important ways. First, given the prospective design, we could demonstrate an exposure-response relationship between stress assessed in the prenatal period and compare these results to stress experienced in early infancy (first two years) as predictors of childhood asthma onset. To our knowledge, this is the first study to make this comparison. Second, these analyses begin to elucidate the interplay between sex- and temporal-specific effects of early life stress exposure on asthma development by age six years. Notably, all children were at increased risk of developing asthma when exposed to stress in the perinatal period. However, boys were more vulnerable to increased maternal stress during the prenatal period whereas higher stress in the postnatal period was most significantly associated with asthma in girls. Also, there was evidence in girls for an interaction between higher stress in both the pre- and postnatal periods associated with an increased likelihood of being diagnosed with asthma. Our results illustrate the importance of considering both gender and timing of exposure in understanding associations between early life stress and asthma development in children. The observed temporal- and sex-specific associations between perinatal stress and asthma in these children suggest that different mechanisms may operate in particular life stages with differential effects due to child sex.

Understanding gender differences may elucidate potential pathways involved in stress-asthma programming (e.g., sex hormones, immune development, metabolism, placental function, etc.). During fetal life, cells differentiate and respond to signals induced by the maternal environment via the placenta, setting a “program” that prepares the fetus for its ex utero life(49, 50). Toxins transferred across the placenta may induce altered production of hormones, cytokines and inflammatory mediators that indirectly influence development(51–53). Prenatal maternal stress may negatively affect neuroendocrine function at the maternal-fetal interface and consequent inflammation and immune signals that begin to program these processes in the fetus(54–57). For example, prenatal stress may alter the maternal sympathetic and adrenomedullary (SAM) system(58) and the hypothalamic-pituitary-adrenal (HPA) axis(12, 55), leading to an increase in placental secretion of corticotropin-releasing hormone (CRH) and increased fetal exposure to glucocorticoids (GCs). Increased exposure to GCs can, in turn, influence fetal neural and immune development.

Our finding that, compared to girls, boys seemed more impacted by increased stress exposure in utero is consistent with animal research more typically showing a male vulnerability to prenatal stress(59). The importance of the placenta in mediating sex-specific effects of prenatal stress is increasingly recognized(60, 61). In animal models, the female placenta autoregulates 11β-HSD2 activity, resulting in a relatively protective sex-specific placental-fetal glucocorticoid response(24, 25). Sex differences in prenatal epigenetic programming of stress gene pathways through differential methylation of placental genes may also play a role(24, 60). Oxidative stress, decreased antioxidant defenses, and/or failure to repair oxidative damage are linked to disruption of key prenatal programming regulatory processes(62–64) and are increasingly implicated in respiratory disorders including asthma(65). The placenta regulates oxidant balance at the maternal-fetal interface, preventing toxicity and promoting optimal development(66). Moreover, prenatal glucocorticoid exposure alters placental pro-oxidant-antioxidant balance in a sex-specific manner with boys being more vulnerable to an induced pro-oxidant state compared to girls(67).

Other mechanisms underlying differential effects of prenatal stress on offspring health relative to fetal sex have been proposed. Sex is an important modifier of effects of stress-system genetic variation (e.g., HPA axis genetic variation) on programming(18, 68). Sex-specific effects of prenatal stress on respiratory control processes may also play a role, with males being more adversely impacted(69). Bidirectional interactions between the HPA and the hypothalamic-pituitary-gonadal (HPG) axes during development may also contribute to sex differences in early life stress exposures(70, 71). Notably, a recent study in a pregnancy cohort (n=409) found a relationship between lower prenatal maternal progesterone levels early in pregnancy and increased cumulative incidence of asthma and allergic rhinitis at 3–5 years of age among girls but not among boys(72). The authors conceptualized reduced progesterone as a surrogate marker of stress, given known interactions between the HPA and HPG axes. This argument was buttressed by their finding in a parallel animal study that prenatal supplementation of stress-challenged pregnant mice with a progesterone derivative attenuated stress-induced airway hyperresponsiveness in female but not male offspring(71).

In contrast, increased maternal stress in the postnatal period (first two years of life) was more strongly associated with higher odds of asthma in girls. Indeed, the exposure-response relationship was only evident postnatally for girls, while being present in boys for both periods. When mutually adjusting for pre- and postnatal stress exposure, the association between stress and asthma remained significant in girls exposed to the highest level of postnatal stress. Postnatally, caregiver stress has been associated with poor child stress regulation (19, 20) and disrupted immune development(73), which independent of prenatal maternal stress, may increase the risk of subsequent asthma development. Moreover, a `two hit' model with an interaction between pre- and postnatal stress was seen in girls but not boys. This is consistent with data showing that females may be more adaptive in utero albeit at a cost of adverse health effects later in life(74). For example, animal models suggest that prenatal stress is associated with increased stress responses throughout postnatal life (e.g. the HPA axis and autonomic function) in females more often than males(70, 75). Human studies also suggest that the postnatal caregiving environment can modify effects of prenatal stress(76). The more typical increase in stress reactivity in females exposed to in utero stress may, in part, explain their greater vulnerability to stress-induced health effects after birth(74).

Strengths of this study include the prospective study design, with assessment of stress both prenatally and in the first two years of life (i.e., previously identified vulnerable developmental windows for asthma risk and stress programming) using the same validated measure of maternal life events. Other strengths include our focus in an ethnically diverse lower income population more likely to be impacted by both increased stress and asthma, and our ability to adjust for a number of important confounders and pathway variables. We also acknowledge limitations. Children's doctor-diagnosed asthma was reported by mothers. The majority of these children were given a diagnosis of asthma after the age of 3 years (78.6%), reducing the likelihood that cases represented wheezing respiratory illnesses other than asthma albeit this remains a possibility (Figure E1, online supplement). Chronic stress was assessed based on maternal report of negative events occurring in the past 6 months in both the pre- and postnatal periods and thus may not capture all stressful events. This measurement error would be expected to be similar in women regardless of whether or not their child goes on to develop asthma (i.e., nondifferential misclassification) resulting in an underestimation of the association between stress and asthma.

As we follow these children, it will be informative to see if similar associations hold for more objective measures (e.g., spirometry, airway reactivity). Also, it will be important to reproduce these findings in future studies using even larger sample sizes given the likely complex relationships between time- and sex-dependent effects of early life stress.

Future studies should also incorporate biomarker measures of stress response systems including the HPA and HPG axes, autonomic nervous system functioning and immune function over early development that may be sexually dimorphic. There should be increased focus on placental functioning, including epigenetic programming, in relation to prenatal stress effects on childhood asthma development including sex-specific effects. As noted for other disorders, elucidating the mechanisms underlying both basic sex differences in stress-response systems and, in turn, how they relate to differential asthma expression in early life will be essential to developing sex-specific treatment strategies for stress-elicited asthma(77, 78).

In conclusion, these data show that both boys and girls are at increased risk of developing asthma when exposed to higher stress in the perinatal period. Thus, clinicians should counsel pregnant women and young mothers on the role of psychological stress in this context; validation by a healthcare provider will raise awareness of the links between stress and physical health. Interventions focused on reducing stress in the prenatal and early postnatal periods may reduce asthma development among all children. Such interventions should be examined in clinical trials. It will also be necessary to shift the focus from the individual to include social, economic, and policy interventions on multiple levels to reduce stress in the lives of women of childbearing age and young families, particularly among the most socially disadvantaged(79). Moreover, understanding temporal- and sex-specific stress effects on asthma may provide unique insights into underlying programming mechanisms. We know that respiratory disorders such as asthma have significant sex biases in natural history, pathophysiology, and response to treatment, which are not well understood(80, 81). Studies examining the programming of sex differences at varying time points in development in response to maternal and early life stress may provide unique insights into asthma etiology, natural history, and novel treatment strategies in the future.

Key Messages.

• When considered independently, a dose-response relationship was demonstrated between both pre- and postnatal maternal stress and childhood asthma.

• Sex-stratified analyses demonstrated a dose-response relationship between both pre- and postnatal maternal stress and asthma among boys; the dose-response relationship between stress and asthma was only evident postnatally among girls.

• Higher stress in both the pre- and postnatal periods was associated with increased odds of being diagnosed with asthma in girls but not boys.

Capsule summary.

These analyses begin to elucidate the interplay between sex- and temporal-specific associations between early life stress and childhood asthma development which may provide unique insight into asthma etiology and natural history.

Abbreviations

11β-HSD2

11β-hydroxysteroid dehydrogenase type 2

ACCESS

Asthma Coalition on Community, Environment, and Social Stress

BC

black carbon

Bla g

Blatella Germanica

BMI

body mass index BMI

BWGA

birth weight for gestational age

CI

confidence interval

CRH

corticotropin-releasing hormone

CRISYS-R

Crisis in Family Systems-Revised survey

GCs

glucocorticoids

HPA

hypothalamic-pituitary-adrenal

HPG

hypothalamic-pituitary-gonadal

IQR

interquartile range

Kg/m²

kilogram per meter squared

NLEs

negative life events

OR

odds ratio

SAM

sympathetic and adrenomedullary

SAS

Statistical Analysis Software

SD

standard deviation

SES

socioeconomic status

U/g

Unit per gram

Yrs

years