BACKGROUND: Prenatal exposure to metabolic disturbances is associated with increased risk of offspring neurodevelopmental impairment and autism spectrum disorder, while little is known about the joint effect of maternal obesity and diabetes. With this study, we aim to assess the joint effect of maternal obesity and diabetes on the risk for offspring psychiatric and mild neurodevelopmental disorders.
METHODS: Nationwide registries were used to link data of all live births in Finland between 2004 and 2014 (n = 649 043). Cox proportional hazards modeling adjusting for potential confounders was applied to estimate the effect of maternal obesity, pregestational diabetes mellitus (PGDM), and gestational diabetes mellitus, as well as their joint effects, on the outcomes of offspring psychiatric and mild neurodevelopmental diagnoses and offspring prescription of psychotropic drugs.
RESULTS: Among mothers without diabetes, severely obese mothers had 67% to 88% increased risk of having a child with mild neurodevelopmental disorders (hazard risk ratio [HR] = 1.69; 95% confidence interval [CI] = 1.54–1.86), attention-deficit/hyperactivity disorder or conduct disorder (HR = 1.88; 95% CI = 1.58–2.23), and psychotic, mood, and stress-related disorders (HR = 1.67; 95% CI = 1.31–2.13) compared with mothers with a normal BMI. PGDM implied a further risk increase for all groups of psychiatric diagnoses with onset in childhood or adolescence in mothers with severe obesity. Marked effects were found particularly for autism spectrum disorder (HR = 6.49; 95% CI = 3.08–13.69), attention-deficit/hyperactivity disorder and conduct disorder (HR = 6.03; 95% CI = 3.23–11.24), and mixed disorders of conduct and emotions (HR = 4.29; 95% CI = 2.14–8.60). Gestational diabetes mellitus did not increase the risk highly for these offspring disorders.
CONCLUSIONS: Maternal PGDM combined with severe maternal obesity markedly increases the risk of several children’s psychiatric and mild neurodevelopmental disorders.
- ADHD —
- attention-deficit/hyperactivity disorder
- ASD —
- autism spectrum disorder
- ATC —
- anatomic therapeutic chemical
- CI —
- confidence interval
- DM —
- diabetes mellitus
- GDM —
- gestational diabetes mellitus
- HILMO —
- Finnish Care Registers for Health Care
- HR —
- hazard risk ratio
- ICD-10 —
- International Classification of Diseases, 10th Revision
- MBR —
- medical birth register
- PGDM —
- pregestational diabetes mellitus
- RRD —
- Finnish Register on Reimbursement Drugs
- SES —
- socioeconomic status
- THL —
- Finnish National Institute for Health and Welfare
What’s Known on This Subject:
Prenatal exposure to metabolic disturbances was associated with offspring neurodevelopmental impairment and autism spectrum disorder. No study has examined the joint effects of maternal prepregnancy obesity and diabetes on the risk of other offspring psychiatric and mild neurodevelopmental disorders.
What This Study Adds:
The combination of maternal pregestational insulin-treated diabetes (PGDM) and severe obesity was associated with a markedly higher risk for attention- deficit/hyperactivity disorder and conduct disorder, as well as mixed disorders of conduct and emotions, than obesity or diabetes alone.
Maternal prepregnancy obesity is one of the prenatal metabolic risks in humans.1–3 Prenatal exposure to obesity-related metabolic disturbances is associated not only with increased risk of metabolic dysfunction in the offspring4,5 but also increased risk of offspring neurodevelopmental impairment and psychiatric disorders, specifically decreased cognitive performance, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD).6–8 A long-term impact of maternal prepregnancy obesity on offspring neurodevelopment9,10 has recently been hypothesized to be linked to an altered intrauterine environment owing to increased inflammation,11–13 metabolic stress,14 and lipotoxicity.15
Authors of studies have suggested that maternal diabetes is also associated with an increased rate of learning difficulties, ASD, and possibly also ADHD in the offspring.16,17 Maternal diabetes is categorized into a diabetes diagnosis any time before the pregnancy (pregestational diabetes mellitus [PGDM]) and diabetes with onset during pregnancy (gestational diabetes mellitus [GDM]). PGDM is known to increase the risk for embryopathy, present in 5% to 10% of the live births of mothers with PGDM, the most common being neural tube defects and cardiovascular malformations. Hyperglycemia during critical morphogenesis periods appears to be a major teratogen16 with downstream events being hyperglycemia-induced hypoxia and oxidative stress followed by apoptosis.16,18 Findings from animal models suggest that epigenetic changes mediate or mark long-term effects of an inflammatory and/or hyperglycemic embryonic environment.19 There are previous reports of maternal PGDM effects also on offspring postnatal neurodevelopment, where cognitive function in particular is well studied and considered normal in offspring from mothers with good glycemic control.16 Less studied is the effect of maternal PGDM on milder neurodevelopmental variations and psychiatric condition in the offspring. There are reports of an association between in utero exposure to PGDM and risk of ASD,20 GDM and ASD,21–23 and between GDM and risk of ADHD.24 Although the maternal PGDM and GDM associations to offspring ASD have been supported by several studies,21,22 the effect size of GDM exposure on ASD is smaller than that of PGDM22 and therefore likely less consistent.25 The combined effects of diabetes and obesity on ASD risk were explored in an attempt to further clarify this; Li et al20 reported that both maternal PGDM and GDM increased the risk for offspring ASD but only in obese mothers. This might reflect a stronger neural effect of exposure to concomitant inflammation, lipotoxicity, metabolic stress, and hyperglycemia than to only hyperglycemia. However, whether there are effects of PGDM and GDM on risk for other offspring psychiatric disorders than ASD is quite unexplored.
Our aim with this study was to assess the risk of maternal pregestational obesity and diabetes, categorized into PGDM or GDM, as well as the combined risk of obesity and PGDM or GDM on the risk for a spectrum of psychiatric and mild neurodevelopmental disorders up to the age of 11 years. To this end, we used nationwide registries in Finland that covered all live births between 2004 and 2014.
Study Population and Data Sources
All pregnancies ending in live birth in Finland between 2004 and 2014 were identified by using the drugs and pregnancy database26 and included 649 043 births (Table 1). These data stem from the medical birth register (MBR), the register on induced abortions, and the register of congenital malformations, all currently kept at the Finnish National Institute for Health and Welfare (THL). The MBR includes information since 1987 on all live births and stillbirths in Finland with a gestational age of >21 weeks or with a birth weight ≥500 g. Information on maternal and offspring drug purchases was extracted from the Finnish Register on Reimbursement Drugs (RRD) maintained by the National Social Insurance Institution. Prescription-only medicines are sold only in pharmacies, and dispensing requires a prescription issued by a physician or dentist. All Finnish citizens and permanent residents are entitled to reimbursement of prescribed medicine. RRD automatically registers all reimbursed drug prescriptions (anatomic therapeutic chemical [ATC] code) that were dispensed at pharmacies since 1996. All medicines for mothers and offspring were identified from reimbursement of costs for drug purchasing. Maternal and offspring medical diagnoses were obtained from the Finnish Care Registers for Health Care (HILMO). HILMO contains information on all hospital in-patient treatments (since 1969), information on out-patient treatments by physicians in specialized care (since 1998), and covers psychiatric diagnoses well according to validation studies.27 The International Classification of Diseases, 10th Revision (ICD-10) was in routine use over the period between 2004 and 2014.
Information from the different registers was merged through record linkages by using unique personal identification numbers assigned to all Finnish citizens and permanent residents. Register linkages were conducted as described in the permission from the registers (National Social Insurance Institution and THL). The steering committee of the drugs and pregnancy database and the data protection authority in Finland gave their approval for this study. The registered women and their children were not contacted, and informed consents were not required, according to Finnish regulations.
Definition of the Exposures for Maternal Obesity and Diabetes
The data on prepregnancy (pregestational) BMI as recorded at the first prenatal visit (gestational week 7–10) were obtained from the drugs and pregnancy database, originally from MBR. The use of BMI restricted the inclusion to earliest 2004. BMI was calculated as weight in kilograms divided by the square of height in meters and categorized according to the following World Health Organization classification: underweight (BMI <18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), obese (30 ≤ BMI < 35), and severely obese (BMI ≥35).
PGDM was identified on the basis of the RRD as insulin-treated diabetes; that is, all PGDM cases were on insulin treatment. GDM was identified on the basis of ICD-10 (O24.4) in HILMO. The presence of a PGDM diagnosis excluded a GDM diagnosis.
Definition of Offspring and Maternal Psychiatric Disorders
Data on psychiatric disorders, as primary or secondary diagnoses, for the offspring and the mothers were obtained from HILMO. For the offspring, the diagnosis groups indicated by the following ICD-10 codes were studied as outcome variables: F80 to F83 (developmental disorders of speech and language, scholastic skills, and motor function), F84 (ASD), F90 to F91 (ADHD and conduct disorders), F92 to F95 (mixed disorders of conduct and emotions, emotional disorders with onset specific to childhood, disorders of social functioning with onset specific to childhood and adolescence, and tic disorders) and F98 (other behavioral and emotional disorders with onset usually occurring in childhood and adolescence), F20 to F45 (psychotic, mood, neurotic and stress related, and somatization disorders), F50 (eating disorders), and F51 (nonorganic sleeping disorders). The grouping of diagnoses was based on symptom similarities and performed to improve the statistical power in the analyses.
Information on prescription of psychotropic drugs to offspring was obtained from the RRD and used as outcome variables in a second model. The following ATC codes were used: N05 (antipsychotics, anxiolytics, hypnotics, and sedatives), N06A (antidepressants), and N06B (psychostimulants and nootropics). From HILMO, we also received information on the mothers’ previous in-patient care caused by mental health disorders before pregnancy (International Classification of Diseases, Eighth Revision: 290–317 during 1969–1986, International Classification of Diseases, Ninth Revision: 290–319 during 1987–1995, and ICD-10: F00–F99 during 1996–2014), which was used as a covariate.
Other Variables Used as Covariates
Information on offspring birth year, sex, perinatal problems and offspring birth weight according to gestational age, number of fetuses, mode of delivery, maternal age at delivery, parity, family situation, mother’s country of birth, and maternal smoking were obtained from the drugs and pregnancy database. Data on mothers’ diagnoses related to systemic inflammatory disorders (ICD-10: M30–M36 during 1996–2014) were used as primary or secondary diagnoses.
Cox proportional hazards modeling was used to estimate the effect of the exposures maternal prepregnancy obesity, PGDM, and GDM (the latter 2 stratified by BMI categories) on the outcomes offspring psychiatric diagnosis and prescription of psychotropic drug (sensitivity analysis). For maternal BMI, the strata overweight, obese, and severely obese were compared with those with BMI <25. Births to underweight mothers (BMI <18.5) were included in the reference group because there was no detectable effect of underweight on the risk for the offspring psychiatric diagnoses. Covariates were adjusted for as indicated in Tables 2 and 3. Hazard risk ratios (HRs) with 95% confidence intervals (CIs) were reported as measures of effect size. All statistical analyses were performed by using SAS version 9.3 (SAS Institute, Inc, Cary, NC).
Description of the Study Population
Of the 649 043 births, the prepregnancy BMI was normal for 59.2%, whereas 20.7% of births had maternal overweight, 7.67% had obesity, and 3.66% had severe obesity. In addition, for 0.62% (n = 4000) of the births, the mother had PGDM, and for 15.7% (n = 101 696) of the births, the mother had GDM. Among the offspring, 5.4% (n = 34 892) of the children were diagnosed with a psychiatric disorder between 2004 and 2014, that is up to the age of 11 years for the oldest children. Therein, we identified 17 923 (2.8%) with developmental disorders of speech and language, scholastic skills, motor function (ICD-10: F80–F83); 2346 (0.36%) with ASD (F84)30; 5263 (0.81%) with ADHD or conduct disorder (F90–F91)31; 5301 (0.82%) with mixed disorders of conduct and emotions with childhood onset (F92–F95); 8506 (1.31%) with other behavioral and emotional disorders (F98); 2928 (0.45%) children with a psychotic, mood, neurotic or stress-related, or somatization disorder (F20–F45); 279 (0.043%) with eating disorders; and, finally, 2219 (0.34%) with sleep disorders. Additionally, a total of 13 436 (2.1%) children had been prescribed a psychotropic medication during the period between 2004 and 2014, including antipsychotics, hypnotics, and anxiolytics (N05; 9445 cases); antidepressants (N06A; 334 cases); and stimulants (N06B; 4613 cases). Additional descriptive characteristics of mothers and their offspring are shown in Table 1.
Increased Risk for Psychiatric Disorders in Offspring to Mothers With Obesity and Diabetes
Table 2 shows the relationship for maternal obesity, PGDM, and GDM to the risk of offspring psychiatric and mild neurodevelopmental disorders up to the age of 11 years, after adjusting for potential confounders. Firstly, among mothers without any type of diabetes, there were, to varying degrees, associations between higher maternal BMI and increased risk for the following neurodevelopmental and psychiatric disorder categories in the ICD-10: F80 to F83, F90 to F91, and F20 to F45 in offspring. The hazard ratio for these F-diagnosis categories was 67% to 88% increased for offspring to the mothers with severe obesity. Thus, severely obese mothers had an increased risk of having a child with F80 to F83 (developmental disorders of speech, language, motor, and scholastic skills; HRseverely obese = 1.69; 95% CI = 1.54–1.86), F90 to F91 (ADHD, conduct disorder; HRseverely obese = 1.88; 95% CI = 1.58–2.23), and F20 to F45 (psychosis and mood and anxiety disorders; HRseverely obese = 1.67; 95% CI = 1.31–2.13) compared with mothers with a BMI <25. Secondly, maternal PGDM implied an additionally increased risk for offspring neurodevelopmental and psychiatric disorder. For the combined group of any studied offspring F-diagnosis, PGDM implied a twofold increased risk for F-diagnosis among severely obese mothers with PGDM compared with severe obesity only (HRPGDM = 2.97; 95% CI = 2.23–3.96; HRno diabetes = 1.45; 95% CI = 1.35–1.56). Marked effects were found particularly for ASD and ADHD and/or conduct disorder. Mothers with PGDM and severe obesity had a sixfold higher risk of having a child with ASD (HR = 6.49; 95% CI = 3.08–13.69, Fig 1) or ADHD and/or conduct disorder (HR = 6.03; 95% CI = 3.23–11.24, Fig 2) compared with normal weight mothers without PGDM. In fact, PGDM implied an overrepresentation of all groups of F-diagnoses with onset in childhood or adolescence (F80–F98) in mothers with severe obesity, with the category F92 to F95 also revealing markedly increased risk (mixed disorders of emotions and conduct, disorders of social function, and tics; HR = 4.29; 95% CI = 2.14–8.60, Fig 3). In addition, PGDM in combination with ordinary obesity associated with increased offspring risk for ASD (HR = 3.64; 95% CI = 1.63–8.16). Also, the diagnosis group F20 to F45 (nonjuvenile psychosis and mood and anxiety disorders) were overrepresented in offspring to mothers with PGDM and obesity (HR = 3.08; 95% CI = 1.28–7.43), a twofold risk relative to those without PGDM (HR = 1.58; 95% CI = 1.36–1.85). Maternal GDM, on the other hand, had only a borderline statistically significant influence on the risk for psychiatric disorders (for mothers with severe obesity, HRgdm = 1.66; 95% CI = 1.55–1.77; HRno diabetes = 1.45, 95% CI = 1.35–1.56). Sex-specific analyses for ASD, ADHD and/or conduct disorder, and F92 to F95 revealed that, of the cases, 79.4%, 80.2%, and 67.3%, respectively, were boys and that the HRs for obesity and diabetes on these diagnoses were similar comparing boys and girls (Supplemental Tables 4 and 5). In addition, because cases with diagnoses of ASD or F92 to F95 were found in birth cohorts between 2004 and 2013 and cases with ADHD and/or conduct disorder in birth cohorts between 2004 and 2012, a sensitivity analysis was performed excluding birth year 2014 for ASD and F92 to F95 and birth years 2013 and 2014 for ADHD and/or conduct disorder; the HRs were similar (Supplemental Table 6) to those when the birth cohorts 2013 and 2014 were included (Table 2). Finally, a sensitivity analysis in which the underweight mothers (pregestational BMI <18.5) were excluded (Supplemental Table 7) revealed HRs similar to those in which underweight mothers were included in the normal BMI group (Table 2).
Association for Maternal Obesity and Diabetes to Prescription of Offspring Psychotropic Medication
For a second, but likely less sensitive, measure of offspring psychiatric disorders, we used prescription of psychotropic medication including the ATC groups N05 (antipsychotics, hypnotics, and anxiolytics), N06A (antidepressants), and N06B (stimulants). Table 3 reveals that both increased maternal prepregnancy BMI and PGDM were associated with increased prescription of psychotropic medication to offspring, after adjusting for potential confounders. As above, offspring to mothers with PGDM and severe obesity had the highest signal of psychiatric disorder here indicated by prescription of any of N05, N06A, and N06B. There was a marked increase in prescription of N05, N06A, or N06B among offspring to severely obese mothers with PGDM (HR = 4.54; 95% CI = 2.89–7.13) compared with among offspring to severely obese mother without PGDM (HR = 1.69; 95% CI = 1.51–1.90). Both N05 and N06B prescriptions were each overrepresented among offspring to severely obese mothers with PGDM (HRN05 = 3.71; 95% CI = 2.10–6.54; HRN06B = 6.20; 95% CI = 2.95–13.03) compared with when mothers were severely obese without PGDM (HRN05 = 1.53; 95% CI = 1.33–1.77; HRN06B = 2.28; 95% CI = 1.92–2.72). The offspring N06A prescriptions, however, were too few to estimate effects. Presence of maternal GDM had no effect on offspring prescription of psychotropic medication.
In this large prospective population-based cohort study, we provide evidence of an increased risk for different pediatric psychiatric and mild neurodevelopmental disorders by joint effects of maternal obesity and PGDM. To our knowledge, this is the first study used to explore a joint effect of maternal obesity and diabetes, stratified in PGDM and GDM, on the risk of a wide spectrum of psychiatric and mild neurodevelopmental disorders in offspring. We demonstrate that maternal prepregnancy obesity was associated with a slightly increased risk of offspring’s psychiatric and mild neurodevelopmental disorders, but the risk effects were most pronounced when mothers had both maternal PGDM and severe obesity. This pattern of risk was observed for children diagnosed particularly with ASD and ADHD and/or conduct disorder but also those with most of the other studied neurodevelopmental and psychiatric disorders with onset in childhood or adolescence (F80–83, F92–F95, and F98). These joint effects of severe obesity and PGDM might reflect a stronger neural effect of exposure to long-term concomitant inflammation, lipotoxicity, metabolic stress, and hyperglycemia than that of metabolic stress and hyperglycemia (PGDM only).11–16,18 GDM, however, did not increase the risk highly for these offspring disorders. This might reflect milder in utero metabolic disturbances, adequate GDM treatment, as well as timing of the GDM (unavailable in our study) as the vulnerability period was recently suggested to be the first 26 gestational weeks.21
Specifically, we found that mothers with PGDM and severe obesity had a >6 times higher risk of giving birth to a child developing ASD, with a 95% CI of 3.1–13.7, whereas PGDM and obesity implied an HR for ASD of 3.6 (95% CI = 1.6–8.2) compared with nondiabetic mothers with normal weight. These risks are comparable to that of the previous BMI-stratified study of 2734 children including 102 with ASD born to obese or severely obese mothers in Boston, Massachusetts (HRASD = 3.91 [95% CI = 1.76–8.68]).20 We did not find any clear effects of GDM on ASD risk. Li et al,20 however, reported an effect on ASD risk also of GDM in obese or severely obese mothers (HRASD = 3.04 [95% CI = 1.21–7.63]). Likewise, a meta-analysis detected effects of both maternal PGDM and GDM on offspring ASD risk without considering BMI (RRpoint estimates of 1.7–2.2 for PGDM and 1.4–1.5 for GDM).22 Similar risks for ASD were found also later among mothers with type 2 diabetes mellitus (DM) (HRASD <1.5) and first trimesters-GDM (HRASD <1.8).21 Differences in findings between reports20–22,25 may depend on that screening procedures, diagnostic criteria, and treatment guidelines for GDM. We also found a sixfold increase in risk for offspring AHDH and/or conduct disorder when mothers had PGDM and severe obesity but no clear effect of GDM on ADHD, compared with that of nondiabetic mothers with normal weight. Whereas Li et al20 reported no effect of maternal PGDM or GDM on risk for ADHD in normal-weight or obese mothers, Nomura et al24 proposed, from a small study (n = 212), an increased risk for ADHD symptoms in offspring exposed to a combination of GDM and low socioeconomic status (SES).16,28 Thus, different maternal SES and BMI distributions, possibly interdependent, may explain discrepancies in the effect of maternal diabetes on offspring ADHD between studies. In our study, we not only stratified for BMI but also adjusted for SES through smoking and marital status, which correlated highly with more sophisticated measures of SES.
Although the association between maternal diabetes and offspring psychiatric disorders other than ASD is previously unexplored, it is well known that maternal obesity is associated with an increased risk of offspring neurodevelopmental impairment and psychiatric disorders, specifically decreased cognitive performance, ASD, and ADHD.6–8 In line with previous studies, our study supports an increased risk of offspring’s psychiatric disorders associated with maternal prepregnancy obesity. Among the largest previous studies on this topic6 is a Swedish population-based cohort study (n = 673 632 births) in which authors reported a dose-dependent increase in ADHD symptoms in children as maternal prepregnancy BMI increased from overweight to obese, with effect sizes (HRADHD = 1.7) similar to ours after adjusting for measured covariates.7 An Australian prospective cohort (n = 2785 births) revealed that higher maternal prepregnancy BMI was associated with an increased risk of internalizing problems (including withdrawal and depression) after adjusting for confounders.29 Authors of a cohort study including >1500 Australian adolescents reported that increase in maternal prepregnancy BMI increased the odds of eating disorders (anorexia, bulimia, and binge eating) in offspring.24
Finally, we performed a sensitivity analysis estimating the risk for psychotropic medication by the exposures maternal prepregnancy obesity and diabetes. The hazard ratios observed supported our findings from the F-diagnosis–based analyses.
Our study has some limitations. First, whereas the oldest birth year cohort could be followed-up for 11 years (until 2014), those born at later birth years were followed-up for a shorter time, reducing the sample size of later onset disorders. Second, offspring disorders were grouped (eg, F20–F45) to avoid too small group sizes. Third, CIs of the effect sizes for outcome diagnoses were wide but overlapped with that of outcome psychotropic medication and previous studies. Fourth, PGDM was defined on the basis of reimbursement for insulin prescription. Although insulin is used to treat primarily type 1 DM, also a minor proportion of severe type 2 DM may be treated with insulin. Young adults in Finland were recently reported to have almost similar nationwide prevalence of type 1 DM as type 2 DM.32 Fifth, maternal BMI was available from only 1 time point, so risk of change in gestational BMI on psychiatric disorders could not be studied. Missing BMI data were due to the recent clinical implementation of the registration of BMI at prenatal visit. Sixth, although we adjusted for maternal in-patient psychiatric disorders, potential residual confounding from genetic predisposition, such as data for maternal and paternal out-patient psychiatric conditions, were unavailable. In addition, a recent article revealed that suboptimal maternal cholesterol levels may increase the risk of ADHD in offspring.33 Thus, the recent emerging factors such as maternal dyslipidemia is also worth considering in future studies.
The combination of maternal pregestational insulin-treated diabetes and severe obesity was associated with greater risk for a wide variety of children’s psychiatric and mild neurodevelopmental disorders than either obesity or diabetes alone. Further studies are required to explore the biological mechanisms by which maternal diabetes and obesity may influence this long-term mental and behavioral health.
We thank Dr Anna-Maria Lahesmaa-Korpinen, THL National Institute for Health and Welfare for excellent register assistance.
- Accepted June 4, 2018.
- Address correspondence to Catharina Lavebratt, MSc, PhD, Neurogenetics Unit, Centre for Molecular Medicine, Karolinska University Hospital L8:00, 171 76 Stockholm, Sweden. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the National Institute for Health and Welfare: Drugs and Pregnancy project (Dr Gissler), the Swedish Research Council (Dr Lavebratt), the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet Stockholm County Council (Dr Lavebratt), the China Scholarship Council (www.csc.edu.cn; Mr Kong), and the Swedish Brain Foundation (Dr Lavebratt).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2018 by the American Academy of Pediatrics