Autism Spectrum Disorders in Children Exposed in Utero to Hyperemesis Gravidarum

Darios Getahun; Michael J. Fassett; Steven J. Jacobsen; Anny H. Xiang; Harpreet S. Takhar; Deborah A. Wing; Morgan R. Peltier

doi:10.1055/s-0039-1696670

American Journal of Perinatology, Table of Contents

Am J Perinatol 2021; 38(03): 265-272
DOI: 10.1055/s-0039-1696670

Original Article

Autism Spectrum Disorders in Children Exposed in Utero to Hyperemesis Gravidarum

Darios Getahun

¹Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena

²Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey

,

Michael J. Fassett

³Department of Obstetrics and Gynecology, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, California

,

Steven J. Jacobsen

¹Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena

,

Anny H. Xiang

¹Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena

,

Harpreet S. Takhar

¹Department of Research and Evaluation, Kaiser Permanente, Southern California, Pasadena

,

Deborah A. Wing

⁴Department of Obstetrics and Gynecology, University of California, Irvine, California

⁵Korn Ferry, Los Angeles, California

,

Morgan R. Peltier

⁶Department of Obstetrics and Gynecology, Winthrop University Hospital Research Institute, Winthrop University Hospital, Mineola, New York

⁷Department of Obstetrics and Gynecology, Winthrop University Hospital, Mineola, New York

› Author Affiliations

Abstract

Objective This study aimed to determine if hyperemesis gravidarum (HG) is associated with autism spectrum disorder (ASD) risk, and how this association is influenced by race, ethnicity, sex, exposure timing, and medication used to treat it.

Study Design This is a retrospective cohort study using records from 469,789 mother–child pairs who delivered at Kaiser Permanente Southern California (KPSC) hospital (1991–2014). Singleton-born children were followed longitudinally from 2 to 17 years of age. Clinical records were used to determine the diagnosis of HG and specialist-confirmed diagnosis of ASD.

Results Children exposed to HG in-utero had higher rates of ASD than unexposed children (2.87 vs. 1.71/1,000 person-years; adjusted hazard ratio [adj.HR]: 1.53; 95% confidence interval [CI]: 1.37–1.70). Children exposed at first and second trimester of pregnancies were more likely to develop ASD; 1.58-fold (95% CI: 1.40–1.79), and 1.36-fold (95% CI: 1.05–1.75), respectively, compared with unexposed children. HG was associated with ASD for boys (adj.HR: 1.50; 95% CI: 1.33–1.70) and girls (adj.HR: 1.62; 95% CI: 1.28–2.05). HG was significantly associated with ASD risk in white and Hispanic children. The medications used to treat HG did not contribute to ASD risk.

Conclusion HG diagnosis is associated with ASD risk and may be helpful in identifying at-risk children who could benefit from enhanced surveillance and earlier diagnosis and intervention.

Keywords

autism - neurodevelopment - hyperemesis gravidarum - race - ethnicity

Full Text

References

References
1 Baio J, Wiggins L, Christensen DL. et al; Centers for Disease Control and Prevention. Morbidity and mortality weekly report. Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. Surveillance Summaries 2018; 67 (06) 1-23
2 Newschaffer CJ, Croen LA, Daniels J. et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007; 28: 235-258
3 Biao J. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 2012; 61 (03) 1-19
4 Montes G, Halterman JS. Association of childhood autism spectrum disorders and loss of family income. Pediatrics 2008; 121 (04) e821-e826
5 Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. Economic burden of childhood autism spectrum disorders. Pediatrics 2014; 133 (03) e520-e529
6 Croen LA, Grether JK, Selvin S. Descriptive epidemiology of autism in a California population: who is at risk?. J Autism Dev Disord 2002; 32 (03) 217-224
7 Kogan MD, Blumberg SJ, Schieve LA. et al. Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 2009; 124 (05) 1395-1403
8 Durkin MS, Maenner MJ, Newschaffer CJ. et al. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol 2008; 168 (11) 1268-1276
9 Xiang AH, Wang X, Martinez MP. et al. Association of maternal diabetes with autism in offspring. JAMA 2015; 313 (14) 1425-1434
10 Getahun D, Fassett MJ, Peltier MR. et al. Association of perinatal risk factors with autism spectrum disorder. Am J Perinatol 2017; 34 (03) 295-304
11 Hall RW, Huitt TW, Thapa R, Williams DK, Anand KJ, Garcia-Rill E. Long-term deficits of preterm birth: evidence for arousal and attentional disturbances. Clin Neurophysiol 2008; 119 (06) 1281-1291
12 Moore GS, Kneitel AW, Walker CK, Gilbert WM, Xing G. Autism risk in small- and large-for-gestational-age infants. Am J Obstet Gynecol 2012; 206 (04) 314e1–319
13 Xie F, Peltier M, Getahun D. Is the risk of autism in younger siblings of affected children moderated by sex, race/ethnicity, or gestational age?. J Dev Behav Pediatr 2016; 37 (08) 603-609
14 Grønborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr 2013; 167 (10) 947-953
15 Vasa RA, Anderson C, Marvin AR. et al. Mood disorders in mothers of children on the autism spectrum are associated with higher functioning autism. Autism Res Treat 2012; 2012: 435646
16 Bailit JL. Hyperemesis gravidarium: epidemiologic findings from a large cohort. Am J Obstet Gynecol 2005; 193 (3, Pt 1): 811-814
17 Einarson TR, Piwko C, Koren G. Prevalence of nausea and vomiting of pregnancy in the USA: a meta analysis. J Popul Ther Clin Pharmacol 2013; 20 (02) e163-e170
18 Einarson TR, Piwko C, Koren G. Quantifying the global rates of nausea and vomiting of pregnancy: a meta analysis. J Popul Ther Clin Pharmacol 2013; 20 (02) e171-e183
19 Godsey RK, Newman RB. Hyperemesis gravidarum. A comparison of single and multiple admissions. J Reprod Med 1991; 36 (04) 287-290
20 Fejzo MS, Ingles SA, Wilson M. et al. High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. Eur J Obstet Gynecol Reprod Biol 2008; 141 (01) 13-17
21 Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995; 5 (05) 425-434
22 Schiff MA, Reed SD, Daling JR. The sex ratio of pregnancies complicated by hospitalisation for hyperemesis gravidarum. BJOG 2004; 111 (01) 27-30
23 Cedergren M, Brynhildsen J, Josefsson A, Sydsjo A, Sydsjo G. Hyperemesis gravidarum that requires hospitalization and the use of antiemetic drugs in relation to maternal body composition. Am J Obstet Gynecol 2008; 198 (04) 412–415
24 Brown AS, Susser ES, Lin SP, Neugebauer R, Gorman JM. Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944-45. Br J Psychiatry 1995; 166 (05) 601-606
25 Neugebauer R, Hoek HW, Susser E. Prenatal exposure to wartime famine and development of antisocial personality disorder in early adulthood. JAMA 1999; 282 (05) 455-462
26 Román GC, Ghassabian A, Bongers-Schokking JJ. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 2013; 74 (05) 733-742
27 Getahun D, Rhoads GG, Fassett MJ. et al. Accuracy of reporting maternal and infant perinatal service system coding and clinical utilization coding. J Med Stat Inform 2013; 1-3 ; doi:10.7243/2053-7662-1-3
28 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Publishing; 2000
29 Coleman KJ, Lutsky MA, Yau V. et al. Validation of autism spectrum disorder diagnoses in large healthcare systems with electronic medical records. J Autism Dev Disord 2015; 45 (07) 1989-1996
30 Clinical Practice. Guideline. Kaiser permanent Southern California preventive services for children and adolescents. Accessed August 17, 2019 at: https://cl.kp.org/scal/home/refcontainerpage.dam.html?damrefpath=/content/dam/clinicallibrary/scal/cpg/cpg/html/kpsc_preventive_care_child_adolescent_update.pdf
31 Robins DL, Fein D, Barton ML, Green JA. The modified checklist for autism in toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord 2001; 31 (02) 131-144
32 VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med 2017; 167 (04) 268-274
33 Stein Z, Susser M, Saenger G, Marolla F. Famine and Human Development. The Dutch Hunger Winter of 1944–1945. New York, NY: Oxford University Press; 1975
34 Brown AS, van Os J, Driessens C, Hoek HW, Susser ES. Further evidence of relation between prenatal famine and major affective disorder. Am J Psychiatry 2000; 157 (02) 190-195
35 Hulshoff Pol HE, Hoek HW, Susser E. et al. Prenatal exposure to famine and brain morphology in schizophrenia. Am J Psychiatry 2000; 157 (07) 1170-1172
36 O'Connor TG, Heron J, Golding J, Glover V. ; ALSPAC Study Team. Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis. J Child Psychol Psychiatry 2003; 44 (07) 1025-1036
37 Morgane PJ, Austin-LaFrance R, Bronzino J. et al. Prenatal malnutrition and development of the brain. Neurosci Biobehav Rev 1993; 17 (01) 91-128
38 Madore C, Nadjar A, Delpech JC. et al. Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes. Brain Behav Immun 2014; 41: 22-31
39 Bolin M, Åkerud H, Cnattingius S, Stephansson O, Wikström AK. Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study. BJOG 2013; 120 (05) 541-547
40 Mayeur S, Silhol M, Moitrot E. et al. Placental BDNF/TrkB signaling system is modulated by fetal growth disturbances in rat and human. Placenta 2010; 31 (09) 785-791
41 de Rooij SR, Wouters H, Yonker JE, Painter RC, Roseboom TJ. Prenatal undernutrition and cognitive function in late adulthood. Proc Natl Acad Sci U S A 2010; 107 (39) 16881-16886
42 Farias PS, dos S Souza K, Fioretto ET, dos Santos MR, Aires MB. Maternal diabetes affects rat placental morphology and pregnancy. Endocrine 2014; 45 (03) 497-501
43 Heasman L, Clarke L, Firth K, Stephenson T, Symonds ME. Influence of restricted maternal nutrition in early to mid gestation on placental and fetal development at term in sheep. Pediatr Res 1998; 44 (04) 546-551
44 Peng C, Aron L, Klein R. et al. Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons. J Neurosci 2011; 31 (36) 12802-12815
45 Miyazaki K, Narita N, Sakuta R. et al. Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Brain Dev 2004; 26 (05) 292-295
46 Hultman CM, Sparén P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology 2002; 13 (04) 417-423
47 Buka SL, Shenassa ED, Niaura R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry 2003; 160 (11) 1978-1984
48 McEachin JJ, Smith T, Lovaas OI. Long-term outcome for children with autism who received early intensive behavioral treatment. Am J Ment Retard 1993; 97 (04) 359-372

Supplementary Material

Supplementary Material