Prenatal alcohol exposure (PAE) impacts the neurodevelopment of the fetus, including the infant’s ability to self-regulate. Heart rate variability (HRV), that is, the beat-to-beat variability in heart rate, is a non-invasive measurement that can indicate autonomic nervous system (ANS) function/dysfunction.
The study consisted of a subset of our ENRICH-2 cohort: 80 participants (32 PAE and 48 Controls) who had completed three visits during pregnancy. The participants completed a comprehensive assessment of PAE and other substances throughout pregnancy and assessments for stress, anxiety, and depression in the third trimester. At 24 h of age, infant HRV was assessed in the hospital during the clinically indicated heel lance; 3- to 5-min HRV epochs were obtained during baseline, heel lancing, and recovery episodes.
Parameters of HRV differed in infants with PAE compared to Controls during the recovery phase of the heel lance (respiratory sinus arrhythmia (RSA) and high-frequency (HF), p < 0.05). Increased maternal stress was also strongly associated with abnormalities in RSA, HF, and low-frequency / high-frequency (LF/HF, p’s < 0.05).
Alterations in ANS regulation associated with PAE and maternal stress may reflect abnormal development of the hypothalamic-pituitary-adrenal axis and have long term implications for infant responsiveness and self-regulation.
Previous studies have focused on effects of moderate to heavy prenatal alcohol exposure (PAE) on autonomic dysregulation, but little is known about the effects of lower levels of PAE on infant self-regulation and heart rate variability (HRV).
Prenatal stress is another risk factor for autonomic dysregulation.
Mild PAE impacts infant self-regulation, which can be assessed using HRV.
However, the effect of prenatal stress is stronger than that of mild PAE or other mental health variables on autonomic dysregulation.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 13 print issues and online access
$259.00 per year
only $19.92 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Pruett, D., Waterman, E. H. & Caughey, A. B. Fetal alcohol exposure: consequences, diagnosis, and treatment. Obstet. Gynecol. Surv. 68, 62–69 (2013).
Dejong, K., Olyaei, A. & Lo, J. O. Alcohol use in pregnancy. Clin. Obstet. Gynecol. 62, 142–155 (2019).
Green, P. P., McKnight-Eily, L. R., Tan, C. H., Mejia, R. & Denny, C. H. Vital signs: alcohol-exposed pregnancies–United States, 2011-2013. MMWR Morb. Mortal. Wkly Rep. 65, 91–97 (2016).
Bakhireva, L. N. et al. Prevalence of alcohol use in pregnant women with substance use disorder. Drug Alcohol Depend. 187, 305–310 (2018).
Lange, S. et al. Global prevalence of fetal alcohol spectrum disorder among children and youth: a systematic review and meta-analysis. JAMA Pediatr. 171, 948–956 (2017).
Denny, C. H., Acero, C. S., Naimi, T. S. & Kim, S. Y. Consumption of alcohol beverages and binge drinking among pregnant women aged 18-44 years - United States, 2015-2017. MMWR Morb. Mortal. Wkly Rep. 68, 365–368 (2019).
Popova, S., Lange, S., Probst, C., Parunashvili, N. & Rehm, J. Prevalence of alcohol consumption during pregnancy and fetal alcohol spectrum disorders among the general and Aboriginal populations in Canada and the United States. Eur. J. Med. Genet. 60, 32–48 (2017).
Oh, S., Reingle Gonzalez, J. M., Salas-Wright, C. P., Vaughn, M. G. & DiNitto, D. M. Prevalence and correlates of alcohol and tobacco use among pregnant women in the United States: evidence from the NSDUH 2005-2014. Prev. Med. 97, 93–99 (2017).
Pollard, M. S., Tucker, J. S. & Green, H. D. Jr. Changes in adult alcohol use and consequences during the COVID-19 pandemic in the US. JAMA Netw. Open 3, e2022942 (2020).
Popova, S., Dozet, D., Shield, K., Rehm, J., Burd, L. Alcohol’s impact on the fetus. Nutrients 13 https://doi.org/10.3390/nu13103452 (2021).
Underwood, M. A., Gilbert, W. M. & Sherman, M. P. Amniotic fluid: not just fetal urine anymore. J. Perinatol. 25, 341–348 (2005).
Heller, M. & Burd, L. Review of ethanol dispersion, distribution, and elimination from the fetal compartment. Birth Defects Res A Clin. Mol. Teratol. 100, 277–283 (2014).
Burd, L., Blair, J. & Dropps, K. Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn. J. Perinatol. 32, 652–659 (2012).
May, P. A. et al. Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking. Drug Alcohol Depend. 133, 502–512 (2013).
Williams, J. F. & Smith, V. C. Committee On Substance A. Fetal alcohol spectrum disorders. Pediatrics 136, e1395–e1406 (2015).
May, P. A. et al. Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics 134, 855–866 (2014).
Ahluwalia, B. et al. Alcohol modulates cytokine secretion and synthesis in human fetus: an in vivo and in vitro study. Alcohol 21, 207–213 (2000).
Bake, S. et al. Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats. Brain Behav. Immun. 98, 86–100 (2021).
Bodnar, T. S. et al. Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure. J. Neuroinflamm. 17, 39 (2020).
Burd, L., Roberts, D., Olson, M. & Odendaal, H. Ethanol and the placenta: a review. J. Matern Fetal Neonatal Med 20, 361–375 (2007).
Abbott, C. W., Kozanian, O. O., Kanaan, J., Wendel, K. M. & Huffman, K. J. The impact of prenatal ethanol exposure on neuroanatomical and behavioral development in mice. Alcohol Clin. Exp. Res. 40, 122–133 (2016).
Abernathy, K., Chandler, L. J. & Woodward, J. J. Alcohol and the prefrontal cortex. Int Rev. Neurobiol. 91, 289–320 (2010).
Astley, S. J. et al. Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. 33, 1671–1689 (2009).
Wozniak, J. R. et al. Microstructural corpus callosum anomalies in children with prenatal alcohol exposure: an extension of previous diffusion tensor imaging findings. Alcohol Clin. Exp. Res. 33, 1825–1835 (2009).
Cuzon Carlson, V. C., Gremel, C. M. & Lovinger, D. M. Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring. Nat. Commun. 11, 2555 (2020).
Carter, R. C. et al. Fetal alcohol growth restriction and cognitive impairment. Pediatrics 138 https://doi.org/10.1542/peds.2016-0775 (2016).
Dodge, N. C. et al. Spatial navigation in children and young adults with fetal alcohol spectrum disorders. Alcohol Clin. Exp. Res. https://doi.org/10.1111/acer.14210 (2019).
Gupta, K. K., Gupta, V. K. & Shirasaka, T. An Update on fetal alcohol syndrome-pathogenesis, risks, and treatment. Alcohol Clin. Exp. Res. 40, 1594–1602 (2016).
Sood, B. et al. Prenatal alcohol exposure and childhood behavior at age 6 to 7 years: I. dose-response effect. Pediatrics 108, E34 (2001).
Hamilton, D. A., Kodituwakku, P., Sutherland, R. J. & Savage, D. D. Children with fetal alcohol syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task. Behav. Brain Res. 143, 85–94 (2003).
Caprara, D. L., Nash, K., Greenbaum, R., Rovet, J. & Koren, G. Novel approaches to the diagnosis of fetal alcohol spectrum disorder. Neurosci. Biobehav Rev. 31, 254–260 (2007).
Hoyme, H. E. et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics 138 https://doi.org/10.1542/peds.2015-4256 (2016).
Kalberg, W. O. & Buckley, D. FASD: what types of intervention and rehabilitation are useful. Neurosci. Biobehav. Rev. 31, 278–285 (2007).
Petryk, S., Siddiqui, M. A., Ekeh, J. & Pandey, M. Prenatal alcohol history—setting a threshold for diagnosis requires a level of detail and accuracy that does not exist. BMC Pediatr. 19, 372 (2019).
Beauchamp, K. G. et al. Self-regulation and emotional reactivity in infants with prenatal exposure to opioids and alcohol. Early Hum. Dev. 148, 105119 (2020).
Babkina, N. Experimental research into conscious self-regulation in first-graders with developmental delay. Behav. Sci. (Basel) 9. https://doi.org/10.3390/bs9120158 (2019).
Oliveira, V. et al. Early postnatal heart rate variability in healthy newborn infants. Front. Physiol. 10, 922 (2019).
Rajendra Acharya, U., Paul Joseph, K., Kannathal, N., Lim, C. M. & Suri, J. S. Heart rate variability: a review. Med. Biol. Eng. Comput. 44, 1031–1051 (2006).
Stone, M. L. et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J. Perinatol. 33, 847–850 (2013).
Bellodas Sanchez, J. & Kadrofske, M. Necrotizing enterocolitis. Neurogastroenterol. Motil. 31, e13569 (2019).
Rakow, A., Katz-Salamon, M., Ericson, M., Edner, A. & Vanpee, M. Decreased heart rate variability in children born with low birth weight. Pediatr. Res. 74, 339–343 (2013).
Yasova Barbeau, D. et al. Heart rate variability and inflammatory markers in neonates with hypoxic-ischemic encephalopathy. Physiol. Rep. 7, e14110 (2019).
Ask, T. F. et al. The association between heart rate variability and neurocognitive and socio-emotional development in Nepalese infants. Front. Neurosci. 13, 411 (2019).
Oberlander, T. F. et al. Prenatal alcohol exposure alters biobehavioral reactivity to pain in newborns. Alcohol Clin. Exp. Res. 34, 681–692 (2010).
Jurczyk, M., Dylag, K. A., Skowron, K. & Gil, K. Prenatal alcohol exposure and autonomic nervous system dysfunction: a review article. Folia Med Crac. 59, 15–21 (2019).
Fifer, W. P., Fingers, S. T., Youngman, M., Gomez-Gribben, E. & Myers, M. M. Effects of alcohol and smoking during pregnancy on infant autonomic control. Dev. Psychobiol. 51, 234–242 (2009).
Bolten, M. I., Fink, N. S. & Stadler, C. Maternal self-efficacy reduces the impact of prenatal stress on infant’s crying behavior. J. Pediatr. 161, 104–109 (2012).
Planalp, E. M., Nowak, A. L., Tran, D., Lefever, J. B. & Braungart-Rieker, J. M. Positive parenting, parenting stress, and child self-regulation patterns differ across maternal demographic risk. J. Fam. Psychol. 36, 713–724 (2022).
Korja, R., Nolvi, S., Grant, K. A. & McMahon, C. The relations between maternal prenatal anxiety or stress and child’s early negative reactivity or self-regulation: a systematic review. Child Psychiatry Hum. Dev. 48, 851–869 (2017).
Foss, S. et al. Associations among maternal lifetime trauma, psychological symptoms in pregnancy, and infant stress reactivity and regulation. Dev. Psychopathol. 1–18 https://doi.org/10.1017/S0954579422000402 (2022).
Meneses-Gaya, C. et al. Is the full version of the AUDIT really necessary? Study of the validity and internal construct of its abbreviated versions. Alcohol Clin. Exp. Res. 34, 1417–1424 (2010).
Reinert, D. F. & Allen, J. P. The alcohol use disorders identification test: an update of research findings. Alcohol Clin. Exp. Res. 31, 185–199 (2007).
Frank, D. et al. Effectiveness of the AUDIT-C as a screening test for alcohol misuse in three race/ethnic groups. J. Gen. Intern Med. 23, 781–787 (2008).
Ernhart, C. B., Morrow-Tlucak, M., Sokol, R. J. & Martier, S. Underreporting of alcohol use in pregnancy. Alcohol Clin. Exp. Res. 12, 506–511 (1988).
Bradley, K. A., Boyd-Wickizer, J., Powell, S. H. & Burman, M. L. Alcohol screening questionnaires in women: a critical review. JAMA 280, 166–171 (1998).
Dawson, D. A., Grant, B. F., Stinson, F. S. & Zhou, Y. Effectiveness of the derived Alcohol Use Disorders Identification Test (AUDIT-C) in screening for alcohol use disorders and risk drinking in the US general population. Alcohol Clin. Exp. Res. 29, 844–854 (2005).
Bakhireva, L. N., Leeman, L., Roberts, M., Rodriguez, D. E. & Jacobson, S. W. You didn’t drink during pregnancy, did you? Alcohol Clin. Exp. Res. 45, 543–547 (2021).
Jacobson, S. W., Chiodo, L. M., Sokol, R. J. & Jacobson, J. L. Validity of maternal report of prenatal alcohol, cocaine, and smoking in relation to neurobehavioral outcome. Pediatrics 109, 815–825 (2002).
Bakhireva, L. N. & Savage, D. D. Focus on: biomarkers of fetal alcohol exposure and fetal alcohol effects. Alcohol Res. Health J. Natl Inst. Alcohol Abus. Alcohol. 34, 56–63 (2011).
Bakhireva, L. N., Lowe, J. R., Gutierrez, H. L., Stephen, J. M. Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort: study design considerations. Adv. Pediatr. Res. 2 https://doi.org/10.12715/apr.2015.2.10 (2015).
Kable, J. A. & Mukherjee, R. A. Neurodevelopmental disorder associated with prenatal exposure to alcohol (ND-PAE): a proposed diagnostic method of capturing the neurocognitive phenotype of FASD. Eur. J. Med. Genet 60, 49–54 (2017).
Cohen, S., Kamarck, T. & Mermelstein, R. A global measure of perceived stress. J. Health Soc. Behav. 24, 385–396 (1983).
Simpson, W., Glazer, M., Michalski, N., Steiner, M. & Frey, B. N. Comparative efficacy of the generalized anxiety disorder 7-item scale and the Edinburgh Postnatal Depression Scale as screening tools for generalized anxiety disorder in pregnancy and the postpartum period. Can. J. Psychiatry 59, 434–440 (2014).
Bergink, V. et al. Validation of the Edinburgh depression scale during pregnancy. J. Psychosom. Res. 70, 385–389 (2011).
Gibson, J., McKenzie-McHarg, K., Shakespeare, J., Price, J. & Gray, R. A systematic review of studies validating the Edinburgh Postnatal Depression Scale in antepartum and postpartum women. Acta Psychiatr. Scand. 119, 350–364 (2009).
Sherbourne, C. D. & Stewart, A. L. The MOS social support survey. Soc. Sci. Med. 32, 705–714 (1991).
Barratt, W. The Barratt Simplified Measure of Social Status (BSMSS) (Indiana State University, 2006).
Bakhireva, L. N. et al. The validity of phosphatidylethanol in dried blood spots of newborns for the identification of prenatal alcohol exposure. Alcohol Clin. Exp. Res. 38, 1078–1085 (2014).
Bakhireva, L. N. et al. The feasibility and cost of neonatal screening for prenatal alcohol exposure by measuring phosphatidylethanol in dried blood spots. Alcohol Clin. Exp. Res. 37, 1008–1015 (2013).
Heart rate variability. standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 93, 1043–1065 (1996).
Abel, E. L., Kruger, M. L. & Friedl, J. How do physicians define “light,” “moderate,” and “heavy” drinking. Alcohol Clin. Exp. Res. 22, 979–984 (1998).
DeGiorgio, C. M. et al. RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: the SUDEP-7 Inventory. Epilepsy Behav. 19, 78–81 (2010).
Rotenberg, S. & McGrath, J. J. Inter-relation between autonomic and HPA axis activity in children and adolescents. Biol. Psychol. 117, 16–25 (2016).
Abraham, E., Zagoory-Sharon, O. & Feldman, R. Early maternal and paternal caregiving moderates the links between preschoolers’ reactivity and regulation and maturation of the HPA-immune axis. Dev. Psychobiol. 63, 1482–1498 (2021).
Reilly, E. B. & Gunnar, M. R. Neglect, HPA axis reactivity, and development. Int J. Dev. Neurosci. 78, 100–108 (2019).
Quirin, M., Pruessner, J. C. & Kuhl, J. HPA system regulation and adult attachment anxiety: individual differences in reactive and awakening cortisol. Psychoneuroendocrinology 33, 581–590 (2008).
Cohen, S., Janicki-Deverts, D. & Miller, G. E. Psychological stress and disease. JAMA 298, 1685–1687 (2007).
DeSocio, J. E. Epigenetics, maternal prenatal psychosocial stress, and infant mental health. Arch. Psychiatr. Nurs. 32, 901–906 (2018).
Jacobson, S. W. et al. Maternal recall of alcohol, cocaine, and marijuana use during pregnancy. Neurotoxicol. Teratol. 13, 535–540 (1991).
Class, Q. A., Khashan, A. S., Lichtenstein, P., Langstrom, N. & D’Onofrio, B. M. Maternal stress and infant mortality: the importance of the preconception period. Psychol. Sci. 24, 1309–1316 (2013).
Perera, M. J. et al. Factor structure of the Perceived Stress Scale-10 (PSS) across English and Spanish language responders in the HCHS/SOL Sociocultural Ancillary Study. Psychol. Assess. 29, 320–328 (2017).
Weinberg, J., Sliwowska, J. H., Lan, N. & Hellemans, K. G. Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome. J. Neuroendocrinol. 20, 470–488 (2008).
Kapoor, A., Dunn, E., Kostaki, A., Andrews, M. H. & Matthews, S. G. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J. Physiol. 572, 31–44 (2006).
Spitzer, R. L., Kroenke, K., Williams, J. B. & Lowe, B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch. Intern Med. 166, 1092–1097 (2006).
Cox, J. L., Holden, J. M. & Sagovsky, R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br. J. Psychiatry 150, 782–786 (1987).
Hellemans, K. G., Sliwowska, J. H., Verma, P. & Weinberg, J. Prenatal alcohol exposure: fetal programming and later life vulnerability to stress, depression and anxiety disorders. Neurosci. Biobehav. Rev. 34, 791–807 (2010).
Reid, N. & Petrenko, C. L. M. Applying a developmental framework to the self-regulatory difficulties of young children with prenatal alcohol exposure: a review. Alcohol Clin. Exp. Res. 42, 987–1005 (2018).
Howland, M. A., Sandman, C. A., Davis, E. P. & Glynn, L. M. Prenatal maternal psychological distress and fetal developmental trajectories: associations with infant temperament. Dev. Psychopathol. 32, 1685–1695 (2020).
Ruffaner-Hanson, C. et al. The maternal-placental-fetal interface: adaptations of the HPA axis and immune mediators following maternal stress and prenatal alcohol exposure. Exp. Neurol. 355, 114121 (2022).
Price, A., Cook, P. A., Norgate, S. & Mukherjee, R. Prenatal alcohol exposure and traumatic childhood experiences: a systematic review. Neurosci. Biobehav. Rev. 80, 89–98 (2017).
Popova, S., Dozet, D., Akhand Laboni, S., Brower, K. & Temple, V. Why do women consume alcohol during pregnancy or while breastfeeding. Drug Alcohol Rev. 41, 759–777 (2022).
Lucchini, M. et al. Effects of prenatal exposure to alcohol and smoking on fetal heart rate and movement regulation. Front Physiol. 12, 594605 (2021).
The authors would like to thank Dominique Rodriguez, Laura Stacy, Sandra Beauman, Conra Lacy, Elizabeth Kuan, and Nicole Salazar for their help with data collection and data management.
Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R01AA021771. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare no competing interests.
Informed participant consent was obtained prior to initiation of study activities.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Maxwell, J.R., DiDomenico, J., Roberts, M.H. et al. Impact of low-level prenatal alcohol exposure and maternal stress on autonomic regulation. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02799-5