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Alcohol exposure during late gestation: multiple developmental outcomes in sheep

Published online by Cambridge University Press:  30 April 2012

K. Kenna*
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
F. Sozo
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
R. De Matteo
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
T. Hanita
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
S. P. Gray
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
M. Tare
Affiliation:
Department of Physiology, Monash University, Clayton, Victoria, Australia
K. Moritz
Affiliation:
School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia
J. F. Bertram
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
M. Jane Black
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
J. F. Brien
Affiliation:
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
H. C. Parkington
Affiliation:
Department of Physiology, Monash University, Clayton, Victoria, Australia
D. W. Walker
Affiliation:
Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
R. Harding
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
*
*Address for correspondence: Dr K. Kenna, Department of Anatomy and Developmental Biology, Building 76, Monash University, Clayton, Victoria, Australia. Email [email protected]

Abstract

Alcohol consumption during pregnancy remains common in many countries. Exposure to even low amounts of alcohol (i.e. ethanol) in pregnancy can lead to the heterogeneous fetal alcohol spectrum disorders (FASD), while heavy alcohol consumption can result in the fetal alcohol syndrome (FAS). FAS is characterized by cerebral dysfunction, growth restriction and craniofacial malformations. However, the effects of lower doses of alcohol during pregnancy, such as those that lead to FASD, are less well understood. In this article, we discuss the findings of recent studies performed in our laboratories on the effects of fetal alcohol exposure using sheep, in which we investigated the effects of late gestational alcohol exposure on the developing brain, arteries, kidneys, heart and lungs. Our studies indicate that alcohol exposure in late gestation can (1) affect cerebral white matter development and increase the risk of hemorrhage in the fetal brain, (2) cause left ventricular hypertrophy with evidence of altered cardiomyocyte maturation, (3) lead to a decrease in nephron number in the kidney, (4) cause altered arterial wall stiffness and endothelial and smooth muscle function and (5) result in altered surfactant protein mRNA expression, surfactant phospholipid composition and pro-inflammatory cytokine mRNA expression in the lung. These findings suggest that fetal alcohol exposure in late gestation can affect multiple organs, potentially increasing the risk of disease and organ dysfunction in later life.

Type
Review
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012

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References

1.Ethen, MK, Ramadhani, TA, Scheuerle, AE, et al. . Alcohol consumption by women before and during pregnancy. Matern Child Health J. 2009; 13, 274285.Google Scholar
2.Colvin, L, Payne, J, Parsons, D, et al. . Alcohol consumption during pregnancy in nonindigenous West Australian women. Alcohol Clin Exp Res. 2007; 31, 276284.Google Scholar
3.May, PA, Gossage, JP, Kalberg, WO, et al. . Prevalence and epidemiologic characteristics of fasd from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev. 2009; 15, 176192.CrossRefGoogle ScholarPubMed
5.Hutson, JR, Rao, C, Fulga, N, et al. . An improved method for rapidly quantifying fatty acid ethyl esters in meconium suitable for prenatal alcohol screening. Alcohol. 2010; 45, 193199.Google Scholar
6.Hoyme, HE, May, PA, Kalberg, WO, et al. . A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 Institute of Medicine Criteria. Pediatrics. 2005; 115, 3947.Google Scholar
7.May, PA, Gossage, JP, Marais, AS, et al. . The epidemiology of fetal alcohol syndrome and partial fas in a South African community. Drug Alcohol Depend. 2007; 88, 259271.Google Scholar
8.de Boo, HA, Harding, JE. The developmental origins of adult disease (Barker) hypothesis. Aust N Z J Obstet Gynaecol. 2006; 46, 414.Google Scholar
9.Wright, JT, Waterson, EJ, Barrison, IG, et al. . Alcohol consumption, pregnancy, and low birthweight. Lancet. 1983; 1, 663665.Google Scholar
10.Patra, J, Bakker, R, Irving, H, et al. . Dose–response relationship between alcohol consumption before and during pregnancy and the risks of low birthweight, preterm birth and small for gestational age (SGA) – a systematic review and meta-analyses. BJOG. 2011; 118, 14111421.Google Scholar
11.Jaddoe, VW, Bakker, R, Hofman, A, et al. . Moderate alcohol consumption during pregnancy and the risk of low birth weight and preterm birth. The Generation R Study. Ann Epidemiol. 2007; 17, 834840.Google Scholar
12.Parazzini, F, Chatenoud, L, Surace, M, et al. . Moderate alcohol drinking and risk of preterm birth. Eur J Clin Nutr. 2003; 57, 13451349.Google Scholar
13.O'Leary, CM, Nassar, N, Kurinczuk, JJ, et al. . The effect of maternal alcohol consumption on fetal growth and preterm birth. BJOG. 2009; 116, 390400.Google Scholar
14.Hannigan, JH, Armant, DR. Alcohol in pregnancy and neonatal outcome. Semin Neonatol. 2000; 5, 243254.Google Scholar
15.Lumeng, JC, Cabral, HJ, Gannon, K, et al. . Pre-natal exposures to cocaine and alcohol and physical growth patterns to age 8 years. Neurotoxicol Teratol. 2007; 29, 446457.Google Scholar
16.Autti-Ramo, I, Fagerlund, A, Ervalahti, N, et al. . Fetal alcohol spectrum disorders in finland: clinical delineation of 77 older children and adolescents. Am J Med Genet A. 2006; 140, 137143.Google Scholar
17.Potter, BJ, Belling, GB, Mano, MT, et al. . Experimental production of growth retardation in the sheep fetus after exposure to alcohol. Med J Aust. 1980; 2, 191193.Google Scholar
18.Kenna, K, De Matteo, R, Hanita, T, et al. . Daily ethanol exposure during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology. Am J Physiol Regul Integr Comp Physiol. 2011; 301, R926RR36.Google Scholar
19.Dalitz, P, Cock, M, Harding, R, et al. . Injurious effects of acute ethanol exposure during late gestation on developing white matter in fetal sheep. Int J Dev Neurosci. 2008; 26, 391399.Google Scholar
20.Murillo-Fuentes, L, Artillo, R, Carreras, O, et al. . Effects of maternal chronic alcohol administration in the rat: lactation performance and pup's growth. Eur J Nutr. 2001; 40, 147154.Google Scholar
21.Kaminen-Ahola, N, Ahola, A, Flatscher-Bader, T, et al. . Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome. Birth Defects Res A Clin Mol Teratol. 2010; 88, 818826.Google Scholar
22.Oxendine, SL, Cowden, J, Hinton, DE, et al. . Vulnerable windows for developmental ethanol toxicity in the Japanese medaka fish (Oryzias latipes). Aquat Toxicol. 2006; 80, 396404.Google Scholar
23.Church, MW, Morbach, CA, Subramanian, MG. Comparative effects of prenatal cocaine, alcohol, and undernutrition on maternal/fetal toxicity and fetal body composition in the Sprague-Dawley rat with observations on strain-dependent differences. Neurotoxicol Teratol. 1995; 17, 559567.Google Scholar
24.David, P, Subramaniam, K. Prenatal alcohol exposure and early postnatal changes in the developing nerve–muscle system. Birth Defects Res A Clin Mol Teratol. 2005; 73, 897903.Google Scholar
25.Aros, S, Mills, JL, Iniguez, G, et al. . Effects of prenatal ethanol exposure on postnatal growth and the insulin-like growth factor axis. Horm Res Paediatr. 2010; 75, 166173.Google Scholar
26.Breese, CR, D'Costa, A, Ingram, RL, et al. . Long-term suppression of insulin-like growth factor-1 in rats after in utero ethanol exposure: relationship to somatic growth. J Pharmacol Exp Ther. 1993; 264, 448456.Google Scholar
27.Gatford, KL, Dalitz, PA, Cock, ML, et al. . Acute ethanol exposure in pregnancy alters the insulin-like growth factor axis of fetal and maternal sheep. Am J Physiol Endocrinol Metab. 2007; 292, E494E500.Google Scholar
28.Halmesmaki, E, Valimaki, M, Karonen, SL, et al. . Low somatomedin c and high growth hormone levels in newborns damaged by maternal alcohol abuse. Obstet Gynecol. 1989; 74, 366370.Google Scholar
29.Mauceri, HJ, Unterman, T, Dempsey, S, et al. . Effect of ethanol exposure on circulating levels of insulin-like growth factor I and II, and insulin-like growth factor binding proteins in fetal rats. Alcohol Clin Exp Res. 1993; 17, 12011206.CrossRefGoogle ScholarPubMed
30.Aros, S, Mills, JL, Iniguez, G, et al. . Effects of prenatal ethanol exposure on postnatal growth and the insulin-like growth factor axis. Horm Res Paediatr. 2011; 75, 166173.Google Scholar
31.Spong, CY, Abebe, DT, Gozes, I, et al. . Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome. J Pharmacol Exp Ther. 2001; 297, 774779.Google Scholar
32.Salihu, HM, Kornosky, JL, Lynch, O, et al. . Impact of prenatal alcohol consumption on placenta-associated syndromes. Alcohol. 2011; 45, 7379.Google Scholar
33.Turan Akay, M, Arzu Kockaya, E. The effects of alcohol on rat placenta. Cell Biochem Funct. 2005; 23, 435445.Google Scholar
34.Aufrere, G, Le Bourhis, B. Effect of alcohol intoxication during pregnancy on foetal and placental weight: experimental studies. Alcohol Alcohol. 1987; 22, 401407.Google Scholar
35.Li, Y, Yan, YE, Wang, H. Enhancement of placental antioxidative function and P-Gp expression by sodium ferulate mediated its protective effect on rat IUGR induced by prenatal tobacco/alcohol exposure. Environ Toxicol Pharmacol. 2011; 32, 465471.Google Scholar
36.Nayak, RB, Murthy, P. Fetal alcohol spectrum disorder. Indian Pediatr. 2008; 45, 977983.Google Scholar
37.Tikkanen, J, Heinonen, OP. Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology. 1991; 43, 591600.Google Scholar
38.Kvigne, VL, Leonardson, GR, Neff-Smith, M, et al. . Characteristics of children who have full or incomplete fetal alcohol syndrome. J Pediatr. 2004; 145, 635640.CrossRefGoogle ScholarPubMed
39.Stromland, K, Pinazo-Duran, MD. Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol Alcohol. 2002; 37, 28.Google Scholar
40.Church, MW, Eldis, F, Blakley, BW, et al. . Hearing, language, speech, vestibular, and dentofacial disorders in fetal alcohol syndrome. Alcohol Clin Exp Res. 1997; 21, 227237.Google Scholar
41.Taylor, CL, Jones, KL, Jones, MC, et al. . Incidence of renal anomalies in children prenatally exposed to ethanol. Pediatrics. 1994; 94, 209212.Google Scholar
42.Assadi, FK. Renal tubular dysfunction in fetal alcohol syndrome. Pediatr Nephrol. 1990; 4, 4851.Google Scholar
43.Burd, L, Carlson, C, Kerbeshian, J. Fetal alcohol spectrum disorders and mental illness. Special Issue on neuropsychological effects of alcohol use and misuse. Int J Disabil Hum Dev. 2007; 6, 383396.Google Scholar
44.Mattson, SN, Riley, EP. A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res. 1998; 22, 279294.Google Scholar
45.Olson, HC, Feldman, JJ, Streissguth, AP, et al. . Neuropsychological deficits in adolescents with fetal alcohol syndrome: clinical findings. Alcohol Clin Exp Res. 1998; 22, 19982012.Google Scholar
46.Streissguth, AP, Barr, HM, Sampson, PD, et al. . Prenatal alcohol and offspring development: the first fourteen years. Drug Alcohol Depend. 1994; 36, 8999.Google Scholar
47.Riley, EP, McGee, CL. Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med (Maywood). 2005; 230, 357365.Google Scholar
48.Mattson, SN, Crocker, N, Nguyen, TT. Fetal alcohol spectrum disorders: neuropsychological and behavioral features. Neuropsychol Rev. 2011; 21, 81101.Google Scholar
49.Chen, Y, Ozturk, NC, Ni, L, et al. . Strain differences in developmental vulnerability to alcohol exposure via embryo culture in mice. Alcohol Clin Exp Res. 2011; 35, 12931304.Google Scholar
50.Cudd, TA. Animal model systems for the study of alcohol teratology. Exp Biol Med (Maywood). 2005; 230, 389393.Google Scholar
51.Clarke, DW, Smith, GN, Patrick, J, et al. . Activity of alcohol dehydrogenase and aldehyde dehydrogenase in maternal liver, fetal liver and placenta of the near-term pregnant ewe. Dev Pharmacol Ther. 1989; 12, 3541.CrossRefGoogle ScholarPubMed
52.Rees, S, Nitsos, I, Rawson, J. The development of cutaneous afferent pathways in fetal sheep: a structural and functional study. Brain Res. 1994; 661, 207222.Google Scholar
53.Gimonet, V, Bussieres, L, Medjebeur, AA, et al. . Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb. Am J Physiol. 1998; 274, F1062F1069.Google ScholarPubMed
54.Burrell, JH, Boyn, AM, Kumarasamy, V, et al. . Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec A Discov Mol Cell Evol Biol. 2003; 274, 952961.Google Scholar
55.Alcorn, DG, Adamson, TM, Maloney, JE, et al. . A morphologic and morphometric analysis of fetal lung development in the sheep. Anat Rec. 1981; 201, 655667.Google Scholar
56.Burri, PH. Fetal and postnatal development of the lung. Annu Rev Physiol. 1984; 46, 617628.Google Scholar
57.Goh, JM, Bensley, JG, Kenna, K, et al. . Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function. Am J Physiol Heart Circ Physiol. 2011; 300, H645H651.Google Scholar
58.Gray, SP, Kenna, K, Bertram, JF, et al. . Repeated ethanol exposure during late gestation decreases nephron endowment in fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2008; 295, R568R574.Google Scholar
59.Sozo, F, O'Day, L, Maritz, G, et al. . Repeated ethanol exposure during late gestation alters the maturation and innate immune status of the ovine fetal lung. Am J Physiol Lung Cell Mol Physiol. 2009; 296, L510L518.Google Scholar
60.Sozo, F, Vela, M, Stokes, V, et al. . Effects of prenatal ethanol exposure on the lungs of postnatal lambs. Am J Physiol Lung Cell Mol Physiol. 2011; 300, L139L147.Google Scholar
61.Bonthius, DJ, Goodlett, CR, West, JR. Blood alcohol concentration and severity of microencephaly in neonatal rats depend on the pattern of alcohol administration. Alcohol. 1988; 5, 209214.Google Scholar
62.Bonthius, DJ, West, JR. Blood alcohol concentration and microencephaly: a dose–response study in the neonatal rat. Teratology. 1988; 37, 223231.Google Scholar
63.Pierce, DR, West, JR. Blood alcohol concentration: a critical factor for producing fetal alcohol effects. Alcohol. 1986; 3, 269272.Google Scholar
64.Pierce, DR, West, JR. Alcohol-induced microencephaly during the third trimester equivalent: relationship to dose and blood alcohol concentration. Alcohol. 1986; 3, 185191.Google Scholar
65.Gladstone, J, Nulman, I, Koren, G. Reproductive risks of binge drinking during pregnancy. Reprod Toxicol. 1996; 10, 313.Google Scholar
66.McLeod, W, Brien, J, Loomis, C, et al. . Effect of maternal ethanol ingestion on fetal breathing movements, gross body movements, and heart rate at 37 to 40 weeks’ gestational age. Am J Obstet Gynecol. 1983; 145, 251257.Google Scholar
67.Smith, GN, Brien, JF, Carmichael, L, et al. . Development of tolerance to ethanol-induced suppression of breathing movements and brain activity in the near-term fetal sheep during short-term maternal administration of ethanol. J Dev Physiol. 1989; 11, 189197.Google Scholar
68.Bocking, AD, Carmichael, LJ, Abdollah, S, et al. . Effect of ethanol on immature ovine fetal breathing movements, fetal prostaglandin E2, and myometrial activity. Am J Physiol. 1994; 266, R1297R1301.Google Scholar
69.Stratton, K, Howe, C, Battaglia, FC. Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment (1996) 1996 Washington, DC: National Academy Press.Google Scholar
70.Kuroiwa, M, Aoki, H, Kobayashi, S, et al. . Role of GTP-protein and endothelium in contraction induced by ethanol in pig coronary artery. J Physiol. 1993; 470, 521537.Google Scholar
71.Berry, CL, Looker, T, Germain, J. Nucleic acid and scleroprotein content of the developing human aorta. J Pathol. 1972; 108, 265274.Google Scholar
72.Davis, EC. Elastic lamina growth in the developing mouse aorta. J Histochem Cytochem. 1995; 43, 11151123.Google Scholar
73.Humphrey, JD, Na, S. Elastodynamics and arterial wall stress. Ann Biomed Eng. 2002; 30, 509523.Google Scholar
74.Mayock, DE, Ngai, AC, Mondares, RL, et al. . Effects of binge alcohol exposure in the second trimester on intracerebral arteriolar function in third trimester fetal sheep. Brain Res. 2008; 1226, 111115.Google Scholar
75.Iveli, MF, Morales, S, Rebolledo, A, et al. . Effects of light ethanol consumption during pregnancy: increased frequency of minor anomalies in the newborn and altered contractility of umbilical cord artery. Pediatr Res. 2007; 61, 456461.Google Scholar
76.Turcotte, LA, Aberle, NS, Norby, FL, et al. . Influence of prenatal ethanol exposure on vascular contractile response in rat thoracic aorta. Alcohol. 2002; 26, 7581.Google Scholar
77.Morley, R, Dwyer, T, Hynes, KL, et al. . Maternal alcohol intake and offspring pulse wave velocity. Neonatology. 2010; 97, 204211.Google Scholar
78.DeLoach, SS, Townsend, RR. Vascular stiffness: its measurement and significance for epidemiologic and outcome studies. Clin J Am Soc Nephrol. 2008; 3, 184192.Google Scholar
79.Parkington, H, Kenna, K, De Matteo, R, et al. . Persistence of vascular effects of prenatal alcohol exposure. J Paediatr Child Health. 2010; 46(Suppl. 1), 296.Google Scholar
80.Parkington, HC, Coleman, H, Kenna, K, et al. . Maternal alcohol in pregnancy: arterial stiffness and endothelial vasodilator dysfunction in the fetus. J Paediatr Child Health. 2008; 44, 37 (abstract).Google Scholar
81.Parkington, HC, Coleman, H, Kenna, K, et al. . Maternal alcohol in pregnancy leads to generalised arterial stiffness and endothelial vasodilator disturbances in the fetus. J Paediatr Child Health. 2009; 45, 67 (abstract).Google Scholar
82.Tare, M, Kenna, K, Sozo, F, et al. . Regional differences in the regulation of vascular function following in utero alcohol exposure. J Vasc Res. 2009; 46, 4 (abstract).Google Scholar
83.Kim, S, Iwao, H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000; 52, 1134.Google Scholar
84.Chen, QM, Tu, VC, Purdon, S, et al. . Molecular mechanisms of cardiac hypertrophy induced by toxicants. Cardiovasc Toxicol. 2001; 1, 267283.Google Scholar
85.Adickes, ED, Mollner, TJ, Makoid, MC. Ethanol-induced teratogenic alterations in developing cardiomyocytes in culture. Alcohol Alcohol Suppl. 1993; 2, 283288.Google Scholar
86.Ren, J, Wold, LE, Natavio, M, et al. . Influence of prenatal alcohol exposure on myocardial contractile function in adult rat hearts: role of intracellular calcium and apoptosis. Alcohol Alcohol. 2002; 37, 3037.Google Scholar
87.Gray, SP, Cullen-McEwen, LA, Bertram, JF, et al. . Mechanism of alcohol-induced impairments in renal development: could it be reduced retinoic acid? Clin Exp Pharmacol Physiol. 2011. Epub ahead of print. doi:10.1111/j.1440-1681.2011.05597.x.Google Scholar
88.Wintour, EM, Moritz, KM, Johnson, K, et al. . Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol. 2003; 549(pt 3), 929935.Google Scholar
89.Langley-Evans, SC, Welham, SJ, Jackson, AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999; 64, 965974.Google Scholar
90.Singh, RR, Cullen-McEwen, LA, Kett, MM, et al. . Prenatal corticosterone exposure results in altered AT1/AT2, nephron deficit and hypertension in the rat offspring. J Physiol. 2007; 579(Pt 2), 503513.Google Scholar
91.Wlodek, ME, Mibus, A, Tan, A, et al. . Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J Am Soc Nephrol. 2007; 18, 16881696.Google Scholar
92.Gray, SP, Denton, KM, Cullen-McEwen, L, et al. . Prenatal exposure to alcohol reduces nephron number and raises blood pressure in progeny. J Am Soc Nephrol. 2010; 21, 18911902.Google Scholar
93.Haczku, A. Protective role of the lung collectins surfactant protein A and surfactant protein D in airway inflammation. J Allergy Clin Immunol. 2008; 122, 861879.Google Scholar
94.Ikegami, M, Whitsett, JA, Chroneos, ZC, et al. . IL-4 increases surfactant and regulates metabolism in vivo. Am J Physiol Lung Cell Mol Physiol. 2000; 278, L75L80.Google Scholar
95.Haczku, A. Role and regulation of lung collectins in allergic airway sensitization. Pharmacol Ther. 2006; 110, 1434.Google Scholar
96.Cura, MA, Bugnone, A, Becker, GJ. Midaortic syndrome associated with fetal alcohol syndrome. J Vasc Interv Radiol. 2002; 13, 11671170.Google Scholar
97.Lazic, T, Wyatt, TA, Matic, M, et al. . Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia. Alcohol. 2007; 41, 347355.Google Scholar
98.Lazic, T, Sow, FB, Van Geelen, A, et al. . Exposure to ethanol during the last trimester of pregnancy alters the maturation and immunity of the fetal lung. Alcohol. 2011; 45, 673680.Google Scholar
99.Johnson, S, Knight, R, Marmer, DJ, et al. . Immune deficiency in fetal alcohol syndrome. Pediatr Res. 1981; 15, 908911.Google Scholar
100.Church, MW, Gerkin, KP. Hearing disorders in children with fetal alcohol syndrome: findings from case reports. Pediatrics. 1988; 82, 147154.Google Scholar