Advertisement
Advances in Pediatrics

Human Teratogens: Current Controversies

      It is estimated that approximately 10% of congenital structural anomalies are the result of the adverse effect of environmental factors on prenatal development [
      • Rl Brent
      The cause and prevention of human birth defects: what have we learned in the past 50 years?.
      ]. This means that approximately 1 in 250 newborn infants have structural defects caused by an environmental exposure and, presumably, a larger number of children have growth retardation or functional abnormalities resulting from nongenetic causes, in other words, from the effects of teratogens. A teratogen is defined as any environmental factor that can produce a permanent abnormality in structure or function, restriction of growth, or death of the embryo or fetus. These factors comprise medications, drugs, chemicals, and maternal conditions or diseases, including infections (Table 1). The term is used more commonly, however, to refer only to medications, drugs, and chemicals and, less frequently to maternal conditions or diseases that may be associated with birth defects in the offspring. This review uses the term in its widest connotation.
      Table 1Examples of environmental factors that may adversely affect prenatal development
      Type Examples
      Medications Thalidomide, isotretinol, anticonvulsants, dicumarol
      Social drugs Alcohol, cocaine
      Chemicals Organic mercury
      Maternal diseases and conditions Rubella, cytomegalovirus, varicella
      Diabetes mellitus, lupus, hyperthermia
      Obesity
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Advances in Pediatrics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rl Brent
        The cause and prevention of human birth defects: what have we learned in the past 50 years?.
        Congenit Anom (Kyoto). 2001; 41: 3-21
        • Karnofsky D.A.
        Mechanisms of action of certain growth-inhibiting drugs.
        in: Wilson J.G. Warkany J. Teratologic principles and techniques. Chicago University Press, Chicago1965: 185-213
        • Prolifka J.E.
        • Friedman J.M.
        Clinical teratology: identifying teratogenic risks in humans.
        Clin Genet. 1999; 56: 409-420
        • Johnson E.M.
        Screening for teratogenic hazards: nature of the problem.
        Annu Rev Pharmacol Toxicol. 1985; 21: 414-429
        • Wilson J.G.
        Current status of teratology. General principles and mechanisms derived from animal studies.
        in: Wilson J.G. Fraser F.C. Handbook of teratology. vol. 1. Plenum Press, New York1977: 47-74
        • Schardein J.L.
        Chemically induced birth defects.
        3rd edition. Marcel Dekker, New York2000 (p. 44)
        • Bánhidy F.
        • Lowry R.B.
        • Czeizel A.E.
        Risk and benefit of drug use during pregnancy.
        Int J Med Sci. 2005; 2: 100-106
        • Rutledge J.C.
        • Generoso W.M.
        • Shourbaji A.
        • et al.
        Developmental anomalies derived from exposure of zygotes and first-cleavage embryos to mutagens.
        Mutat Res. 1992; 296: 167-177
        • Rutledge J.C.
        Developmental toxicity induced during early stages of mammalian embryogenesis.
        Mutat Res. 1997; 396: 113-127
        • Opitz J.M.
        Blastogenesis and the ‘primary field’ in human development.
        Birth Defects Orig Artic Ser. 1993; 29: 3-37
        • Opitz J.M.
        Development: clinical and evolutionary considerations.
        Am J Med Genet. 2007; 143: 2853-2861
        • Gilbert S.F.
        Developmental biology.
        7th edition. Sinauer Associates, Inc., Sunderland (MA)2003 (p. 694–696)
        • Frías J.L.
        • Thomas I.T.
        Teratogens and teratogenesis: general principles of teratology.
        Ann Clin Lab Sci. 1988; 18: 174-179
        • Finnell H.F.
        • Gelineau-van Waes J.
        • Eudy J.D.
        • et al.
        Molecular basis of environmentally induced birth defects.
        Annu Rev Pharmacol Toxicol. 2002; 42: 181-208
        • Prolifka J.E.
        • Friedman J.M.
        Medical genetics: 1. Clinical teratology in the age of genomics.
        CMAJ. 2002; 167: 265-273
        • Miller R.W.
        • Mulvihill J.J.
        Small head size after atomic radiation.
        in: Sever J.L. Brent R.L. Teratogen update: environmentally induced birth defect risks. Alan R. Liss, Inc, New York1986: 141-143
        • Goldman S.A.
        Critical periods of toxic insults.
        in: Schwarz R.H. Yaffe S.J. Drug and chemical risks to the fetus and newborn. Alan R. Liss, Inc, New York1980: 9-31
        • Newman C.G.H.
        Clinical aspects of thalidomide embryopathy—a continuing preoccupation.
        in: Sever J.L. Brent R.L. Teratogen update: environmentally induced birth defects risk. Alan R Liss, New York1986: 1-12
        • Frias J.L.
        • Carey J.C.
        Mild errors of morphogenesis.
        Adv Pediatr. 1996; 43: 27-75
        • Spranger J.
        • Benirschke K.
        • Hall J.G.
        • et al.
        Errors of morphogenesis: concepts and terms. Recommendations of an international working group.
        J Pediatr. 1982; 100: 160-165
        • Brent R.L.
        Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents).
        Pediatrics. 2004; 113: 984-995
        • Chung K.C.
        • Kowalski C.P.
        • Kim H.M.
        • et al.
        Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate.
        Plast Reconstr Surg. 2000; 105: 485-491
        • Martínez-Frías M.L.
        • Bermejo E.
        • Rodríguez-Pinilla E.
        • et al.
        Risk for congenital anomalies associated with different sporadic and daily doses of alcohol consumption during pregnancy: a case-control study.
        Birth Defects Res A Clin Mol Teratol. 2004; 70: 194-200
        • Little J.
        • Cardy A.
        • Arslan M.T.
        • et al.
        United Kingdom-based case-control study. Smoking and orofacial clefts: a United Kingdom-based case-control study.
        Cleft Palate Craniofac J. 2004; 41: 381-386
        • Holmes L.B.
        • Harvey E.A.
        • Coull B.A.
        • et al.
        The teratogenicity of anticonvulsant drugs.
        N Engl J Med. 2001; 344: 1132-1138
        • Diehl R.S.
        • Erickson R.P.
        Genome scan for teratogen-induced clefting susceptibility loci in the mouse: evidence of both allelic and locus heterogeneity distinguishing cleft lip and cleft palate.
        Proc Natl Acad Sci. 1997; 94: 5231-5236
        • Botto L.D.
        • Mastroiacovo P.
        Exploring gene–gene interactions in the etiology of neural tube defects.
        Clin Genet. 1998; 53: 456-459
        • Hwang S.J.
        • Beaty T.H.
        • Panny S.R.
        • et al.
        Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene–environment interaction in a population-based sample of infants with birth defects.
        Am J Epidemiol. 1995; 141: 629-636
        • Stoler J.M.
        • Ryan L.M.
        • Holmes L.B.
        Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome.
        J Pediatr. 2002; 141: 780-785
        • Avila J.R.
        • Jezewski P.A.
        • Vieira A.R.
        • et al.
        PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations.
        Am J Med Genet. 2006; 140: 2562-2570
        • Kapron C.M.
        • Trasler D.G.
        Genetic determinants of teratogen-induced abnormal development in mouse and rat embryos in vitro.
        Int J Dev Biol. 1997; 41: 337-344
        • Newman L.M.
        • Johnson E.M.
        • Staples R.E.
        Assessment of the effectiveness of animal developmental toxicity testing for human safety.
        Reprod Toxicol. 1993; 7: 359-390
        • Harris M.J.
        • Juriloff D.M.
        Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.
        Teratology. 1999; 60: 292-305
        • Shimizu H.
        • Lee G.S.
        • Beedanagari S.R.
        • et al.
        Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid-induced forelimb ectrodactyly.
        Birth Defects Res A Clin Mol Teratol. 2007; 79: 465-482
        • Rothman K.J.
        • Greenland S.
        Modern epidemiology.
        2nd edition. Lippincott Williams & Wilkins, Philadelphia1998 (p. 115–134)
        • Carey J.C.
        Editor's note.
        Am J Med Genet. 2002; 111 ([letter]): 54
        • Labeling and prescription drug advertising. Content and format for labeling human prescription drugs. U.S. Food and Drug Administration
        Fed Regist. 1980; 44: 37434-37467
        • Lo W.Y.
        • Friedman J.M.
        Teratogenicity of recently introduced medications in human pregnancy.
        Obstet Gynecol. 2002; 100: 465-473
        • Trussell J.
        The cost of unintended pregnancy in the United States.
        Contraception. 2007; 75: 168-170
        • Forrest J.D.
        Epidemiology of unintended pregnancy and contraceptive use.
        Am J Obstet Gynecol. 1994; 170: 1485-1489
        • Kim S.
        • Iwao H.
        Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases.
        Pharmacol Rev. 2000; 52: 11-34
        • Barr Jr., M.
        Teratogen update: angiotensin-converting enzyme inhibitors.
        Teratology. 1994; 50: 399-409
        • Piper J.M.
        • Ray W.A.
        • Rosa F.W.
        Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors.
        Obstet Gynecol. 1992; 80: 429-432
        • Rhabbour M.
        • Lenoir S.
        • Bouissou F.
        • et al.
        Effets fœtaux et neonatals d'un traitement maternel par inhibiteur de l'enzyme de conversion de l'angiotensine.
        Arch Pediatr. 1994; 1 (497–500)
        • Shotan A.
        • Widerhorn J.
        • Hurst A.
        • et al.
        Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use.
        Am J Med. 1994; 96: 451-456
        • Tabacova S.
        Mode of action: angiotensin-converting enzyme inhibition—developmental effects associated with exposure to ACE inhibitors.
        Crit Rev Toxicol. 2005; 35: 747-755
        • Barr Jr., M.
        • Cohen Jr., M.M.
        ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection.
        Teratology. 1991; 44: 485-495
        • Brent R.L.
        • Beckman D.A.
        Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors.
        Teratology. 1991; 43: 543-546
        • Laube G.F.
        • Kemper M.J.
        • Schubiger G.
        • et al.
        Angiotensin-converting enzyme inhibitor fetopathy: long-term outcome.
        Arch Dis Child Fetal Neonatal Ed. 2007; 92: F402-F403
        • Buttar H.S.
        An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development.
        Mol Cell Biochem. 1997; 176: 61-71
        • Ducsay C.A.
        • Umezaki H.
        • Kaushal K.M.
        • et al.
        Pharmacokinetic and fetal cardiovascular effects of enalaprilat administration to maternal rhesus macaques.
        Am J Obstet Gynecol. 1996; 175: 50-55
        • Sadler T.W.
        Langman's medical embryology.
        10th edition. Lippincott Williams & Wilkins, Baltimore (MD)2006 (p. 217)
        • Schaefer C.
        Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity.
        Birth Defects Res A Clin Mol Teratol. 2003; 67: 591-594
        • Alwan S.
        • Polifka J.E.
        • Friedman J.M.
        Angiotensin II receptor antagonist treatment during pregnancy.
        Birth Defects Res A Clin Mol Teratol. 2005; 73: 123-130
        • Roger N.
        • Popovic I.
        • Madelenat P.
        • et al.
        Toxicité foetale des antagonistes des récepteurs de l'angiotensine II. A propos d'un cas.
        Gynecol Obstet Fertil. 2007; 35: 556-560
        • Allanson J.E.
        • Pantzar J.T.
        • MacLeod P.M.
        Possible new autosomal recessive syndrome with unusual renal histopathological changes.
        Am J Med Genet. 1983; 16: 57-60
        • Lacoste M.
        • Cai Y.
        • Guicharnaud L.
        • et al.
        Renal tubular dysgenesis, a not uncommon autosomal recessive disorder leading to oligohydramnios: role of the Renin-Angiotensin system.
        J Am Soc Nephrol. 2006; 17: 2253-2263
        • Cooper W.O.
        • Hernandez-Diaz S.
        • Arbogast P.G.
        • et al.
        Major congenital malformations after first-trimester exposure to ACE inhibitors.
        N Engl J Med. 2006; 354: 2443-2451
        • Scialli A.R.
        • Lione A.
        ACE inhibitors and major congenital malformations.
        N Engl J Med. 2006; 355 ([letter]): 1280
        • Ray J.G.
        • Vermeulen M.J.
        • Koren G.
        Taking ACE inhibitors during early pregnancy: is it safe?.
        Can Fam Physician. 2007; 53: 1439-1440
        • Pirraglia P.A.
        • Stafford R.S.
        • Singer D.E.
        Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care.
        Prim Care Companion J Clin Psychiatry. 2003; 5: 153-157
        • Bakker M.K.
        • Kölling P.
        • van den Berg P.B.
        • et al.
        Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from The Netherlands.
        Br J Clin Pharmacol. October 22, 2007; ([Epub ahead of print])
        • Vaswani M.
        • Linda F.K.
        • Ramesh S.
        Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review.
        Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27: 85-102
        • Reefhuis J.
        • Rasmussen S.A.
        • Friedman J.M.
        Selective serotonin-reuptake inhibitors and persistent pulmonary hypertension of the newborn.
        N Engl J Med. 2006; 354: 2188-2190
        • Pastuszak A.
        • Schick-Boschetto B.
        • Zuber C.
        • et al.
        Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac).
        JAMA. 1993; 269: 2246-2248
        • Chambers C.D.
        • Johnson K.A.
        • Dick L.M.
        • et al.
        Birth outcomes in pregnant women taking fluoxetine.
        N Engl J Med. 1996; 335: 1010-1015
        • Goldstein D.J.
        • Corbin L.A.
        • Sundell K.L.
        Effects of first-trimester fluoxetine exposure on the newborn.
        Obstet Gynecol. 1997; 89: 713-718
        • Kulin N.A.
        • Pastuszak A.
        • Sage S.R.
        • et al.
        Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study.
        JAMA. 1998; 279: 609-610
        • Cohen L.S.
        • Heller V.L.
        • Bailey J.W.
        • et al.
        Birth outcomes following prenatal exposure to fluoxetine.
        Biol Psychiatry. 2000; 48: 996-1000
        • Simon G.E.
        • Cunningham M.L.
        • Davis R.L.
        Outcomes of prenatal antidepressant exposure.
        Am J Psychiatry. 2002; 159: 2055-2061
        • Wisner K.L.
        • Gelenberg A.J.
        • Leonard H.
        • et al.
        Pharmacologic treatment of depression during pregnancy.
        JAMA. 1999; 282: 1264-1269
        • Addis A.
        • Koren G.
        Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies.
        Psychol Med. 2000; 30: 89-94
        • Einarson T.R.
        • Einarson A.
        Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies.
        Pharmacoepidemiol Drug Saf. 2005; 14: 823-827
        • Malm H.
        • Klaukka T.
        • Neuvonen P.J.
        Risks associated with selective serotonin reuptake inhibitors in pregnancy.
        Obstet Gynecol. 2005; 106: 1289-1296
        • Wogelius P.
        • Nørgaard M.
        • Gislum M.
        • et al.
        Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations.
        Epidemiology. 2006; 17: 701-704
        • Diav-Citrin O.
        • Shechtman S.
        • Weinbaum D.
        • et al.
        Paroxetine and fluoxetine in pregnancy: a multicenter, prospective, controlled study.
        Reprod Toxicol. 2005; 20 ([abstract]): 459
        • Källén B.A.
        • Otterblad Olausson P.
        Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations.
        Birth Defects Res A Clin Mol Teratol. 2007; 79: 301-318
        • Bérard A.
        • Ramos E.
        • Rey E.
        • et al.
        First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage.
        Birth Defects Res B Dev Reprod Toxicol. 2007; 80: 18-27
        • Alwan S.
        • Reefhuis J.
        • Rasmussen S.A.
        • et al.
        National birth defects prevention study use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects.
        N Engl J Med. 2007; 356: 2684-2692
        • Louik C.
        • Lin A.E.
        • Werler M.M.
        • et al.
        First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
        N Engl J Med. 2007; 356: 2675-2683
        • Bar-Oz B.
        • Einarson T.
        • Einarson A.
        • et al.
        Paroxetine and congenital malformations: meta-Analysis and consideration of potential confounding factors.
        Clin Ther. 2007; 29: 918-926
        • Cole J.A.
        • Ephross S.A.
        • Cosmatos I.S.
        • et al.
        Paroxetine in the first trimester and the prevalence of congenital malformations.
        Pharmacoepidemiol Drug Saf. 2007; 16: 1075-1085
        • U.S. Food and Drug Administration
        FDA Public health advisory.
        (Available at:) (Accessed December 9, 2007)
        • Marden P.M.
        • Smith D.W.
        • Mcdonald M.J.
        Congenital anomalies in the newborn infant, including minor variations. A study of 4,412 babies by surface examination for anomalies and buccal smear for sex chromatin.
        J Pediat. 1964; 64: 357-371
        • Leppig K.A.
        • Werler M.M.
        • Cann C.I.
        • et al.
        Predictive value of minor anomalies. I. Association with major malformations.
        J Pediatr. 1987; 110: 531-537
        • Tsai F.J.
        • Tsai C.H.
        • Peng C.T.
        • et al.
        Different race, different face: minor anomalies in Chinese newborn infants.
        Acta Paediatr. 1999; 88: 323-326
        • Costei A.M.
        • Kozer E.
        • Ho T.
        • et al.
        Perinatal outcome following third trimester exposure to paroxetine.
        Arch Pediatr Adolesc Med. 2002; 156: 1129-1132
        • Haddad P.M.
        • Pal B.R.
        • Clarke P.
        • et al.
        Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?.
        J Psychopharmacol. 2005; 19 (554-547)
        • Austin M.P.
        To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects.
        Psychol Med. 2006; 36: 1663-1670
        • Chambers C.D.
        • Hernandez-Diaz S.
        • Van Marter L.J.
        • et al.
        Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn.
        N Engl J Med. 2006; 354: 579-587
        • U.S. Food and Drug Administration
        Information for Healthcare Professionals. Paroxetine (marketed as Paxil).
        (Available at:) (Accessed December 9, 2007)
        • Nordeng H.
        • Spigset O.
        Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on the infant.
        Drug Saf. 2005; 28: 565-581
        • Nulman I.
        • Rovet J.
        • Stewart D.E.
        • et al.
        Neurodevelopment of children exposed in utero to antidepressant drugs.
        N Engl J Med. 1997; 336: 258-262
        • Gentile S.
        SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome.
        CNS Drugs. 2005; 19: 623-633
        • Casper R.C.
        • Fleisher B.E.
        • Lee-Ancajas J.C.
        • et al.
        Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.
        J Pediatr. 2003; 142: 402-408
        • Mortensen J.T.
        • Olsen J.
        • Larsen H.
        • et al.
        Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics.
        Eur J Epidemiol. 2003; 18: 769-771
        • Nonacs R.
        • Cohen L.S.
        Assessment and treatment of depression during pregnancy: an update.
        Psychiatr Clin North Am. 2003; 26: 547-562
        • Gentile S.
        The safety of newer antidepressants in pregnancy and breastfeeding.
        Drug Saf. 2005; 28: 137-152
        • Cohen L.S.
        • Altshuler L.L.
        • Harlow B.L.
        • et al.
        Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment.
        JAMA. 2006; 295: 499-507
        • Marchetti F.
        • Romero M.
        • Bonati M.
        • et al.
        Use of psychotropic drugs during pregnancy. A report of the international co-operative drug use in pregnancy (DUP) study. Collaborative Group on Drug Use in Pregnancy (CGDUP).
        Eur J Clin Pharmacol. 1993; 45: 495-501
        • Beall J.R.
        Study of the teratogenic potential of diazepam and SCH 12041.
        Can Med Assoc J. 1972; 106: 1061
        • Weber L.W.
        Benzodiazepines in pregnancy-academical debate or teratogenic risk?.
        Biol Res Pregnancy Perinatol. 1985; 6: 151-167
        • Buttar H.S.
        Effects of chlordiazepoxide on the pre- and postnatal development of rats.
        Toxicology. 1980; 17: 311-321
        • Miller R.P.
        • Becker B.A.
        Teratogenicity of oral diazepam and diphenylhydantoin in mice.
        Toxicol Appl Pharmacol. 1975; 32: 53-61
        • Katz R.A.
        Effect of diazepam on the embryonic development of the palate in the rat.
        J Craniofac Genet Dev Biol. 1988; 8: 155-166
        • Shah R.M.
        • Donaldson D.
        • Burdett D.
        Teratogenic effects of diazepam in the hamster.
        Can J Physiol Pharmacol. 1979; 57: 556-561
        • Saxen I.
        • Saxen L.
        Association between maternal intake of diazepam and oral clefts.
        Lancet. 1975; 2 ([letter]): 489
        • Bracken M.B.
        • Holford T.R.
        Exposure to prescribed drugs in pregnancy and association with congenital malformations.
        Obstet Gynecol. 1981; 58: 336-344
        • Laegreid L.
        • Olegård R.
        • Walström J.
        • et al.
        Teratogenic effects of benzodiazepine use during pregnancy.
        J Pediatr. 1989; 114: 126-131
        • Laegreid L.
        • Olegård R.
        • Conradi N.
        • et al.
        Congenital malformations and maternal consumption of benzodiazepines: a case-control study.
        Dev Med Child Neurol. 1990; 32: 432-441
        • Rosenberg L.
        • Mitchell A.A.
        • Parsells J.L.
        • et al.
        Lack of relation of oral clefts to diazepam use during pregnancy.
        N Engl J Med. 1983; 309: 1282-1285
        • Aselton P.
        • Jick H.
        • Milunsky A.
        • et al.
        First-trimester drug use and congenital disorders.
        Obstet Gynecol. 1985; 65: 451-455
        • Czeizel A.
        Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary.
        Reprod Toxicol. 1987–1988; 1: 183-188
        • McElhatton P.R.
        • Garbis H.M.
        • Eléfant E.
        • et al.
        The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS).
        Reprod Toxicol. 1996; 10: 285-294
        • Ornoy A.
        • Arnon J.
        • Shechtman S.
        • et al.
        Is benzodiazepine use during pregnancy really teratogenic?.
        Reprod Toxicol. 1998; 12: 511-515
        • Dolovich L.R.
        • Addis A.
        • Vaillancourt J.M.
        • et al.
        Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.
        BMJ. 1998; 317: 839-843
        • Addis A.
        • Dolovich L.R.
        • Einarson T.R.
        • et al.
        Can we use anxiolytics during pregnancy without anxiety?.
        Can Fam Physician. 2000; 46: 549-551
        • Eros E.
        • Czeizel A.E.
        • Rockenbauer M.
        • et al.
        A population-based case-control teratologic study of nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatment during pregnancy.
        Eur J Obstet Gynecol Reprod Biol. 2002; 101: 147-154
        • Czeizel A.E.
        • Rockenbauer M.
        • Sørensen H.T.
        • et al.
        A population-based case-control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities.
        Neurotoxicol Teratol. 2004; 26: 593-598
        • Bonnot O.
        • Vollset S.E.
        • Godet P.F.
        • et al.
        Exposition in utero au lorazépam et atrésie anale: signal épidémiologique.
        Encephale. 2003; 29: 553-559
        • Collins R.
        • Armitage J.
        • Parish S.
        • et al.
        Heart Protection Study Collaborative Group.
        Lancet. 2003; 361: 2005-2016
        • Baigent C.
        • Keech A.
        • Kearney P.M.
        • et al.
        Cholesterol treatment trialist's group. Efficacy and safety of cholesterol-lowering treatment: prospective data-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366: 1267-1278
        • Ming J.E.
        • Roessler E.
        • Muenke M.
        Human developmental disorders and the Sonic hedgehog pathway.
        Mol Med Today. 1998; 4: 343-349
        • Murone M.
        • Rosenthal A.
        • de Sauvage F.J.
        Hedgehog signal transduction: from flies to vertebrates.
        Exp Cell Res. 1999; 253: 25-33
        • Incardona J.P.
        • Roelink H.
        The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly.
        Cell Mol Life Sci. 2000; 57: 1709-1719
        • Cohen M.M.
        • Shiota K.
        Teratogenesis of holoprosencephaly.
        Am J Med Genet. 2002; 109: 1-15
        • Irons M.
        • Elias E.R.
        • Salen G.
        • et al.
        Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome.
        Lancet. 1993; 341 ([letter]): 1414
        • Herman G.E.
        Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.
        Hum Mol Genet. 2003; 12: R75-R88
        • Kelley R.I.
        Inborn errors of cholesterol biosynthesis.
        Adv Pediatr. 2000; 47: 1-52
        • Porter F.D.
        Human malformation syndromes due to inborn errors of cholesterol synthesis.
        Curr Opin Pediatr. 2003; 15: 607-613
        • Ghidini A.
        • Sicherer S.
        • Willner J.
        Congenital abnormalities (VATER) in baby born to mother using lovastatin.
        Lancet. 1992; 339: 1416-1417
        • Hayes A.
        • Gilbert A.
        • López G.
        • et al.
        Mevacor–a new teratogen?.
        Am J Hum Genet. 1995; 57 ([abstract]): A92
        • Edison R.J.
        • Muenke M.
        Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins.
        Am J Med Genet. 2004; 131: 287-298
        • Pollack P.S.
        • Shields K.E.
        • Burnett D.M.
        • et al.
        Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.
        Birth Defects Res A Clin Mol Teratol. 2005; 73: 888-896
        • Manson J.M.
        • Freyssinges C.
        • Ducrocq M.B.
        • et al.
        Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.
        Reprod Toxicol. 1996; 10: 439-446
        • Petersen E.E.
        • Rasmussen S.A.
        • Carey J.C.
        • et al.
        Maternal exposure to statins and risk for birth defects: a case-series approach.
        Birth Defects Res A Clin Mol Teratol. 2007; 79 ([abstract]): 367
        • Ofori B.
        • Rey E.
        • Bérard A.
        Risk of congenital anomalies in pregnant users of statin drugs.
        Br J Clin Pharmacol. 2007; 64: 496-509
        • Berkowitz G.S.
        • Holford T.R.
        • Berkowitz R.L.
        Effects of cigarette smoking, alcohol, coffee and tea consumption on preterm delivery.
        Early Hum Dev. 1982; 7: 239-250
        • Kramer M.S.
        Determinants of low birth weight: methodological assessment and meta-analysis.
        Bull World Health Organ. 1987; 65: 663-737
        • Wen S.W.
        • Goldenberg R.L.
        • Cutter G.R.
        • et al.
        Smoking, maternal age, fetal growth, and gestational age at delivery.
        Am J Obstet Gynecol. 1990; 162: 53-58
        • Harlow B.L.
        • Frigoletto F.D.
        • Cramer D.W.
        • et al.
        Determinants of preterm delivery in low-risk pregnancies. The RADIUS study group.
        J Clin Epidemiol. 1996; 49: 441-448
        • Hellerstedt W.L.
        • Himes J.H.
        • Story M.
        • et al.
        The effects of cigarette smoking and gestational weight change on birth outcomes in obese and normal-weight women.
        Am J Public Health. 1997; 87: 591-596
        • Higgins S.
        Smoking in pregnancy.
        Curr Opin Obstet Gynecol. 2002; 14: 145-151
        • Secker-Walker R.H.
        • Vacek P.M.
        Relationships between cigarette smoking during pregnancy, gestational age, maternal weight gain, and infant birthweight.
        Addict Behav. 2003; 28: 55-66
        • Kyrklund-Blomberg N.B.
        • Granath F.
        • Cnattingius S.
        Maternal smoking and causes of very preterm birth.
        Acta Obstet Gynecol Scand. 2005; 84: 572-577
        • Salihu H.M.
        • Wilson R.E.
        Epidemiology of prenatal smoking and perinatal outcomes.
        Early Hum Dev. 2007; 83: 713-720
        • Werler M.M.
        • Pober B.R.
        • Holmes L.B.
        Smoking and pregnancy.
        Teratology. 1985; 32: 473-481
        • Saxen I.
        Cleft lip and palate in Finland: parental histories, course of pregnancy and selected environmental factors.
        Int J Epidemiol. 1974; 3: 263-270
        • Evans D.R.
        • Newcombe R.G.
        • Campbell H.
        Maternal smoking habits and congenital malformations: a population study.
        BMJ. 1979; 2: 171-173
        • Werler M.M.
        • Lammer E.J.
        • Rosenberg L.
        • et al.
        Maternal cigarette smoking during pregnancy in relation to oral clefts.
        Am J Epidemiol. 1990; 132: 926-932
        • Lieff S.
        • Olshan A.F.
        • Werler M.
        • et al.
        Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns.
        Am J Epidemiol. 1999; 150: 683-694
        • Shaw G.M.
        • Wasserman C.R.
        • Lammer E.J.
        • et al.
        Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants.
        Am J Hum Genet. 1996; 58: 551-561
        • Wyszynski D.F.
        • Duffy D.L.
        • Beaty T.H.
        Maternal cigarette smoking and oral clefts: a meta-analysis.
        Cleft Palate Craniofac J. 1997; 34: 206-210
        • Lorente C.
        • Cordier S.
        • Goujard J.
        • et al.
        Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational exposure and congenital malformation working group.
        Am J Public Health. 2000; 90: 415-419
        • Bille C.
        • Olsen J.
        • Vach W.
        • et al.
        Oral clefts and life style factors—a case-cohort study based on prospective Danish data.
        Eur J Epidemiol. 2007; 22: 173-181
        • Beaty T.H.
        • Maestri N.E.
        • Hetmanski J.B.
        • et al.
        Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992–1996.
        Cleft Palate Craniofac J. 1997; 34: 447-454
        • Romitti P.A.
        • Lidral A.C.
        • Munger R.G.
        • et al.
        Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts.
        Teratology. 1999; 59: 39-50
        • Van Rooij I.A.
        • Wegerif M.J.
        • Roelofs H.M.
        • et al.
        Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction.
        Epidemiology. 2001; 12: 502-507
        • Lammer E.J.
        • Shaw G.M.
        • Iovannisci D.M.
        • et al.
        Maternal smoking and the risk of orofacial clefts: Susceptibility with NAT1 and NAT2 polymorphisms.
        Epidemiology. 2004; 15: 150-156
        • Shi M.
        • Christensen K.
        • Weinberg C.R.
        • et al.
        Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.
        Am J Hum Genet. 2007; 80: 76-90
        • Honein M.A.
        • Paulozzi L.J.
        • Watkins M.L.
        Maternal smoking and birth defects: validity of birth certificate data for effect estimation.
        Public Health Rep. 2001; 116: 327-335
        • Werler M.M.
        • Mitchell A.A.
        • Shapiro S.
        Demographic, reproductive, medical, and environmental factors in relation to gastroschisis.
        Teratology. 1992; 45: 353-360
        • Werler M.M.
        • Sheehan J.E.
        • Mitchell A.A.
        Association of vasoconstrictive exposures with risks of gastroschisis and small intestinal atresia.
        Epidemiology. 2003; 14: 349-354
        • Goldbaum G.
        • Daling J.
        • Milham S.
        Risk factors for gastroschisis.
        Teratology. 1990; 42: 397-403
        • Haddow J.E.
        • Palomaki G.E.
        • Holman M.S.
        Young maternal age and smoking during pregnancy as risk factors for gastroschisis.
        Teratology. 1993; 47: 225-228
        • Torfs C.P.
        • Velie E.M.
        • Oechsli F.W.
        • et al.
        A population-based study of gastroschisis: demographic, pregnancy, and lifestyle risk factors.
        Teratology. 1994; 50: 44-53
        • Martinez-Frías M.L.
        • Rodriguez-Pinilla E.
        • Prieto L.
        Prenatal exposure to salicylates and gastroschisis: a case-control study.
        Teratology. 1997; 56: 241-243
        • Hougland K.T.
        • Hanna A.M.
        • Meyers R.
        • et al.
        Increasing prevalence of gastroschisis in Utah.
        J Pediatr Surg. 2005; 40: 535-540
        • Lam P.K.
        • Torfs C.P.
        Interaction between maternal smoking and malnutrition in infant risk of gastroschisis.
        Birth Defects Res A Clin Mol Teratol. 2006; 76: 182-186
        • Torfs C.P.
        • Christianson R.E.
        • Iovannisci D.M.
        • et al.
        Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis.
        Birth Defects Res A Clin Mol Teratol. 2006; 76: 723-730
        • Alderman B.
        • Bradley C.
        • Greene C.
        • et al.
        Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy.
        Teratology. 1994; 50: 13-18
        • Reehuis J.
        • de Walle H.E.
        • Cornel M.C.
        Maternal smoking and deformities of the foot: results of the EUROCAT Study. European registries of congenital anomalies.
        Am J Public Health. 1998; 88: 1554-1555
        • Honein M.A.
        • Paulozzi L.J.
        • Moore C.A.
        Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction.
        Am J Epidemiol. 2000; 152: 658-665
        • Skelly A.C.
        • Holt V.L.
        • Mosca V.S.
        • et al.
        Talipes equinovarus and maternal smoking: a population-based case-control study in Washington State.
        Teratology. 2002; 66: 91-100
        • Dickinson K.C.
        • Meyer R.E.
        • Kotch J.
        Maternal smoking and the risk for clubfoot in infants.
        Birth Defects Res A Clin Mol Teratol. Nov 16, 2007; ([Epub ahead of print])
        • Alderman B.W.
        • Takahashi E.R.
        • LeMier M.K.
        Risk indicators for talipes equinovarus in Washington State, 1987–1989.
        Epidemiology. 1991; 2: 289-292
        • Källén K.
        Maternal smoking and craniosynostosis.
        Teratology. 1999; 60: 146-150
        • Honein M.A.
        • Rasmussen S.A.
        Further evidence for an association between maternal smoking and craniosynostosis.
        Teratology. 2000; 62: 145-146
        • Carmichael S.L.
        • Ma C.
        • Rasmussen S.A.
        • et al.
        the National Birth Defects Prevention Study. Craniosynostosis and maternal smoking.
        Birth Defects Res A Clin Mol Teratol. Nov 29, 2007; ([Epub ahead of print])
        • Tikkanen J.
        • Heinonen O.P.
        Risk factors for cardiovascular malformations in Finland.
        Eur J Epidemiol. 1990; 6: 348-356
        • Tikkanen J.
        • Heinonen O.P.
        Risk factors for atrial septal defect.
        Eur J Epidemiol. 1992; 8: 509-515
        • Tikkanen J.
        • Heinonen O.P.
        Risk factors for coarctation of the aorta.
        Teratology. 1993; 47: 565-572
        • Tikkanen J.
        • Heinonen O.P.
        Risk factors for hypoplastic left heart syndrome.
        Teratology. 1994; 50: 112-117
        • Pradat P.
        A case-control study of major congenital heart defects in Sweden–1981-1986.
        Eur J Epidemiol. 1992; 8: 789-796
        • Cedergren M.I.
        Maternal morbid obesity and the risk of adverse pregnancy outcome.
        Obstet Gynecol. 2004; 103: 219-224
        • Källén K.
        Maternal smoking and congenital heart defects.
        Eur J Epidemiol. 1999; 15: 731-737
        • Wasserman C.R.
        • Shaw G.M.
        • O'Malley C.D.
        • et al.
        Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb.
        Teratology. 1996; 53: 261-267
        • Ferencz C.
        • Loffredo C.A.
        • Correa-Villaseñor A.
        • et al.
        Genetic and environmental risk factors of major cardiovascular malformations: the Baltimore-Washington infant study 1981–1989.
        Futura Publishing Co., Armonk (NY)1997 (p. 359–82)
        • Steinberger E.K.
        • Ferencz C.
        • Loffredo C.A.
        Infants with single ventricle: a population-based epidemiological study.
        Teratology. 2002; 65: 106-115
        • Yuan P.
        • Okazaki I.
        • Kuroki Y.
        Anal atresia: effect of smoking and drinking habits during pregnancy.
        Jpn J Hum Genet. 1995; 40: 327-332
        • Källén K.
        Maternal smoking during pregnancy and limb reduction malformations in Sweden.
        Am J Public Health. 1997; 87: 29-32
        • Li D.K.
        • Mueller B.A.
        • Hickok D.E.
        • et al.
        Maternal smoking during pregnancy and the risk of congenital urinary tract anomalies.
        Am J Public Health. 1996; 86: 249-253
        • Källen K.
        Maternal smoking and urinary organ malformations.
        Int J Epidemiol. 1997; 26: 571-574
        • Thorup J.
        • Cortes D.
        • Petersen B.L.
        The incidence of bilateral cryptorchidism is increased and the fertility potential is reduced in sons born to mothers who have smoked during pregnancy.
        J Urol. 2006; 176: 734-737
        • Jensen M.S.
        • Toft G.
        • Thulstrup A.M.
        • et al.
        Cryptorchidism according to maternal gestational smoking.
        Epidemiology. 2007; 18: 220-225
        • Källén K.
        Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring.
        Teratology. 2002; 66: 185-191
        • Brouwers M.M.
        • Feitz W.F.
        • Roelofs L.A.
        • et al.
        Risk factors for hypospadias.
        Eur J Pediatr. 2007; 166: 671-678
        • Carmichael S.L.
        • Shaw G.M.
        • Laurent C.
        • et al.
        The National Birth Defects Prevention Study. Hypospadias and maternal exposures to cigarette smoke.
        Paediatr Perinat Epidemiol. 2005; 19: 406-412
        • Källén K.
        Multiple malformations and maternal smoking.
        Paediatr Perinat Epidemiol. 2000; 14: 227-233
        • Steptoe P.C.
        • Edwards R.G.
        Birth after the reimplantation of a human embryo.
        Lancet. 1978; 2 ([letter]): 366
        • Centers for Disease Control and Prevention
        Assisted Reproductive Technology (ART) Report.
        (Available at:) (Accessed November 7, 2007)
        • Reddy U.M.
        • Wapner R.J.
        • Rebar R.W.
        • et al.
        Infertility, assited reproductive technologies, and adverse pregnancy outcomes. Executive summary of a National Institute of Child Health and Development workshop.
        Obstet Gynecol. 2007; 109: 967-977
        • Anthony S.
        • Buitendijk S.E.
        • Dorrepaal C.A.
        • et al.
        Congenital malformations in 4224 children conceived after IVF.
        Hum Reprod. 2002; 17: 2089-2095
        • Strömberg B.
        • Dahlquist G.
        • Ericson A.
        • et al.
        Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
        Lancet. 2002; 359: 461-465
        • Klemetti R.
        • Sevón T.
        • Gissler M.
        • et al.
        Health of children born as a result of in vitro fertilization.
        Pediatrics. 2006; 118: 1819-1827
        • Helmerhorst F.M.
        • Perquin D.A.
        • Donker D.
        • et al.
        Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies.
        BMJ. 2004; ([published 23 January])https://doi.org/10.1136/bmj.37957.560278.EE
        • Ombelet W.
        • Martens G.
        • De Sutter P.
        • et al.
        Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study.
        Hum Reprod. 2006; 21: 1025-1032
        • Schieve L.A.
        • Meikle S.F.
        • Ferre C.
        • et al.
        Low and very low birth weight in infants conceived with use of assisted reproductive technology.
        N Engl J Med. 2002; 346: 731-737
        • Mitchell A.A.
        Infertility treatment—more risks and challenges.
        N Engl J Med. 2002; 346: 769-770
        • Schieve L.A.
        • Rasmussen S.A.
        • Reefhuis J.
        Risk of birth defects among children conceived with assisted reproductive techniques: providing an epidemiologic context to the data.
        Fertil Steril. 2005; 84: 1320-1324
        • Sutcliffe A.G.
        • Ludwig M.
        Outcome of assisted reproduction.
        Lancet. 2007; 370: 351-359
        • Rufat P.
        • Olivennes F.
        • de Mouzon J.
        • et al.
        Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989).
        Fertil Steril. 1994; 61: 324-330
        • Dhont M.
        • de Neubourg F.
        • van der Elstand J.
        • et al.
        Perinatal outcome of pregnancies after assisted reproduction: a case-control study.
        J Assist Reprod Genet. 1997; 14: 575-580
        • Olivennes F.
        • Kerbrat V.
        • Rufat P.
        • et al.
        Follow-up of a cohort of 422 children aged 6 to 13 years conceived by in vitro fertilization.
        Fertil Steril. 1997; 67: 284-289
        • Bergh T.
        • Ericson A.
        • Hillensjö T.
        • et al.
        Deliveries and children born after in-vitro fertilisation in Sweden 1982–95: a retrospective cohort study.
        Lancet. 1999; 354: 1579-1585
        • Van Steirteghem A.
        • Bonduelle M.
        • Devroey P.
        • et al.
        Follow-up of children born after ICSI.
        Hum Reprod Update. 2002; 8: 111-116
        • Ludwig M.
        • Katalinic A.
        Malformation rate in fetuses and children conceived after intracytoplasmic sperm injection (ICSI): results of a prospective cohort study.
        Reprod Biomed Online. 2002; 5: 171-178
        • Hansen M.
        • Kurinczuk J.J.
        • Bower C.
        • et al.
        Risk of major birth defects after the intracytoplasmic sperm injection and in vitro fertilization.
        N Engl J Med. 2002; 346: 725-730
        • Katalinic A.
        • Rösch C.
        • Ludwig M.
        ICSI Follow-Up Study Group. Pregnancy course and outcome after intracytoplasmic sperm injection: a controlled, prospective cohort study.
        Fertil Steril. 2004; 81: 1604-1616
        • Klemetti R.
        • Gissler M.
        • Sevón T.
        • et al.
        Children born after assisted fertilization have an increased rate of major congenital anomalies.
        Fertil Steril. 2005; 84: 1300-1307
        • Olson C.K.
        • Keppler-Noreuil K.M.
        • Romitti P.A.
        • et al.
        In vitro fertilization is associated with an increase in major birth defects.
        Fertil Steril. 2005; 84: 1308-1315
        • Nygren K.G.
        • Finnström O.
        • Källén B.
        • et al.
        Population-based Swedish studies of outcomes after in vitro fertilisation.
        Acta Obstet Gynecol Scand. 2007; 86: 774-782
        • Hansen M.
        • Bower C.
        • Milne E.
        • et al.
        Assisted reproductive technologies and the risk of birth defects–a systematic review.
        Hum Reprod. 2005; 20: 328-338
        • Rimm A.A.
        • Katayama A.C.
        • Diaz M.
        • et al.
        A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children.
        J Assist Reprod Genet. 2004; 21: 437-443
        • Lie R.T.
        • Lyngstadaas A.
        • Ørstavik K.H.
        • et al.
        Birth defects in children conceived by ICSI compared with children conceived by other IVF-methods; a meta-analysis.
        Int J Epidemiol. 2005; 34: 696-701
        • Buitendijk S.E.
        Children after in vitro fertilization: an overview of the literature.
        Int J Technol Assess Health Care. 1999; 15: 52-65
        • De Kretser D.M.
        The potential of intracytoplasmic sperm injection (ICSI) to transmit genetic defects causing male infertility.
        Reprod Fertil Dev. 1995; 7: 137-142
        • Kurinczuk J.J.
        • Bower C.
        Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation.
        BMJ. 1997; 315: 1260-1265
        • Patrizio P.
        Intracytoplasmic sperm injection (ICSI): potential genetic concerns.
        Hum Reprod. 1995; 10: 2520-2523
        • Hawkins M.M.
        • Barratt C.L.
        • Sutcliffe A.G.
        • et al.
        Male infertility and increased risk of diseases in future generations.
        Lancet. 1999; 354: 1906-1907
        • Van Voorhis B.J.
        Outcomes from assisted reproductive technology.
        Obstet Gynecol. 2006; 107: 183-200
        • Mau-Holzmann U.A.
        Somatic chromosomal abnormalities in infertile men and women.
        Cytogenet Genome Res. 2005; 111: 317-336
        • Allen V.M.
        • Wilson R.D.
        • Cheung A.
        Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC), Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Pregnancy outcomes after assisted reproductive technology.
        J Obstet Gynaecol Can. 2006; 28: 220-250
        • In't Veld P.A.
        • van Opstal D.
        • van den Berg C.
        • et al.
        Increased incidence of cytogenetic abnormalities in chorionic villus samples from pregnancies established by in vitro fertilization and embryo transfer (IVF-ET).
        Prenat Diagn. 1995; 15: 975-980
        • Egozcue J.
        • Blanco J.
        • Vidal F.
        Chromosome studies in human sperm nuclei using fluorescence in-situ hybridization (FISH).
        Hum Reprod Update. 1997; 3: 441-452
        • Van Opstal D.
        • Los F.J.
        • Ramlakhan S.
        • et al.
        Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection.
        Hum Reprod. 1997; 12: 682-686
        • Bernardini L.
        • Martini E.
        • Geraedts J.P.
        • et al.
        Comparison of gonosomal aneuploidy in spermatozoa of normal fertile men and those with severe male factor detected by in-situ hybridization.
        Mol Hum Reprod. 1997; 3: 431-438
        • Schreurs A.
        • Legius E.
        • Meuleman C.
        • et al.
        Increased frequency of chromosomal abnormalities in female partners of couples undergoing in vitro fertilization or intracytoplasmic sperm injection.
        Fertil Steril. 2000; 74: 94-96
        • Calogero A.E.
        • de Palma A.
        • Grazioso C.
        • et al.
        High sperm aneuploidy rate in unselected infertile patients and its relationship with intracytoplasmic sperm injection outcome.
        Hum Reprod. 2001; 16: 1433-1439
        • Gekas J.
        • Thepot F.
        • Turleau C.
        • The Association des Cytogénéticiens de Langue Française
        • et al.
        Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men.
        Hum Reprod. 2001; 16: 82-90
        • Martin R.H.
        • Rademaker A.W.
        • Greene C.
        • et al.
        A comparison of the frequecy of sperm chromosome abnormalities in men with mild, moderate, and severe oligozoospermia.
        Biol Reprod. 2003; 69: 535-539
        • Nussbaum R.L.
        • McInnes R.R.
        • Willard H.F.
        Thompson & Thompson genetics in medicine.
        6th edition. WB Saunders Company, Philadelphia2001 (p. 150–51)
        • Lawler A.M.
        • Gearhart J.D.
        Genetic counseling for patients who will be undergoing treatment with assisted reproductive technology.
        Fertil Steril. 1998; 70: 412-413
        • Farfalli V.I.
        • Magli M.C.
        • Ferraretti A.P.
        • et al.
        Role of aneuploidy on embryo implantation.
        Gynecol Obstet Invest. 2007; 64: 161-165
        • Grifo J.
        • Talebian S.
        • Keegan D.
        • et al.
        Ten-year experience with preimplantation genetic diagnosis (PGD) at the New York university school of medicine fertility center.
        Fertil Steril. 2007; 88: 978-981
        • Heng B.C.
        Advanced maternal age as an indication for preimplantation genetic diagnosis (PGD)–the need for more judicious application in clinically assisted reproduction.
        Prenat Diagn. 2006; 26: 1051-1053
        • Devroey P.
        • Fauser B.C.
        Preimplantation aneuploidy screening: a research tool for now.
        Lancet. 2007; 370: 1985-1986
        • Mastenbroek S.
        • Twisk M.
        • van Echten-Arends J.
        • et al.
        In vitro fertilization with preimplantation genetic screening.
        N Engl J Med. 2007; 357: 9-17
        • Cox G.F.
        • Burger J.
        • Lip V.
        • et al.
        Intracytoplasmic sperm injection may increase the risk of imprinting defects.
        Am J Hum Genet. 2002; 71: 162-164
        • Orstavik K.H.
        • Eiklid K.
        • van der Hagen C.B.
        • et al.
        Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection.
        Am J Hum Genet. 2003; 72: 218-219
        • DeBaun M.R.
        • Niemitz E.L.
        • Feinberg A.P.
        Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19.
        Am J Hum Genet. 2003; 72: 156-160
        • Maher E.R.
        • Brueton L.A.
        • Bowdin S.C.
        • et al.
        Beckwith-Wiedemann syndrome and assisted reproduction technology (ART).
        J Med Genet. 2003; 40: 62-64
        • Gicquel C.
        • Gaston V.
        • Mandelbaum J.
        • et al.
        In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to abnormal imprinting of the KCNQ1OT gene.
        Am J Hum Genet. 2003; 72: 1338-1341
        • Chang A.S.
        • Moley K.H.
        • Wangler M.
        • et al.
        Association between Beckwith-Wiedemann syndrome and assisted reproductive technology: a case series of 19 patients.
        Fertil Steril. 2005; 83: 349-354
        • Svensson J.
        • Björnståhl A.
        • Ivarsson S.A.
        Increased risk of Silver-Russell syndrome after in vitro fertilization?.
        Acta Paediatr. 2005; 94: 1163-1165
        • Kagami M.
        • Nagai T.
        • Fukami M.
        • et al.
        Silver-Russell syndrome in a girl born after in vitro fertilization: partial hypermethylation at the differentially methylated region of PEG1/MEST.
        J Assist Reprod Genet. 2007; 24: 131-136
        • Anteby I.
        • Cohen E.
        • Anteby E.
        • et al.
        Ocular manifestations in children born after in vitro fertilization.
        Arch Ophthalmol. 2001; 119: 1525-1529
        • Moll A.C.
        • Imhof S.M.
        • Cruysberg J.R.
        • et al.
        Incidence of retinoblastoma in children born after in-vitro fertilisation.
        Lancet. 2003; 361: 309-310
        • Hossain P.
        • Kawar B.
        • El Nahas M.
        Obesity and diabetes in the developing world–a growing challenge.
        N Engl J Med. 2007; 356: 213-215
        • U.S. Department of Health and Human Services and U.S. Department of Agriculture
        Dietary guidelines for americans.
        6th edition. U.S. Government Printing Office, Washington, DC2005 (p. 28)
        • Ogden C.L.
        • Yanovski S.Z.
        • Carroll M.D.
        • et al.
        The epidemiology of obesity.
        Gastroenterology. 2007; 132: 2087-2102
        • Kim S.Y.
        • Dietz P.M.
        • England L.
        • et al.
        Trends in pre-pregnancy obesity in nine states, 1993–2003.
        Obesity (Silver Spring). 2007; 15: 986-993
        • Hedley A.A.
        • Ogden C.L.
        • Johnson C.L.
        • et al.
        Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002.
        JAMA. 2004; 291: 2847-2850
        • Centers for Disease Control and Prevention
        (Available at:) (Accessed December 20, 2007)
        • Naeye R.L.
        Maternal body weight and pregnancy outcome.
        Am J Clin Nutr. 1990; 52: 273-279
        • Baeten J.M.
        • Bukusi E.A.
        • Lambe M.
        Pregnancy complications and outcomes among overweight and obese nulliparous women.
        Am J Public Health. 2001; 91: 436-440
        • Stephansson O.
        • Dickman P.W.
        • Johansson A.
        • et al.
        Maternal weight, pregnancy weight gain, and the risk of antepartum stillbirth.
        Am J Obstet Gynecol. 2001; 184: 463-469
        • Andreasen K.R.
        • Andersen M.L.
        • Schantz A.L.
        Obesity and pregnancy.
        Acta Obstet Gynecol Scand. 2004; 83: 1022-1029
        • Cedergren M.I.
        • Selbing A.J.
        • Källén B.A.
        Risk factors for cardiovascular malformation–a study based on prospectively collected data.
        Scand J Work Environ Health. 2002; 28: 12-17
        • Smith G.C.
        • Fretts R.C.
        Stillbirth.
        Lancet. 2007; 370: 1715-1725
        • Richards I.D.
        Congenital malformations and environmental influences in pregnancy.
        Br J Prev Soc Med. 1969; 23: 218-225
        • Haddow J.E.
        • Smith D.E.
        • Sever J.
        Effect of maternal weight on maternal serum alpha-fetoprotein.
        Br J Obstet Gynaecol. 1982; 89 ([letter]): 93
        • Wald N.
        • Cuckle H.
        • Boreham J.
        • et al.
        The effect of maternal weight on maternal serum alpha-fetoprotein levels.
        Br J Obstet Gynaecol. 1981; 88: 1094-1096
        • Johnson A.M.
        • Palomaki G.E.
        • Haddow J.E.
        The effect of adjusting maternal serum alpha-fetoprotein levels for maternal weight in pregnancies with fetal open spina bifida. A United States collaborative study.
        Am J Obstet Gynecol. 1990; 163: 9-11
        • Waller D.K.
        • Mills J.L.
        • Simpson J.L.
        • et al.
        Are obese women at higher risk for producing malformed offspring?.
        Am J Obstet Gynecol. 1994; 170: 541-548
        • Watkins M.L.
        • Scanlon K.S.
        • Mulinare J.
        • et al.
        Is maternal obesity a risk factor for anencephaly and spina bifida?.
        Epidemiology. 1996; 7: 507-512
        • Shaw G.M.
        • Velie E.M.
        • Schaffer D.
        Risk of neural tube defect-affected pregnancies among obese women.
        JAMA. 1996; 275: 1093-1096
        • Werler M.M.
        • Louik C.
        • Shapiro S.
        • et al.
        Prepregnant weight in relation to risk of neural tube defects.
        JAMA. 1996; 275: 1089-1092
        • Källén K.
        Maternal smoking, body mass index, and neural tube defects.
        Am J Epidemiol. 1998; 147: 1103-1111
        • Shaw G.M.
        • Todoroff K.
        • Schaffer D.M.
        • et al.
        Maternal height and prepregnancy body mass index as risk factors for selected congenital anomalies.
        Paediatr Perinat Epidemiol. 2000; 14: 234-239
        • Anderson J.L.
        • Waller D.K.
        • Canfield M.A.
        • et al.
        Maternal obesity, gestational diabetes, and central nervous system birth defects.
        Epidemiology. 2005; 16: 87-92
        • Moore L.L.
        • Singer M.R.
        • Bradlee M.L.
        • et al.
        A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus.
        Epidemiology. 2000; 11: 689-694
        • Martínez-Frías M.L.
        • Frias J.P.
        • Bermejo E.
        • et al.
        Pre-gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes.
        Diabet Med. 2005; 22: 775-781
        • Queisser-Luft A.
        • Kieninger-Baum D.
        • Menger H.
        • et al.
        Erhöht mütterliche Adipositas das Risiko für kindliche Fehlbildungen? Analyse von 20248 Neugeborenen des Mainzer Geburtenregisters zur Erfassung angeborener Fehlbildungen.
        Ultraschall Med. 1998; 19: 40-44
        • Watkins M.L.
        • Botto L.D.
        Maternal prepregnancy weight and congenital heart defects in the offspring.
        Epidemiology. 2001; 11: 439-446
        • Mikhail L.N.
        • Walker C.K.
        • Mittendorf R.
        Association between maternal obesity and fetal cardiac malformations in African Americans.
        J Natl Med Assoc. 2002; 94: 695-700
        • Watkins M.L.
        • Rasmussen S.A.
        • Honein M.A.
        • et al.
        Maternal obesity and risk for birth defects.
        Pediatrics. 2003; 111: 1152-1158
        • Waller D.K.
        • Shaw G.M.
        • Rasmussen S.A.
        • National Birth Defects Prevention Study
        • et al.
        Prepregnancy obesity as a risk factor for structural birth defects.
        Arch Pediatr Adolesc Med. 2007; 161: 745-750
        • Prentice A.
        • Goldberg G.
        Maternal obesity increases congenital malformations.
        Nutr Rev. 1996; 54: 146-150
        • Ramsay J.E.
        • Ferrell W.R.
        • Crawford L.
        • et al.
        Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways.
        J Clin Endocrinol Metab. 2002; 87: 4231-4237
        • American Diabetes Association
        Gestational diabetes mellitus.
        Diabetes Care. 2003; 26: S103-S105
        • American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Obstetrics
        ACOG Practice Bulletin No. 30. Clinical management guidelines for obstetrician-gynecologists.
        Gestational diabetes. Obstet Gynecol. 2001; 98: 525-538
        • Simpson J.L.
        • Elias S.
        • Martin A.O.
        • et al.
        Diabetes in pregnancy, Northwestern University Series (1977–1981). I. prospective study of anomalies in offspring of mothers with diabetes mellitus.
        Am J Obstet Gynecol. 1983; 146: 263-270
        • Martínez-Frías M.L.
        Epidemiological analysis of outcomes of pregnancy in diabetic mothers: Identification of the most characteristic and most frequent congenital anomalies.
        Am J Med Genet. 1994; 51: 108-113
        • Albert T.J.
        • Landon M.B.
        • Wheller J.J.
        • et al.
        Prenatal detection of fetal anomalies in pregnancies complicated by insulin-dependent diabetes mellitus.
        Am J Obstet Gynecol. 1996; 174: 1424-1428
        • Casson I.F.
        • Clarke C.A.
        • Howard C.V.
        • et al.
        Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study.
        BMJ. 1997; 315: 275-278
        • Farrell T.
        • Neale L.
        • Cundy T.
        Congenital anomalies in the offspring of women with Type 1, Type 2 and gestational diabetes.
        Diabet Med. 2002; 19: 322-326
        • Yang J.
        • Cummings E.A.
        • O'Connell C.
        • et al.
        Fetal and neonatal outcomes of diabetic pregnancies.
        Obstet Gynecol. 2006; 108: 644-650
        • Sepe S.J.
        • Connell F.A.
        • Geiss L.S.
        • et al.
        Gestational diabetes. Incidence, maternal characteristics, and perinatal outcome.
        Diabetes. 1985; 34: 13-16
        • Kalter H.
        The non-teratogenicity of gestational diabetes.
        Paediatr Perinat Epidemiol. 1998; 12: 456-458
        • Mironiuk M.
        • Kietlin´ska Z.
        • Jezierska-Kasprzyk K.
        • et al.
        A class of diabetes in mother, glycemic control in early pregnancy and occurrence of congenital malformations in newborn infants.
        Clin Exp Obstet Gynecol. 1997; 24: 193-197
        • Bartha J.L.
        • Martínez del Fresno P.
        • Comino-Delgado R.
        Gestational diabetes mellitus and congenital malformations.
        Am J Obstet Gynecol. 2001; 184: 247-248
        • Kalter H.
        Gestational diabetes mellitus and congenital malformations.
        Am J Obstet Gynecol. 2001; 184: 246-248
        • Jenssen P.A.
        • Rothman I.
        • Schwartz S.M.
        Congenital malformations in newborns of women with established and gestational diabetes in Washington State, 1984-1991.
        Paediatr Perinat Epidemiol. 1996; 10: 52-63
        • Martínez-Frías M.L.
        • Bermejo E.
        • Rodríguez-Pinilla E.
        • et al.
        Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers.
        Am J Med Genet. 1998; 78: 140-145
        • Åberg A.
        • Westborn L.
        • Källén B.
        Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes.
        Early Hum Dev. 2001; 61: 85-95
        • Ylinen E.
        • Wikström S.
        Increased risk of multicystic dysplastic kidney among babies of both pre-gestational and gestational diabetic mothers.
        Eur J Pediatr. 2002; 161: 634-635
        • Frías J.L.
        • Frías J.P.
        • Frías P.A.
        • et al.
        Infrequently studied congenital anomalies as clues to the diagnosis of maternal diabetes mellitus.
        Am J Med Genet. 2007; 143: 2904-2909
        • Virtanen H.E.
        • Tapanainen A.E.
        • Kaleva M.M.
        • et al.
        Mild gestational diabetes as a risk factor for congenital cryptorchidism.
        J Clin Endocrinol Metab. 2006; 91: 4862-4865
        • Schaefer U.M.
        • Songster G.
        • Xiang A.
        • et al.
        Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy.
        Am J Obstet Gynecol. 1997; 177: 1165-1171
        • Schaefer-Graf U.M.
        • Buchanan T.A.
        • Xiang A.
        • et al.
        Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes.
        Am J Obstet Gynecol. 2000; 182: 313-320
        • Sheffield J.S.
        • Butler-Koster E.L.
        • Casey B.M.
        • et al.
        Maternal diabetes mellitus and infant malformations.
        Obstet Gynecol. 2002; 100: 925-930
        • Hendricks K.A.
        • Nuno O.M.
        • Suarez L.
        • et al.
        Effects of hyperinsulinemia and obesity on risk of neural tube defects among Mexican Americans.
        Epidemiology. 2001; 12: 630-635