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Thromb Haemost 2001; 85(04): 609-613
DOI: 10.1055/s-0037-1615641
Review Articles
Schattauer GmbH

Coumarins during Pregnancy: Long-term Effects on Growth and Development of School-age Children

J. Wesseling
1   Department of Paediatrics, Beatrix Children’s Hospital, University Hospital Groningen
,
D. Van Driel
1   Department of Paediatrics, Beatrix Children’s Hospital, University Hospital Groningen
,
H. S. A. Heymans
2   Department of Paediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam
,
F. R. Rosendaal
3   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden
,
L. M. Geven-Boere
4   Dutch Federation of Thrombosis Services, The Hague
,
M. Smrkovsky
5   Department of Special Education, University of Groningen
,
B. C. L. Touwen
6   Department of Medical Physiology, Developmental Neurology Section, University of Groningen
,
P. J. J. Sauer
1   Department of Paediatrics, Beatrix Children’s Hospital, University Hospital Groningen
,
E.Van der Veer
7   Pathology & Laboratory Medicine, University Hospital Groningen, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 25 May 2000

Accepted after resubmission 06 November 2000

Publication Date:
08 December 2017 (online)

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Summary

Anticoagulation during pregnancy is complicated because of potential risks for mother and foetus. Unfractionated or low-molecular-weight heparin is used for most anticoagulant indications. Its efficacy, however, in pregnant women with prosthetic heart valves is questioned, therefore coumarins are preferred for this indication.

We studied long-term effects of prenatal coumarin-exposure on growth and on neurological, behavioural and cognitive development in 274 school-age children in comparison with 231 age-matched non-exposed controls. No major abnormalities were found. The exposed children had an increased risk for minor neurological dysfunction and for a low intelligence quotient (IQ below 80). The risk for a combination of two or more (minor) abnormalities was higher for the exposed children, RR = 7.6. We conclude that prenatal exposure to coumarins is associated with an increased risk for disturbances in development in school-age children. However, for the vast majority of children there is no clinical significant effect on growth and long-term development.

Keywords

Anticoagulants - long-term effect - growth - behaviour - neurological development - intelligence
 

  • References

  • 1 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-40.
    CrossrefPubMedGoogle Scholar
  • 2 Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315: 1390-3.
    CrossrefPubMedGoogle Scholar
  • 3 Sareli P, England MJ, Berk MR, Marcus RH, Epstein M, Driscoll J, Meyer T, McIntyre J, Van Gelderen C. Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses. Am J Cardiol 1989; 63: 1462-5.
    CrossrefPubMedGoogle Scholar
  • 4 Howe AM, Lipson AH, De Silva M, Ouvrier R, Webster WS. Severe cervical dysplasia and nasal cartilage calcification following prenatal warfarin exposure. Am J Med Genet 1997; 71: 391-6.
    CrossrefPubMedGoogle Scholar
  • 5 Tamburrini O, Bartolomeo-De Iuri A, Di Guglielmo GL. Chondrodysplasia punctata after warfarin. Case report with 18-month follow-up. Pediatr Radiol 1987; 17: 323-4.
    CrossrefPubMedGoogle Scholar
  • 6 Howe AM, Webster WS. The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 1992; 46: 379-90.
    CrossrefPubMedGoogle Scholar
  • 7 Price PA, Williamson MK, Haba T, Dell RB, Jee WSS. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci USA 1982; 79: 7734-8.
    CrossrefPubMedGoogle Scholar
  • 8 Sundaram KS, Lev M. Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain. J Lipid Res 1988; 29: 1475-9.
    PubMedGoogle Scholar
  • 9 Sundaram KS, Fan JH, Engelke JA, Suttie JW, Lev M. Vitamin K status influences brain sulfatide metabolism in young mice and rats. J Nutr 1996; 126: 2746-51.
    PubMedGoogle Scholar
  • 10 Nelson-Piercy C. Hazards of heparin: allergy, heparin-induced thrombocytopenia and osteoporosis. Bailliere’s Clin Obstet Gynaecol 1997; 11: 489-509.
    PubMedGoogle Scholar
  • 11 Douketis JD, Ginsberg JS, Burrows RF, Duku EK, Webber CE, Brill-Edwards P. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost 1996; 75: 254-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Sanson BJ, Lensing AWA, Prins MH, Ginsberg JS, Barkagan ZS, LavennePardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molcular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynaecol Clin North Am 1997; 24: 499-521.
    PubMedGoogle Scholar
  • 14 Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol 1996; 27: 1698-703.
    CrossrefPubMedGoogle Scholar
  • 15 Caruso A, De Carolis S, Ferrazzani S, Paradisi G, Pomini F, Pompei A. Pregnancy outcome in women with cardiac valve prosthesis. Obstet Gynecol 1994; 54: 7-11.
    PubMedGoogle Scholar
  • 16 Study Group of the Working Group on Valvular Heart Disease of the European Society of Cardiology.. Guidelines for prevention of thromboembolic events in valvular heart disease. Eur Heart J 1995; 16: 1320-30.
    CrossrefPubMedGoogle Scholar
  • 17 Ginsberg JS. Thromboembolism and pregnancy. Thromb Haemost 1999; 82: 620-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Robin F, Lecuru F, Desfeux P, Boucaya V, Taurelle R. Anticoagulant therapy in pregnancy. Eur J. Obstet Gynecol Reprod Biol 1999; 83: 171-7.
    CrossrefPubMedGoogle Scholar
  • 19 Van Driel D, Wesseling J, Rosendaal FR, Odink RJ, Van der Veer E, Gerver WJ, Geven-Boere LM, Sauer PJJ. Growth untill puberty after in utero exposure to coumarins. Am J Med Genet 2001; 95: 438-43.
    PubMedGoogle Scholar
  • 20 Wesseling J, Van Driel D, Heymans HSA, Van der Veer E, Sauer PJJ, Touwen BCL, Smrkovsky M. Behavioural outcome of school-age children afer prenatal exposure to coumarins. Early Hum Dev 2000; 58: 213-24.
    CrossrefPubMedGoogle Scholar
  • 21 Wesseling J, Van Driel D, Smrkovsky M, Van der Veer E, Geven-Boere LM, Sauer PJJ, Touwen BCL. Neurological outcome in school-age children after in utero exposure to coumarins. Submitted.
    PubMedGoogle Scholar
  • 22 Van Driel D, Wesseling J, Sauer PJJ, Van der Veer E, Touwen BCL, Smrkovsky M. In utero exposure to coumarins and cognition at 8-14 years. Pediatr 2001; 107: 123-9.
    CrossrefPubMedGoogle Scholar
  • 23 Weenink GH. Preventie van diep veneuze trombose en longembolie in de zwangerschap en postpartum. In: Consensusbijeenkomst ‘Preventie van Diep Veneuze Trombose’. 1989 March 18, Utrecht. Edn. CIP-gegevens Koninklijke Bibliotheek Den Haag 1989: 61-9.
    Google Scholar
  • 24 Touwen BCL. Examination of the child with minor neurological dysfunctions. Clin Dev Med 1979; 71: 1-141.
    PubMedGoogle Scholar
  • 25 Van Haassen PP, De Bruyn EEJ, Pijl YJ. et al. Wechsler Intelligence Scale for Children-Revised, Nederlandstalige uitgave. Lisse: Swets en Zeitlinger; 1986
    Google Scholar
  • 26 Janssen PJ. Intelligentie: tussen meten en weten in theorie en praktijk. In: Vander Steene J, Vertommen H. editors Leuven: Universitaire Pers; 1986: 149-167.
    Google Scholar
  • 27 Kalverboer AF, Overbeek B, Vaessen W. Social behaviour in hyperactive children as rated by parents and teachers. In: Kalverboer AF. editor. Developmental biopsychology: experimental and observational studies in children at risk. Ann Arbour: The university of Michigan Press; 1990: 115-31.
    Google Scholar
  • 28 Kalverboer AF, Visser J. Manual of the GBS, The Groningen Behaviour Checklist Schoolsituation. Lisse: Swets en Zeitlinger; In press.
    Google Scholar
  • 29 Sixma H, Ultee W. Een beroeps-prestigeschaal voor Nederland in de jaren tachtig. Mens en Maatschappij 1983; 4: 360-81.
    PubMedGoogle Scholar
  • 30 Gerver WJM, De Bruin R. Paediatric morphometrics. Utrecht, The Netherlands: Wetenschappelijke uitgeverij Bunge; 1996
    Google Scholar
  • 31 Burgmeijer RJF, Fredriks AM, Van Buuren S, Verloove-Vanhorick SP, Wit JM. Groeidiagrammen 1997. Houten, The Netherlands: Bohn Stafleu Van Loghum; 1998
    Google Scholar
  • 32 Chong MK, Harvey D, De Swiet M. Follow-up study of children whose mothers were treated with warfarin during pregnancy. Br J Obstet Gynaecol 1984; 91: 1070-3.
    CrossrefPubMedGoogle Scholar
  • 33 Wong V, Cheng CH, Chan KC. Fetal and neonatal outcome of exposure to anticoagulants during pregnancy. Am J Med Genet 1993; 45: 17-21.
    CrossrefPubMedGoogle Scholar
  • 34 Olthof E, De Vries TW, Touwen BCL, Smrkovsky M, Geven-Boere LM, Heymans HSA, Van der Veer E. Late neurological, cognitive and behavioural sequelae of prenatal exposure to coumarins: a pilot study. Early Hum Dev 1994; 38: 97-109.
    CrossrefPubMedGoogle Scholar
  • 35 Verhulst FC, Van der Ende J, Ferdinand RF, Kasius MC. The prevalence of DSM-III-R diagnoses in a national sample of Dutch adolescents. Arch Gen Psychiatr 1997; 54: 329-36.
    CrossrefPubMedGoogle Scholar
  • 36 Touwen BCL. The meaning and value of soft signs in neurology. In: Tupper DE. editor. Soft neurological signs. London: Grune & Stratton, Ltd.; 1987: 281-96.
    Google Scholar
  • 37 Taylor DC. The influence of sexual differentiation on growth, development and disease. In: Davis JA, Dobbing J. ed. Scientific Foundations of Paediatrics. 2nd ed. London: Heinemann Medical Books, Ltd.; 1981: 23-40.
    Google Scholar
  • 38 Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999; 33: 1637-41.
    CrossrefPubMedGoogle Scholar
  • 39 Tanner JM. Growth at adolescence. 2nd ed. Oxford: Blackwell Scientific Publications; 1962
    Google Scholar
  • 40 Hanania G, Thomas D, Michel PL, Garbarz E, Age C, Millaire A, Acar J. Pregnancy and prosthetic heart valves: a French cooperative retrospective study of 155 cases. Eur Heart J 1994; 15: 1651-8.
    CrossrefPubMedGoogle Scholar