Papers

Historical cohort study of in utero exposure to uterotonic drugs and cognitive function in young adult life

Henrik Toft Sørensen, associate professor, ^a Kenneth J Rothman, professor, ^c Matthew W Gillman, associate professor, ^d Flemming Hald Steffensen, research associate professor, ^b Peer Fischer, consultant, ^e Svend Sabroe, associate professor. ^b

^a Department of Internal Medicine V, Aarhus University Hospital, 8000 Aarhus C, Denmark, ^b Danish Epidemiology Science Centre, Department of Epidemiology and Social Medicine, University of Aarhus, 8000 Aarhus C, ^c Department of Epidemiology and Preventive Medicine, Boston University School of Medicine, Boston, MA 02118, USA, ^d Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, ^e Conscription Administration, County of North Jutland, 9000 Aalborg, Denmark

Correspondence to: Dr Sørensen hts{at}soci.au.dk

Oxytocin has potent uterotonic properties which can induce tetany, rupture, and water intoxication. Inappropriately high doses can affect the fetus by inducing abnormal heart rhythms, circulatory collapse, and preterm delivery accompanied by an increased risk of respiratory distress and damage to the central nervous system.¹ Several studies have reported an association between oxytocic drugs and neonatal hyperbilirubinaemia,² which might influence long term cognitive function.³ Little is known, however, of the long term consequences of exposure to uterotonic drugs. We investigated whether in utero exposure to uterotonic drugs affects cognitive performance in draft age men.

	Subjects, methods, and results

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Nearly all Danish men have to register with the draft board at around the age of 18 years, at which time they undergo physical and mental examinations. We studied all men who were born in Denmark after 1 January 1973 and who were drafted while residing in North Jutland and Viborg counties from 1 August 1993 to 31 July 1994.

All draftees took a 45 minute intelligence test, the Boerge Prien test, developed in 1957 for the Danish draft board.⁴ The test includes four time limited subtests covering four categories: letter matrices, verbal analogies, number series, and geometric figures. The test shows high correlations with the Weschler adult intelligence scale verbal intelligence quotient (0.78), the performance intelligence quotient (0.71), and the full scale intelligence quotient (0.82). In the validation study the mean full scale intelligence quotient was 106, equivalent to a mean Boerge Prien test score of 44.2.⁴

We linked data from the draft examination with the Danish Medical Birth Registry by means of a 10 digit unique personal identification number. The registry contains information relating to all births in Denmark since 1973. Oxytocin was the most commonly used uterotonic drug in that period. We examined the mean Boerge Prien test score according to in utero exposure to uterotonic drugs, taking account of possible confounding variables (table).

We identified 4805 conscripts during the study period. We had complete draft medical data on 4300; of the remainder, 495 were exempt from the examination mainly because of asthma, osteochondrosis, and epilepsy, and 10 had incomplete data in the birth registry. Of the 4300 men, 22.8% had been exposed to uterotonic drugs; among those who were exempt from the examination 23.5% had been exposed to uterotonic drugs.

The mean Boerge Prien score was similar for those exposed and not exposed to uterotonic drugs (43.1 v 42.9). We also stratified the subjects by mode of delivery; in subjects born by vaginal delivery the mean Boerge Prien score was 43.0 among those exposed to uterotonic drugs compared with 43.1 among those not exposed. From a multiple linear regression with all above mentioned confounders included we estimated the difference in Boerge Prien score to be 0.58 (95% confidence interval 1.25 to 0.08) between those exposed and not exposed to uterotonic drugs.

	Comment

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Friedman et al examined 156 children 23 to 62 months after births associated with spontaneous labour, labour induced with oxytocin, or labour induced with dinoprostone. The prevalence of neurological or developmental abnormalities not attributable to events after delivery was the same overall in induced and spontaneous labours, but those abnormalities occurring after induction of labour all followed use of oxytocin.⁵ Our data indicate that exposure to uterotonic drugs does not substantially affect cognitive function 20 years later. A small difference due to non-differential misclassification, however, cannot be ruled out. A strength of our study is the large size, the population based design, and complete ascertainment. It is unlikely that selection bias and confounding explain the lack of association.

	Acknowledgments

Contributors: HTS, KJR, and MWG in collaboration with SS initiated the establishment and design of the cohort. HTS initiated this study and discussed the hypothesis with KJR. HTS and FHS analysed the data. PF collected the outcome data. SS linked the data to the birth registry. All authors participated in the interpretation of the findings. HTS, KJR and FHS wrote the first draft of the paper. All participated in editing the paper. HTS is guarantor of the paper.

Funding: Helsefonden (grant No 11/064-94), the EU Biomed II programme (contract No BMH4-CT97-2430), Aarhus University Research Foundation (F-1996-SUN-1-77), and Danish Medical Research Council (grant No 9700677). The activities of the Danish Epidemiology Science Centre are financed by a grant from the Danish National Research Foundation.

Conflict of interest: None declared.

	References

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1. Dawood MY. Evolving concepts of oxytocin for induction of labor. Am J Perinatal 1989; 6: 167-172.
2. Johnson JD, Aldrich M, Angelus P, Stevenson DK, Smith DW, Herschel MJ, et al. Oxytocin and neonatal hyperbilirubinemia. Am J Dis Child 1984; 138: 1047-1050[Abstract/Free Full Text].
3. Seidman DS, Paz I, Stevenson DK. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years at age. Pediatrics 1991; 88: 828-833[Abstract/Free Full Text].
4. Mortensen EL, Reinisch JM, Teasdale TW. Intelligence measured by WAIS and a military draft board group test. Scand J Psychol 1989; 30: 3115-3118.
5. Friedman EA, Sachtleben MR, Wallace AK. Infant outcome following labor induction. Am J Obstet Gynecol 1979; 133: 718-722[Medline].

(Accepted 14 August 1998)