British Journal of Obstetrics and Gynaecology August 1999, Vol106, pp. 874-876

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Insulin sensitivity in pre-eclampsia (Received 5 January 1999)

SiG The recent paper by Roberts et al. (Vol 105, October 1998)' examin- ing insulin sensitivity in pre-eclampsia is interesting and appears to have been well conducted. From their data they conclude that pre- eclampsia is not associated with insulin resistance. However, it should be borne in mind that several other recent studies have also addressed this subject and have concluded that pre-eclampsia is likely to be associated with insulin resistance. For example, Lorentzen ef aL2 noted higher incremental area under the curve for insulin and glu- cose responses to an oral glucose tolerance test in women with pre- eclampsia compared to women with normal pregnancy. Similarly, Joffe el al.' in a large prospective study of 4569 pregnant women reported that plasma glucose 1 hour after a 50g oral glucose challenge was an independent (correcting for body mass index and race) predic- tor of pre-eclampsia. Perhaps more importantly, Sowers et al? demonstrated that elevated second trimester fasting insulin levels preceded development of pre-eclampsia in African American women. Moreover, Fuh et aL5 have shown that when studied two months after delivery, women who developed pre-eclampsia were relatively insulin resistant and byperinsulinaemic when compared to those who had an uncomplicated pregnancy. This finding has recently been extended to include women with pre-eclampsia followed up to 17 years latel.6.

In addition to these clinical studies, there is biological plausibility for the association of pre-eclampsia with insulin resistance. Pre- eclampsia is associated with significantly increased fatty free acid levels, even prior to the onset of clinical manifestations of the dis- ease7. From diabetes research, free fatty acids are now known to cause or amplify insulin resistance in muscle and liver, the major reg- ulators of systemic insulin sensitivity.

Finally, it is noteworthy that the women with pre-eclampsia stud- ied by Roberts et al. had similar lipid levels to the control healthy pregnant population, whereas nearly all other groups have noted sig- nificantly elevated triglyceride concentrations in women with pre- eclampsia7.

Therefore, in contrast to Roberts et al. we suggest that on balance the current burden of evidence supports a role for insulin resistance in the pathophysiology of pre-eclampsia.

*Nave4 Sattar & ?Ian Greer Departments of *Clinical Biochemistry and tobstetrics and Gynaecology, Glasgow Royal Infinnary University NHS Trust

References 1 Roberts RN, Henriksen JE, Hadden DR. Insulin sensitivity in pre-

eclampsia. Br J Obsrer Gynaecoll998; 105: 1095-1100. 2 Lorentzen B, Birkeland KI, Endresen MJ, Henriksen T. Glucose intol-

erance in women with pre-eclampsia. Acta Obstet Gynecol Scand

3 Joffe GM, Esterlitz JR, Levine RJ et al. The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Am J Obstet Gynecoll998; 179: 1032- 1037.

4 Sowers JR, Saleh AA, Sokol RJ. Hyperinsulinaemia and insulin resis- tance are associated with pre-eclampsia in African-American women. Am J Hypertens 1995; 8: 1-4.

5 Fuh MMT, Yin CS, Pei D, Sheu WHH, Jeng CY, Chen YDI, Reaven GM. Resistance to insulin-mediated glucose-uptake and hyperinsuli- naemia in women who had pre-eclampsia during pregnancy. Am J Hypertens 1995; 7: 768-771.

1998; 77: 22-27.

6 Laivuori H, Tikkanen MJ, Ylikorkala 0. Hyperinsulinaemia 17 years after pre-eclamptic first pregnancy. J Clin Endocrinol Mefab 1996; 81: 2908-291 1 .

7 Sattar N, Gaw A, Packard CJ, Geer IA. Potential pathogenic roles of aberrant lipoprotein and fatty acid metabolism in pre-eclampsia. Br J Obstet Gynaecoll996; 103: 614-620.

AUTHOR'S REPIX Sir; I thank Dr Sattar and Professor Greer for their interest in our article. I readily accept that we hold a minority viewpoint, but feel that there is still much room for debate. The studies cited by Lorentzen et ul.', Joffe et al.', Sowers el al.', Fuh et aL4 and Laivuori et aL5 all share the merit of having distinguished between proteinuric and non-protein- uric pregnancy-induced hypertension, but they have all relied on data from oral glucose tolerance tests and one cannot therefore exclude differences in glucose absorption between women with pre-eclamp- sia and normotensive pregnant controls as possible confounding vari- ables. Furthermore, with the exception of the postnatal study by Fuh et al., none have attempted to measure insulin sensitivity per se. Insulin resistance is thus implied and not quantified.

It is interesting to note that although Lorentzen et al.' demon- strated a higher incremental area under the curve for both glucose and insulin response to an oral glucose load, their findings of a signifi- cantly lower fasting glucose and similar fasting insulin to those of the controls are not typical of an insulin resistant state. It is also notewor- thy in the study of Joffe et al.' that although there is a trend towards an increasing incidence of women subsequently developing pre- eclampsia with increasing decile of 1 hour glucose response to a 50g oral glucose load, this pattern is much less obvious for those who went on to develop severe pre-eclampsia.

In the study by Sowers et al.' women who went on to develop pre- eclampsia had significantly higher fasting insulin concentrations at 20 weeks than a pregnant control group. This seems to be at variance with the findings of Lorentzen et al. Furthermore, the pre-eclamptic group already had a significantly higher mean diastolic blood pres- sure than the control group at 20 weeks, and the control group was a combination of women who remained normotensive and those who developed gestational hypertension.

Fuh et aL4 showed that those women who had pre-eclampsia dur- ing pregnancy had a greater insulin response to oral glucose and were relatively insulin resistant (assessed by insulin suppression test), compared with controls when studied eight weeks postpartum. How- ever, these data conflict with those of Jacober et al." who reported that insulin-stimulated glucose disposal was similar when studied post- partum in women who had suffered pre-eclampsia and in normoten- sive controls. This would be in keeping with our own findings. We were able to follow up six matched pairs from the 11 pre-eclamptic and 11 control women three to six months postpartum and found no difference in insulin sensitivity between the two groups. It is also interesting to note in the long term follow up study of Laivuori et aLS that 27% of the women who had pre-eclampsia in this first pregnancy had gestational hypertension in their second pregnancy, suggesting that these women had latent essential hypertension and an alternative reason for insulin resistance.

Our theory is supported by the results of our own retrospective study looking at glycosylated haemoglobin in women with preg- nancy-induced hypertension and also by the work of Solomon et al.7 who showed that women with gestational hypertension had a signifi- cantly higher incidence of abnormal 50g oral glucose loading tests between 24 and 32 weeks compared with normotensive controls. In contrast, women with pre-eclampsia did not have a higher incidence of abnormal glucose loading tests.

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In conclusion, there is still much controversy concerning the rela- tionship, if any, between insulin resistance and pre-eclampsia. To my knowledge, ours is still the only published study which has specifi- cally measured insulin sensitivity during pregnancy in women with pre-eclampsia. There is clearly a need for other carefully performed studies of insulin sensitivity in pregnancy-induced hypertension which make the distinction between pre-eclampsia and gestational hypertension, and I hope that our article may act as a suitable stimulus.

Ralph Roberts Ulster Hospital, Dundonald

References Lorenmn B, Birkeland K1, Endresen MJ, Henriksen T. Glucose intol- erance in women with pre-eclampsia. Acta Obstet Gynecol Scad 1998; 77: 22-27. Joffe GM, Esterlitz JR, Levine RJ et al. The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Am J Obstet Gynecoll998; 179 1032- 1037. Sowers JR, Saleh AA, Sokol RJ. Hyperinsulinaemia and insulin resis- tance are associated with pre-eclampsia in African-American women. Am J Hypertens 1995; 8 1-4. Fuh MMT, Yin CS, Pei D et al. Resistance to insulin-mediated glu- cose-uptake and hyperinsulinaemia in women who had pre-eclampsia during pregnancy. Am JHypertens 1995; 7 768-771. Laivuori H, Tikkanen MJ, Ylikorkala 0. Hyperinsulinaemia 17 years after pre-eclamptic first pregnancy. J CIin Endocrinol Metab 1996;

Jacober SJ, Moms DA, Sowers JR. Postpartum blood pressure and insulin sensitivity in African-American women with recent pre- eclampsia. Am J Hypertens 1994; 7 : 933-936. Solomon CG, Graves SW, Green MF, Seely EW. Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 1994; 23:

81: 2908-2911.

717-721.

Randomised trials in maternal and perinatal medicine: global partnerships are the way forward (Received 3 February 1999)

Sic This article (Vol 105, December 1998) considered some important aspects of perinatal trials as we move towards the new millennium, particularly the wider collaboration between different countries around the world. This global approach to mals is certainly one of the important ways that progress will be made for the health of women and their babies and is to be encouraged. However, this article also addressed the role of joint recruitment of women into more than one trial. I believe some of the points made by the authors require further discussion. First, I agree completely that when two or more interven- tions are to be tested with the ‘expectation’ that an interaction may be present, a factorial design is ideal and sample sizes for the trial will need to be adjusted so that the trial is appropriately powered to detect such a hypothesised interaction. This was, however, not the case with the ORACLE and Antenatal TRH Trials. These two trials were testing different interventions with the same purpose: to improve the health of babies born to women who were at high risk of delivering preterm. There was no reason to believe that an interaction was present, how- ever, if both interventions had been found to be beneficial then both interventions would be used in clinical practice. If the first time the two treatments were used was outside the context of a randomised trial then if any interactions were present, it is unlikely that they would be detected and as a consequence it is possible that no benefit or even harm would have accrued for the women receiving both treatments. This scenario is unlikely but possible and therefore both trial groups felt it was necessary to explore the possibility that an interaction may be present. There was no prespecified hypothesis. The exercise was hypothesis generating and aiming to detect large interactions if they

were present so that appropriate further study could be undertaken if necessary. This course of action was deemed appropriate to protect the future health of women and their babies without compromising scien- tific integrity.

Second, the suggestion that women who consent to enter two tri- als are different to women who enter one trial is valid but no more so than the suggestion that the women who agree to enter trials are dif- ferent from women who do not. The clear description of women who enter a trial is used to indicate the characteristics of women for whom the intervention, if found to be beneficial, can be generalised. Exactly the same approach applies to women who enter more than one trial. Unless of course, the authors of the article have empirical evidence to suggest otherwise.

Finally, the authors mention ethical problems with this approach but then do not discuss them further, which is disappointing. The debate concerning the ethics of joint recruitment needs to continue. If it is reasonable for women to enter one trial why not two? If women are informed about the reasons for joint entry and are informed about the risks and benefits of taking part in both trials, why can’t they decide to enter both trials? And at what point does a researcher or an ethics committee say a pregnant woman or new parent is unable to make their own decision?

Peter Brocklehurst Perinatal Trials Service, Radclife Infirmary, Oxford

Fetal ultrasound biometry: 1. Head reference values (Received 4 February 1999)

Sic Kurmanavicius et al. (Vol 106, February 1999)’ provide us with another set of ultrasound biometric reference values which improve on previous publications and comply with the recommended method- ology of statisticians, such as Altman and Royston. The gold standard they apply for gestation is a menstrual date, or a CRL, if this is more than five days different from the menstrual date. They do not, how- ever, tell us how many were dated by each method. Smith e f al.’ have recently reported a significantly higher percentage of babies which were small for gestational age at birth when the first trimester CRL was between two and six days smaller than expected by menstrual dates. It could be argued that these babies have not grown normally. I understand that the authors did not want to use a ‘super-normal popu- lation’ for their measurements, and exclusions are specified, but it is hard to justify including preterm infants which may have required prolonged intensive care and/or resulted in neonatal death. Were sec- ond trimester miscarriages included in the study? We are, after all, interested in the measurements for normal healthy pregnancies.

Mittendorf et al.’ have shown slight differences in the gestational length according to a number of parameters including ethnicity and parity of the mother and fetal sex. We do not know, however, whether this difference is reflected in ultrasound dating. The country of origin of the women in the study by Kurmanavicius et al. is quite variable, with only one-third from Switzerland. I am only speculating that this could be important, but I am sure more customised charts are needed. Finally Kurmanavicius et al. have made a valuable contribution in their recommendation for the use of fetal Z scores to assess the appro- priateness of fetal growth. Fetal gestation and growth cannot be accu- rately assessed with plotted charts4 and Z scores should allow straightforward computer analysis of fetal parameters.

David J. R. Hutchon Memorial Hospital. Darlington

References 1 Kurmanavicius J, Wright EM, Royston Pet al. Fetal ultrasound biom-

etry: 1. Head reference values. Br J Obstet Gynaecol 1999; 106: 126- 135.

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