AKADEMISK AVHANDLING
kommer att offentligen försvaras i aulan, Danderyds sjukhus,
fredagen den 5 juni 1998, kl 09.00
Anders Björklund
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Anders Björklund, MD
HYPOGLYCAEMIA IN PREGNANCYHypoglycaemic clamp studies during and after pregnancy in women with IDDM
ABSTRACT
Dissertation from KAROLINSKA INSTITUTET DANDERYD HOSPITAL, Division of Obstetrics and Gynaecology and Division of Internal Medicine, SE-182 88 Danderyd, SwedenHuvudhandledare: Docent Ulf Adamson
Fakultetsopponent:
Brian M Frier, BSc, MD, FRCP
Diabetic Department
Royal Infirmary
Edinburgh
KAROLINSKA INSTITUTET DANDERYDS SJUKHUS
enheten för obstetrik och gynekologi och enheten för internmedicin
Problem: In pregnant women with IDDM a strict insulin regimen is generally instituted, which permits the possibility of a normal fetal outcome. This, however, increases the risk of hypoglycaemia, and a high prevalence of severe hypoglycaemia has been reported during pregnancy in these women. Depletion of glucose, the most important source of energy in intrauterine life, most certainly places the fetus at risk. There are also reports that symptoms of hypoglycaemia diminish in pregnant IDDM patients. Such decreased symptomatology, possibly in combination with cognitive impairments, would increase the risk of more severe hypoglycaemia. An impairment in the important hormone response counterregulating hypoglycaemia could be a contributory cause of hypoglycaemia. The placenta secretes several hormones that have a blood-glucose-raising effect, and these might further counteract hypoglycaemia. Alterations in insulin metabolism during pregnancy might also affect the risks in connection with hypoglycaemic events. Thus the aims of the studies were to elucidate: first, whether fetal heart rate, blood flow velocity waveforms in the umbilical artery and placentary hormones are affected by maternal hypoglycaemia; secondly, whether hormonal counterregulation of hypoglycaemia, along with symptoms and cognitive function during hypoglycaemia, are modified during pregnancy, and thirdly whether the clearance of insulin during hypoglycaemia is altered during pregnancy.
Methods: Ten women with IDDM in the third trimester of pregnancy were studied with hyperinsulinaemic, hypoglycaemic clamp methodology, repeated six months to one year after delivery. During the 150-min procedure fetal heart rate was monitored continuously and blood samples were collected for the analysis of insulin and of counterregulatory and placentary hormones. Subjective symptoms of hypoglycaemia were recorded on a visual analogue scale. Before start, in normoglycaemia, Doppler examination of the umbilical artery blood flow velocity waveforms and a computerised cognitive function test were performed, both repeated when the final hypoglycaemic arterial blood glucose level of about 2.2 mmol/l had been reached. To further study the effects observed in cognitive function during pregnancy, the same cognitive test was applied to a group of 15 healthy women during and after pregnancy.
Results: There were no signs of fetal distress during hypoglycaemia, since the fetal heart rate recording disclosed both increased number and increased amplitude of heart rate accelerations, and since blood flow velocity waveform analysis revealed a slightly decreased pulsatility index in the umbilical artery. Further, there were no signs of diminished counterregulatory hormone response to hypoglycaemia, with the exception of pituitary GH. Instead, the serum levels of placental GH increased. This finding of an acute hormonal response by the placenta may represent a new concept in placental physiology. The metabolic clearance rate of insulin was decreased during pregnancy, as were some subjective symptoms of hypoglycaemia; and in addition pregnancy seemed to alter, and in some aspects impair, performance in cognitive function tests. The three latter phenomena could increase the risk of severe hypoglycaemia. For this reason during pregnancy caution is of utmost importance when identifying impending hypoglycaemia.
Key words: Adrenaline; cardiotocography; cognitive function; Doppler; fetal; fetal monitoring; growth hormone; hormonal counterregulation; hypoglycaemia; insulin; insulin-dependent diabetes mellitus; metabolic clearance rate; placenta; pregnancy; subjective symptoms. ISBN 91-628-3053-8
Original papers This thesis is based on studies presented in the following papers, referred to in the text by their Roman numerals: I Björklund A, Adamson U, Almström H, Enocksson E, Gennser G, Lins PE, Westgren M. Effects of hypoglycaemia on fetal heart activity and umbilical artery Doppler velocity waveforms in pregnant women with insulin-dependent diabetes mellitus. British Journal of Obstetrics and Gynaecology 1996; 103: 413-420 II Björklund A, Adamson U, Carlström K, Hennen G, Igout A, Lins PE, Westgren M. Placental hormones during induced hypoglycaemia in pregnant women with insulin-dependent diabetes mellitus: evidence of an active role for placenta in hormonal counter-regulation. British Journal of Obstetrics and Gynaecology 1998; 105 (in press) III Björklund A, Adamson U, Lins PE, Westgren M. Diminished insulin clearance during late pregnancy in patients with insulin-dependent diabetes mellitus. Clinical Science (in press) IV Björklund A, Adamson U, Andréasson K, Carlström K, Hennen G, Igout A, Lins PE, Westgren M. Hormonal counterregulation and subjective symptoms during induced hypoglycemia in insulin-dependent diabetes mellitus patients during and after pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1998; 77 (in press) V Björklund A, Adamson U, Lins PE, Westgren M, Wredling R. Cognitive function during pregnancy in patients with insulin-dependent diabetes mellitus and in healthy women. (submitted)
