Glycaemic control in pregnant women with type 1 diabetes and fetal macrosomia

Transcription

1 Glycaemic control in pregnant women with type 1 diabetes and fetal macrosomia A Stott*, H Nik, MJ Platt, IF Casson, SJ Walkinshaw, V Howard, M Stanisstreet, S Pennycook Introduction Diabetes occurs in approximately four per thousand pregnancies in the UK and consequently is the most common pre-existing medical disorder in pregnancy. 1,2 The majority of these women have type 1 diabetes, although pregnancy in type 2 is increasing. More than a decade ago the St Vincent Declaration produced a series of targets for the improvement in the quality of life of people with diabetes. 3 Despite efforts to improve metabolic control it is disappointing that there is no improvement in pregnancy outcomes. 4,5 Although better glycaemic control has resulted in a marked reduction of perinatal mortality and morbidity, the incidence of fetal macrosomia remains high. 6,7 The cause of macrosomia and adiposity is generally accepted to be fetal hyperglycaemia and hyperinsulinaemia, resulting in the conversion of glucose to fat and protein. 8 The beta-cells of the pancreas are not responsive to glucose levels until after 24 weeks gestation and macrosomia does not appear before 28 weeks gestation, possibly because of low fetal tissue insulin sensitivity. 8 There is, however, conflicting evidence concerning a possible link between maternal glycaemia and fetal size Correlations between maternal blood glucose or glycated haemoglobin (HbA1c) and birth weight have been weak or not statistically significant, 13,14 which makes interpretation of clinical data difficult. ABSTRACT Despite improvements in the clinical management of pregnant women with diabetes, pregnancy outcomes compare unfavourably to those of people without diabetes. The link between maternal glycaemia as a measure of metabolic control and fetal size has been the subject of previous studies. Evidence is conflicting due to the small numbers of cases and/or a mixture of different types of diabetes in most of these studies. This population-based cohort study was carried out on 274 women with type 1 diabetes from 10 maternity units in the Mersey area. We showed that in early (10±2 weeks gestation) and late pregnancy ( 34 weeks gestation), maternal HbA1c is not associated significantly with macrosomic or large for gestational age infants. Good glycaemic control measured by HbA1c in pregnancy, although of proven benefit in reducing perinatal mortality and morbidity, is therefore unable to prevent these problems. Copyright 2004 John Wiley & Sons, Ltd. Practical Diabetes Int 2004; 21(6): KEY WORDS type 1 diabetes; pregnancy; glycated haemoglobin (HbA1c); macrosomia; large for gestational age A model allowing a better understanding of normal fetal growth rates was formulated by Villar and Belizan 15 proposing that fetal weight gain occurs during the third trimester. This proposition was based on evidence cited by Tanner 16 showing that there is a peak in fetal weight at about weeks, followed by a decline. This has been questioned by Lampl and Jeanty 17 whose study showed that the healthy fetus exhibited greater incremental growth during the second trimester. A study involving pregnancies complicated by type 1 diabetes indicated that macrosomic pregnancies exhibited accelerated fetal growth during the third trimester. 18 Studies looking at the relationship between maternal glycaemic control and fetal growth rates have indeed reported the need for good control during the third trimester, 7,19 but others have reported the first trimester 10,20 and the second trimester 11 to be important for glycaemic control. Conversely, a negative correlation between first trimester glycaemic control and fetal growth 21 and no correlation between diabetic control and fetal growth 12 have been reported. Maternal blood glucose levels, two weeks prior to amniocentesis, also have shown no correlation with amniotic fluid insulin levels. 22,23 Studies on birth weight in women with diabetes often have limitations due to the small numbers of cases confounded by ethnic heterogeneity and a mixture of type 1, type 2 and gestational diabetes. This non- A Stott, PhD, FRCPath, Consultant Biochemist H Nik, MB, ChB, Pre-registration House Officer Royal Liverpool and Broadgreen University Hospital MJ Platt, MPH, FRCPCH, MFPHM, Senior Lecturer, Public Health V Howard, MB, ChB, PhD, Senior Lecturer, Developmental Toxico-Pathology M Stanisstreet, PhD, Senior Lecturer, Biological Sciences S Pennycook, Research Nurse, Developmental Toxico-Pathology University of Liverpool IF Casson, MD, FRCP, Consultant Physician in Diabetes and Endocrinology, University Hospital Aintree SJ Walkinshaw, MD, MRCOG, Consultant Obstetrician, Liverpool Women s Hospital *Correspondence to: Dr Anthony Stott, Clinical Chemistry, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK; tony.stott@liv.ac.uk Received: 22 December 2003 Accepted in revised form: 5 April 2004 Pract Diab Int July/August 2004 Vol. 21 No. 6 Copyright 2004 John Wiley & Sons, Ltd. 215

2 interventional study is part of an ongoing, large, population-based cohort study looking at diabetic pregnancy outcomes. It attempts to establish the relationship between HbA1c levels in the first and third trimester of pregnancy among women with type 1 diabetes and macrosomic and large for gestational age (LGA) infants. Standardisation of HbA1c results is vital in undertaking a large multicentre study such as this, allowing comparison of patient results, and there have been various approaches to correct for inter-laboratory analytical variations in different pregnancy studies. Some studies converted HbA1c results to a corrected value, through comparison with those obtained from the local non-diabetic population. 7,21 Our approach was to standardise results to DCCT (Diabetes Control and Complications Trial)-aligned figures, facilitating interpretation and comparison of HbA1c values, and assisting extrapolation from research-based evidence to local practice. 24 Patients and methods The data for this study were collected prospectively by the Mersey Diabetes in Pregnancy Group, from women with pre-gestational type 1 diabetes, within a geographically distinct area in Cheshire, Lancashire and Merseyside, with 10 maternity units participating. The data included obstetric, diabetic management, complications, outcomes and infant details. These were recorded using standardised pre-coded forms and transferred to an electronic database. Singleton pregnancies, which resulted in term births ( 37 weeks gestation), were analysed. Table 1. Pregnancy outcomes in 553 women with established type 1 diabetes in the study population Pregnancy Number of outcomes cases (%) Livebirth 451 (81.6) Miscarriage 72 (13.0) Stillbirth 14 (2.5) Termination 16 (2.9) Figure 1. Distribution of z-scores of all term infants Number of cases Z-score HbA1c values, collected throughout pregnancy, were abstracted from maternal records and standardised to DCCT-aligned values. This was achieved using the Standardisation Initiative for Glycated Haemoglobin Scheme (SIGH), requiring the exchange of blood samples between the laboratories of the 10 participating centres and a secondary reference laboratory (Royal Victoria Infirmary, Newcastle). 24 The latter uses the DCCT reference method with calibration material supplied by a certified American reference laboratory linked to the American National Glycohemoglobin Standards Program (NGSP). Good glycaemic control is indicated by HbA1c values <7.0%. HbA1c values measured at 10±2 weeks and 34 weeks gestation were used in this study to reflect glycaemic control during the first and third trimesters. Throughout the study, the performance of the participating laboratories was assured through participation in the Welsh External Quality Assurance Scheme (WEQAS) for HbA1c. 25 The standard normal deviate (z-score) of birth weights in the study sample was calculated using the mean and standard deviation for each gestational age from the Scottish Low Birthweight study. 26 The association between standardised birth weight and HbA1c was investigated by correlation analysis, t-test, Chi 2 tests and linear regression using the Statistical Package for Social Sciences (SPSS) version 10 and Stata Statistics/Data Analysis (Stata Corp, Texas). A p value of <0.05 was considered to indicate a statistically significant difference. LGA infants were defined as infants with birth weight above or equal to the 95 th centile (z-score 1.645). 26 Macrosomia was defined as birth weight 4500g, irrespective of gestational age, using the definition of the Royal College of Obstetrics and Gynaecology. 27 Data from pregnancies resulting in congenital abnormalities were excluded. Results Data were collected on a total of 553 pre-gestational type 1 diabetic pregnancies and the outcomes of all the pregnancies are shown in Table 1. Of the 451 live births, 296 were delivered at term ( 37 weeks gestation). Eighteen infants born with congenital abnormalities and two pairs of twins were excluded from the study leaving 274 infants for analysis. The distribution of the standardised birth weight (z-scores) of all term infants is shown in Figure 1. The distribution is approximately normal but with slight positive skew and a marked shift to the right compared to the reference population. The mean value is Pract Diab Int July/August 2004 Vol. 21 No. 6 Copyright 2004 John Wiley & Sons, Ltd.

3 Table 2. HbA1c levels at 10±2 weeks in pregnant women with type 1 diabetes and LGA, macrosomic and normal birthweight infants Weight Number Mean 95% CI Difference of infant HbA1c between % means Normal infants (z-score <1.645) LGA infants p=0.93 (z-score 1.645) Normal infants (<4500g) Macrosomic infants p=0.06 ( 4500g) CI = confidence interval. Table 3. HbA1c levels at 34 weeks in pregnant women with type 1 diabetes and LGA, macrosomic and normal birthweight infants Weight Number Mean 95% CI Difference of infant HbA1c between % means Normal infants (z-score <1.645) LGA infants p=0.36 (z-score 1.645) Normal infants (<4500g) Macrosomic infants p=0.67 ( 4500g) CI = confidence interval. standard deviations above the reference population mean. Only 51 of the term infants weighed <50 th centile for gestational age. The difference between birth weights of male and female infants was not significant (p=0.14). Among the 274 infants there were no HbA1c values recorded throughout the pregnancy for 51 women. HbA1c values were available at 10±2 weeks for 163 women and of these 74 also had values at 34 weeks gestation. HbA1c results at 34 weeks gestation were available for 96 pregnancies delivered at term. Missing HbA1c data may be due to the use of fructosamine to monitor glycaemic control, non-compliance, late presentation or where values have been obtained outside the pre-specified gestation window. Missing values during the third trimester are in part a consequence of delivery prior to term. There was no statistically significant difference between the mean HbA1c of pregnant women with normal birth weight and LGA infants (10±2 weeks, p=0.93; 34 weeks, p=0.36) or macrosomic infants ( 34 weeks, p=0.36), (Tables 2 and 3). At 10 weeks gestation, the HbA1c values of women with macrosomic infants were slightly less than those with infants of normal birth weight, although this failed to reach significance (p=0.06), (Table 2). Figures 2 and 3, respectively, show the relationships between HbA1c at 10±2 and 34 weeks for the 74 women with HbA1c values measured on both occasions and delivering normal/lga and normal/macrosomic infants. These demonstrate that maternal HbA1c values, measured in the first and third trimester, are not associated significantly with macrosomic or LGA infants. The data also demonstrate a significant change in HbA1c values during progression of pregnancy from the first to the third trimester for these 74 patients (7.2% to 6.1%; p<0.0001), the HbA1c values showing a significant correlation (r=0.66; p<0.0001). The relationship between z-score (y) and maternal HbA1c (x) demonstrated a slight association at each gestational age, (10±2 weeks, y=-0.067x +1.82; 34 weeks, y=0.081x +1.01). This was not statistically significant in either case (10±2 weeks, p=0.26; 34 weeks, p=0.39). Discussion There are a number of determinants of normal fetal growth as shown in Table 4 28 and assessment of fetal size is an important aspect of clinical surveillance in pregnant women. The improvement in glycaemic control during progression of pregnancy observed in this study is in agreement with other studies 21,29 and the high prevalence of LGA infants and macrosomia found in this study was similar to that reported previously. 7,29 The lack of a statistical difference between the HbA1c levels of the women with normal birth weight infants and LGA or macrosomic infants is in agreement with some studies, 13,14 but not others. 11,19,20 The difficulty of obtaining all of the required HbA1c values in a large non-interventional study such as this may be expected, but the pregnancy outcomes for the women who did not fully comply are no worse than for those who did. Indeed, our data show overlap of z-scores and percentages of LGA/macrosomic infants in all groups and comparison of the groups of women with and without HbA1c values shows the former group to be associated with Pract Diab Int July/August 2004 Vol. 21 No. 6 Copyright 2004 John Wiley & Sons, Ltd. 217

4 larger infants. The incidence of macrosomia has also been compared with maternal glucose levels in some studies and, as with HbA1c, the results have been conflicting. 13,14 However, there is an established relationship between poor glycaemic control and adverse perinatal outcomes such as hyperbilirubinaemia and respiratory distress syndrome and it remains important to measure maternal HbA1c concentrations as an independent verification of glycaemic control. 30 In the Mersey study group, birth weight will have been affected by the same factors as those in the non-diabetic population. There are various maternal risk factors for macrosomia including maternal age, multiparity, previous delivery of macrosomic infant, maternal obesity and excessive weight gain during pregnancy. There also remains the inherent problem of a multifactorially determined outcome variable. This would require mothers to be matched for duration of diabetes, race, parity and similar degree of antenatal care, together with the above risk factors, to rule out possible confounding factors. Different infants may have different responses to the same glycaemic milieu, so that there is a weak relationship between maternal blood glucose and fetal insulin production as shown by amniotic fluid insulin levels. Infants of women with diabetes exhibit a more brisk insulin response to a glucose load than infants of non-diabetic women, the response being greater in macrosomic infants of mothers with diabetes. 31 A study involving macrosomic infants born to non-diabetic mothers, observed that more than 30% of these infants exhibited hyperinsulinaemia, suggesting an exaggerated fetal insulin secretion and anabolism. 32 Other mechanisms could contribute to fetal hyperinsulinaemia, including maternal insulin-binding antibodies capable of transferring insulin from mother to fetus stimulating insulin secretion. 33 However, Rosenn et al. 34 failed to show a relationship between insulin antibodies and birth weight. Placental and/or fetal leptin levels have also been shown to be positively correlated with fetal insulin and birth weight, and evidence suggests that leptin may act as % HbA1c at 34 weeks a fetal growth factor. 35 There are constraints to fetal growth and uteroplacental function may limit massive rapid increases in size. It is possible that fluctuations in glucose levels rather than basal levels are more important and this would be reflected in the weak relationship between HbA1c and birth weight. It has been shown in fetal sheep that it is not continuous high levels of glucose, but rather pulsatile hyperglycaemia that stimulates continuing hyperinsulinaemia. 36 It is also possible that hyperglycaemia in early pregnancy limits the development of the placenta, whereas in later pregnancy episodes of pulsatile hyperglycaemia stimulate fetal insulin production and increase substrate availability. These differential effects at different times of pregnancy would weaken the relationship between HbA1c and birth weight. From fetal ultrasound data in diabetes there is a suggestion that Figure 2. Relationship between maternal HbA1c values at 10±2 and 34 weeks for normal and LGA infants % HbA1c at 34 weeks % HbA1c at 10 weeks Normal LGA Figure 3. Relationship between maternal HbA1c values at 10±2 and 34 weeks for normal and macrosomic infants % HbA1c at 10 weeks Normal Macrosomia 218 Pract Diab Int July/August 2004 Vol. 21 No. 6 Copyright 2004 John Wiley & Sons, Ltd.

5 Table 4. Determinants of normal fetal growth 28 Constitutional factors Genetic factors Fetal hormones: Insulin Insulin-like growth factor (IGF) Thyroid axis Uterine constraints: Placental function Substrate flow Maternal risk factors: Obesity Height Prolonged pregnancy accelerated growth is most likely to occur late in the second trimester. 11 It is possible that glycaemic control in this trimester may contribute most to birth weight, rather than early or very late control. Given the multifactorial nature of birth weight, glycaemic control may influence growth rate rather than absolute weights. Our study has demonstrated that there is no association between birth weight and diabetic control in early or late pregnancy in pregnant women with type 1 diabetes, and it is clear that further research needs to be carried out into the causative factors of fetal macrosomia in diabetes. Conclusion Fetal macrosomia persists despite vigorous attempts at optimum metabolic care. Antenatal diagnosis may be difficult, increasing the risk of traumatic delivery and neonatal metabolic complications. We have shown that, in the first and third trimesters, HbA1c levels are not significantly correlated with birth weight. Management of pregnancies through optimal glycaemic control throughout pregnancy measured by maternal HbA1c, although important in the prevention of perinatal mortalities and morbidities, is not sufficient to prevent the higher incidence of LGA and macrosomia in infants of mothers with diabetes. There is clearly potential for further research to identify other aetiological factors, which influence fetal growth in pregnancies complicated by pre-gestational type 1 diabetes mellitus. Key points Improvements in the management of pregnant women with diabetes have had little impact on pregnancy outcomes Many previous studies have been based on small numbers of cases and mixtures of different types of diabetes HbA1c levels of pregnant women with type 1 diabetes at 10±2 and 34 weeks gestation are not significantly associated with macrosomic or large for gestational age infants Good diabetic control, although necessary to reduce other perinatal mortalities and morbidities, is not sufficient to prevent macrosomia in pregnant women with type 1 diabetes Acknowledgements The authors wish to thank the staff of the participating centres for their assistance. The Bailey Thomas Fund and the University of Liverpool Research Development Fund supported this study. References 1. Cordero L, Landon MB. Infant of the diabetic mother. Clin Perinatol 1993; 20(3): Hawthorne G, Modder J. Maternity services for women with diabetes in the UK. Diabetic Med 2002; 19(Suppl 4): Workshop Report. 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6 conception period and early pregnancy on birth weight in women with IDDM. Diabetes Care 1998; 21: Penney GC, Mair G, Pearson DWM. The relationship between birthweight of maternal glycated haemoglobin (HbA1c) concentration in pregnancies complicated by Type 1 diabetes. Diabetic Med 2003; 20: Crombach G, Hammerschmidt C, Schmitz-Rockerath B, et al. Relationship between amniotic fluid insulin and maternal blood glucose concentrations in patients with carbohydrate intolerance during pregnancy. J Perinat Med 1996; 24: Kainer F, Weiss PA, Huttner U, et al. Levels of amniotic fluid insulin and profiles of maternal blood glucose in pregnant women with diabetes type- 1. Early Hum Dev 1997; 49(2): Stott A, Casson IF, Higgins GJ. Glycated haemoglobin studies. Approaches to standardization of results. Diabetic Med 2001; 18: Thomas MA, Davies KW. Deviation of DCCT target value for HbA1c in the WEQAS national EQA programme. Proc ACB National Meeting, 1997; Scottish Health Service Common Services Agency, Scotland. Birth weight, head circumference and length for gestational age. Edinburgh: SHSCSAS, Dildy GA, Clark SL. Shoulder dystocia; risk identification. Clin Obstet Gynecol 2000; 43(2): Langer O. Fetal macrosomia: Etiological factors. Clin Obstet Gynecol 2000; 43(2): Nordström L, Spetz E, Wallstrom K, et al. Metabolic control and pregnancy outcome among women with insulin-dependent diabetes mellitus. Acta Obstet Gynecol Scand 1998; 77: Cordero L, Treuer SH, Landon MB, et al. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med 1998; 152: Sosenko OR, Kitzmiller JL. The infants of the diabetic mother-correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N Engl J Med 1979; 301: Hoegsberg B, Gruppuso PA, Coustan DR. Hyperinsulinaemia in macrosomic infants of non-diabetic mothers. Diabetes Care 1993; 16: Menon RK, Cohen RM, Sperling MA, et al. Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia. N Engl J Med 1990; 323: Rosenn B, Miodovnik M, Combs CA, et al. Human versus animal insulin in the management of insulin-dependent diabetes in pregnancy; lack of effect on fetal growth. Obstet Gynecol 1991; 78: Wiznitzer A, Furman B, Zuili I, et al. Cord leptin levels and fetal macrosomia. Obstet Gynecol 2000; 96(5): Carver TD, Anderson M, Aldoretta PW, et al. Effect of low-level basal plus marked pulsatile hyperglycaemia on insulin secretion in foetal sheep. Am J Physiol 1996; 271: E865 E871. ANNOUNCEMENT PROUD Professionals United by Diabetes DIABETES NARRATIVES PROJECT PROUD is a network of health professionals who themselves live with diabetes. It is hoped that the unique dual insights of members of PROUD as both professionals and patients may be of interest and use to other professionals living with diabetes, as well as to the diabetes community more generally. As its first project, PROUD is compiling a series of Diabetes Narratives that is, accounts of personal experiences of members which illustrate important aspects of delivery of diabetes care and, in particular, the relationship between the health care professional and the health care consumer. It is intended that the narratives will be displayed as posters at the 23rd Isle of Wight Diabetes Conference on October and also posted on a PROUD website, currently under construction. Readers of Practical Diabetes International who have diabetes or who are carers of immediate family members with diabetes are invited to join PROUD and to submit ideas for Diabetes Narratives. There is no subscription fee for joining nor obligation of any sort, as PROUD is an informal network. Free help will be provided by a professional writer in transforming ideas or rough drafts of Narratives submitted by readers/members into finished accounts. If preferred, published Narratives can be anonymous. Please send your contributions, comments and ideas to James Wroe at the following address: jameswroe@eclipse.co.uk PROUD gratefully acknowledges the unrestricted educational support provided by Novo Nordisk for the Diabetes Narratives project. 220 Pract Diab Int July/August 2004 Vol. 21 No. 6 Copyright 2004 John Wiley & Sons, Ltd.