Type 1 Diabetes and Pregnancy: Trends in Birth Weight Over 40 Years at a Single Clinic.

Abstract


OBJECTIVE:

To examine changes in perinatal mortality and birth weight of babies born to mothers with pregestational type 1 diabetes over 40 years in a single teaching hospital clinic.

METHODS:

This was a retrospective survey of cases from the combined diabetes and obstetrics antenatal clinic at the Royal Infirmary of Edinburgh and Simpson Memorial Maternity Pavilion, Edinburgh, Scotland. Birth weight, standardized birth weight, and perinatal mortality were obtained from 643 singleton babies born after 28 weeks of gestation to mothers with pregestational type 1 diabetes between 1960 and 1999.

RESULTS:

There was a dramatic improvement in perinatal mortality rate, falling from 225 (per 1,000 total births after 28 weeks of gestation) in the 1960s to 102 in the 1970s, 21 in the 1980s, and 10 in the 1990s (for effect of birth year). In contrast, standardized birth weight (adjusted for sex, gestational age, and parity), which was significantly higher than the background population (+1.41 standard deviations above the population norm) showed no significant change over time.

CONCLUSION:

Changes in diabetic management and obstetric practice over the 40 years of our survey have resulted in enormous improvements in the outlook for offspring of mothers with diabetes. Somewhat surprisingly this has not been associated with a reduction in overgrowth of the fetus.

Introduction

The management of type 1 diabetes in pregnancy has changed beyond recognition over the past few decades. The principles underlying management are now better understood. Prepregnancy preparation has increased. Blood glucose monitoring has become outpatient based and more accurate. Glycated hemoglobin assays have become available. Insulin delivery systems have greatly improved. There has been increased attention to team working and the systematic organization of care. There has been a huge and widespread reduction in perinatal mortality rates.

The intuitive expectation is that these changes should be accompanied by a progressive reduction in birth weight. After all, the classic feature of the pregnancy complicated by maternal diabetes is accelerated fetal growth, with a birth weight distribution that is unimodal, approximately normal, but shifted markedly to the right. The underlying treatment paradigm is that the degree of glycemic control relates directly to the abnormality of fetal growth, and there is evidence supportive of this. However, despite the enormous improvements in care of diabetes, the anticipated reduction in fetal growth rate in such a population has not been clinically apparent, and indeed there is current concern that birth weights remain high.

This article examines birth weight for infants born to women with probable type 1 diabetes, in a single center, over the last 40 years. This time period encompasses all the major improvements in care described above.

DISCUSSION

The conclusion is straightforward, although the interpretation is not. Over the last 40 years, mothers with type 1 diabetes have experienced no major decrease in standardized birth weight. This is despite the enormous reduction in perinatal mortality, attributable to advances in obstetric and neonatal management, and to the huge improvements in control of diabetes. A recent survey of birth weight in type 1 diabetes over a shorter 16-year period (1979–1995) found no significant change in birth weight with year of birth. We are now able to extend these findings to 40 years encompassing a period with a more dramatic change in blood glucose control during pregnancy. Similarly, birth weight has not changed greatly over the past 40 years in offspring of Pima women with type 2 diabetes, despite a similar improvement in perinatal mortality.

The strength of these data lies in the very long period of data collection. There are a number of weaknesses. Methods used in the clinic—notably ultrasound dating of pregnancy, recording of pregnancy complications, and assessment of glycemia by HbA1c—were either not available or standardized over the course of the last 40 years. There is likely to have been more variable dating of pregnancy early in the cohort leading to potential error in calculation of standardized birth weights particularly in the first decade. Lack of standardized measures of glycemia means that we cannot address precisely the nature or extent of improvements in glycemic control over the course of study. Nevertheless, those changes were substantial. Standard treatment changed from two injections a day in the 1960s to four injections a day in a basal-bolus pattern in the 1990s. No home monitoring of blood glucose was available in the 1960s, semi-quantitative measures only in the 1970s, while by the 1990s meter home monitoring was standard. Given these changes, it is striking that there is so little change in birth weight over such a long course of data collection.

Over the four decades there were important demographic changes that could have an impact on birth weight. In the general population, an upward trend in birth weight over time is recognized, but it is relatively small in absolute terms and very little of this trend remains unexplained after accounting for factors such as maternal height, age, and smoking. In our cohort of offspring of mothers with diabetes, the increase in maternal weight (about 4 kg per decade) is likely to be associated with an increase in babies' weight. Against this, more women with longstanding diabetes, hypertension, and renal disease are becoming pregnant, and these characteristics are all associated with reduction in birth weight. However, multivariable analysis would suggest that there is little change in birth weight over time even after accounting for maternal weight or the presence of maternal diabetes complications.

It is unlikely that the findings only reflect local practice. No comparison data are available for previous decades from other centers. However, other centers in Scotland have recently reported a similar contemporary mean standardized birth weight 1.57 standard deviations above that expected for nondiabetic pregnancies. Perinatal mortality in this series for the 1990s is lower than, but comparable to, national series of births in 1998–1999. A current audit shows that variations in practice between different centers in Scotland are not large (unpublished data). In Scotland the rate of congenital abnormality in offspring of mothers with type 1 diabetes in 1998–1999 was 60 per 1,000 births. The rate in this series is lower and not comparable because we have recorded only those anomalies thought severe enough to cause death or known to affect growth, stillbirth, and neonatal death. It is likely that some, mainly minor, anomalies have been missed, but the impact on average birth weight should be small.

Overall then the paradox remains. Despite the marked improvement in perinatal mortality over the study period, birth weight remains little changed, and this cannot be explained by known changes in demographics or maternal behavior. Perhaps this finding should make us rethink the paradigms on which management of diabetes in pregnancy is based. Fetal growth is a balance between stimulus and constraint, and maternal diabetes may have complex effects on growth.
A number of effects might be involved. First, hyperglycemia itself might act via changes in placental function to restrain growth. Sustained high levels of glucose inhibit the proliferation of first-trimester trophoblast. High glucose levels in early pregnancy may therefore be a critical determinant of uteroplacental function in later pregnancy.

Second, while overall glycemic control may have improved, maternal blood glucose during pregnancy in women with type 1 diabetes remains far from normal, and this may be enough to significantly affect growth. A number of studies have highlighted the relatively weak relationship of maternal HbA1c and birth weight. In part this may be methodological, studies using multiple HbA1c assays generally showing a weaker relationship, while those at a single center or using a single assay show a stronger relationship.Nevertheless in such studies maternal HbA1c accounts for, at most, only 10–20% of the variance of birth weight. In animal models, short pulsatile surges of hyperglycemia later in pregnancy may be more important than sustained hyperglycemia in inducing fetal hyperinsulinemia and subsequent fetal overgrowth. This is in keeping with human data where postprandial glucose has been shown to more closely correlate with birth weight in pregnancies complicated by type 1 diabetes in most but not all studies.

Use of continuous glucose monitoring systems in women with type 1 diabetes confirms the presence of large fluctuations, including hypoglycemic and hyperglycemic events, which were not recognized by standard self glucose monitoring. At the same time recent data in women without diabetes find that mean capillary blood glucose is generally not greater than 5.8 mmol/L (104 mg/dL) even postprandially. The same authors suggest that birth weight remains normal in offspring of women with type 1 diabetes only when mean maternal glucose remains less than 5.3 mmol/L (95 mg/dL). In keeping with this, many babies in our population are still hyperinsulinemic at birth despite modern management.

If these mechanisms are acting, the overall effect could be as follows. In the 1960s, when control of diabetes was very poor by contemporary standards, very high glucose levels in early pregnancy caused limited proliferation of first-trimester trophoblast and hence reduced uteroplacental function in late pregnancy. The babies became markedly hyperinsulinemic because of pulsatile surges in maternal glucose in the second trimester, and there was a high rate of intrauterine death because growth overran supply. Although they were big, many of the surviving babies may have been relatively growth restricted. More recently, overall glucose control has improved greatly. Mean glucose levels in early pregnancy are not so high as in previous years, and uteroplacental function is now generally satisfactory. However, we still cannot prevent maternal glucose fluctuations in the second trimester. Because they now likely enjoy a greater uteroplacental capacity, they are able to achieve an accelerated growth without running the same risks of sudden decompensation and intrauterine death.

Unfortunately it is impossible to test these hypotheses retrospectively. Consistent measures are not available across the study to assess glycemia. Glycated hemoglobin only became available in 1980, and the type and standardization of the assay have changed several times since.

Alternative outcome measures, such as cord insulin, are not available across the study. It is also remains likely that effects on uteroplacental function and fetal insulinemia are not the whole story. There is no reason why these should balance each other out. They do not explain clinical observations that the biggest babies are sometimes born to women who would be expected to have smaller swings in glucose levels such as those with short duration of type 1 diabetes, type 2 diabetes, or gestational diabetes.

Gestation at delivery may be of more significance. The mean gestation at delivery increased by approximately 1.3 weeks over the 40 years of the study period. This largely reflects changes in the timing of induction of labor or elective caesarean delivery. Longer exposure to maternal diabetes would be expected to result in greater eventual deviation in birth weight from the norm.

Overall, our study attests to the dramatic improvement in perinatal mortality over the past 40 years but suggests that further innovation will be needed before significant changes in birth weight are likely to occur.