Pregnancy in women with pregestational diabetes is associated with high perinatal morbidity and mortality. Stillbirth accounts for the majority of cases with perinatal death. Intrauterine growth restriction, pre-eclampsia, foetal hypoxia and congenital malformations may be contributing factors, but more than 50% of stillbirths are unexplained. Majority of stillbirths are characterised by suboptimal glycaemic control during pregnancy. Foetal hypoxia and cardiac dysfunction secondary to poor glycaemic control are probably the most important pathogenic factors in stillbirths among pregnant diabetic women. There is thus a need for new strategies for improving glycaemic control to near-normal levels throughout pregnancy and for preventing and treating hypertensive disorders in pregnancy. Antenatal surveillance tests including ultrasound examinations of the foetal growth rate, kick counting and non-stress testing of foetal cardiac function are widely used. However, future research should establish better antenatal surveillance tests to identify the infants susceptible to stillbirth before it happens.
Introduction
Stillbirth is defined in the majority of the recent studies as a foetal death after 20–22 gestational weeks. Historically, pregnancy in women with pregestational diabetes is associated with high perinatal morbidity and mortality. This review covers stillbirths in women with diabetes present before pregnancy. The 2002–2003 UK Confidential Enquiry into Maternal and Child Health (CEMACH) showed that offspring of women with type 1 or type 2 diabetes are five times more likely to be stillborn and three times more likely to die in their first month of life compared with those of mothers without diabetes. The perinatal mortality rate was 32 per 1000 births, compared with the national rate of 9 per 1000 births. Approximately 80% of these losses were stillbirths, 80% of these babies being structurally normal. Perinatal mortality in other UK regional studies and in European countries is comparable and ranges from 28 to 48 per 1000 births, and stillbirth accounts for a significant part of the perinatal mortality.
In general, approximately 50% of stillbirths can be explained by likely causes such as intrauterine growth restriction, pre-eclampsia, umbilical cord problems, acute asphyxia, placental abruption, intrauterine infection and congenital malformations, while the remaining 50% are so-called unexplained stillbirths, that is, no obvious cause can be identified by clinical examination or standard autopsy. In a Danish audit on stillbirth in type 1 diabetic pregnancy during 1990–2000, 25 cases were identified and around half of these were unexplained. Interestingly, the majority of the unexplained pregnancies were characterised by suboptimal glycaemic control in late pregnancy. Other characteristics of pregnancies ending with a stillbirth were diabetic nephropathy, smoking and low social status. Among the explained cases many were also related to diabetes, for example, due to congenital malformations and maternal diabetic ketoacidosis.
Pathophysiology of stillbirth
The pathophysiology of foetal death in diabetic pregnancy where the foetus is normally grown or large for gestational age is likely to be multifactorial. The majority of unexplained stillbirths may result from chronic foetal hypoxia and/or foetal acidaemia secondary to maternal and foetal hyperglycaemia and foetal hyperinsulinaemia. Many of the late foetal complications in diabetic pregnancy can be explained by the Pedersen hypothesis. This states that maternal hyperglycaemia results in foetal hyperglycaemia causing marked foetal hyperinsulinaemia via foetal pancreatic beta-cell overstimulation. This, in turn, causes accelerated foetal growth, excess subcutaneous fat and increased hepatic glycogen storage. The increased foetal metabolism associated with hyperglycaemia may lead to relative foetal hypoxia. Animal studies have found that hyperglycaemia and hyperinsulinaemia in foetal lambs result in increased foetal oxygen consumption with a simultaneous decrease in the arterial oxygen content.
The occurrence of stillbirths and foetuses with signs of hypoxia is increased in pregnancies complicated by pre-eclampsia, diabetes and foetuses large or small for gestational age. These are also conditions in which foetal acidosis and increased plasma and amniotic fluid values of erythropoietin (EPO) have been observed. Hypoxia is the major stimulus of EPO synthesis in both the foetus and the adult. Teramo et al. described grossly elevated levels of amniotic fluid values of EPO prior to stillbirth in diabetic women.
Maternal glycosylated haemoglobin (HbA1c) in the third trimester correlates with foetal umbilical venous EPO at delivery, suggesting that antepartum control of maternal hyperglycaemia is a significant factor associated with foetal hypoxia. Foetal amniotic fluid insulin levels correlate significantly with foetal plasma EPO levels independently of maternal glycaemia, suggesting that insulin exerts an effect on foetal oxygenation beyond that of maternal and foetal glycaemia.
Pathophysiology of stillbirth
The pathophysiology of foetal death in diabetic pregnancy where the foetus is normally grown or large for gestational age is likely to be multifactorial. The majority of unexplained stillbirths may result from chronic foetal hypoxia and/or foetal acidaemia secondary to maternal and foetal hyperglycaemia and foetal hyperinsulinaemia. Many of the late foetal complications in diabetic pregnancy can be explained by the Pedersen hypothesis. This states that maternal hyperglycaemia results in foetal hyperglycaemia causing marked foetal hyperinsulinaemia via foetal pancreatic beta-cell overstimulation. This, in turn, causes accelerated foetal growth, excess subcutaneous fat and increased hepatic glycogen storage. The increased foetal metabolism associated with hyperglycaemia may lead to relative foetal hypoxia. Animal studies have found that hyperglycaemia and hyperinsulinaemia in foetal lambs result in increased foetal oxygen consumption with a simultaneous decrease in the arterial oxygen content.
The occurrence of stillbirths and foetuses with signs of hypoxia is increased in pregnancies complicated by pre-eclampsia, diabetes and foetuses large or small for gestational age. These are also conditions in which foetal acidosis and increased plasma and amniotic fluid values of erythropoietin (EPO) have been observed. Hypoxia is the major stimulus of EPO synthesis in both the foetus and the adult. Teramo et al. described grossly elevated levels of amniotic fluid values of EPO prior to stillbirth in diabetic women.
Maternal glycosylated haemoglobin (HbA1c) in the third trimester correlates with foetal umbilical venous EPO at delivery, suggesting that antepartum control of maternal hyperglycaemia is a significant factor associated with foetal hypoxia. Foetal amniotic fluid insulin levels correlate significantly with foetal plasma EPO levels independently of maternal glycaemia, suggesting that insulin exerts an effect on foetal oxygenation beyond that of maternal and foetal glycaemia.
Cardiac dysfunction
Up to 40% of newborn infants of women with type 1 diabetes have echocardiographic signs of cardiomyopathy with cardiac enlargement and asymmetric septal hypertrophy. Most often, these changes are asymptomatic and disappear within the first 6 months of life, but they can also lead to severe morbidity and mortality. It is thus conceivable that cardiac dysfunction could be a cause of stillbirths in pregnancies complicated by diabetes. During foetal life, offspring of women with diabetes often have hyperglycaemia, hyperinsulinaemia and increased concentrations of markers of hypoxic stress, for example, plasma EPO. All these factors could have negative effects on the foetal heart in utero . It has been reported that ST depression in the foetal electrocardiogram during labour was observed more often in diabetic than in non-diabetic pregnancies. Furthermore, abnormal foetal heart rate changes occur more frequently in pregnancies with poor glycaemic control in late diabetic pregnancy than in pregnancies with good control.
B-Type natriuretic peptide (BNP) is a 32-amino-acid peptide produced in excess by cardiac myocytes during cardiac stress. BNP is released as a 108-amino-acid propeptide (proBNP), which is then cleaved into the active BNP (32 amino acids) and an N-terminal fragment. The biological roles of BNP include regulation of the extracellular fluid volume and blood pressure by increasing natriuresis, and inhibiting the renin–angiotensin–aldosterone axis. In the foetus, BNP functions as a vasodilator in the placental circulation. BNP probably also has important protective autocrine effects in the heart by inhibiting fibrosis and hypertrophy. The plasma concentrations of BNP and proBNP are increased in patients with heart failure, including those with hypertrophic cardiomyopathy. Children with congenital heart disease and newborns with severe foetal distress also have increased plasma BNP concentrations.
We have previously studied the level of plasma BNP concentrations in newborn infants of mothers with type 1 diabetes. Infants of diabetic women with suboptimal glycaemic control (HbA1c ≥ 6.2%) before delivery had a higher median plasma proBNP concentration than infants of healthy women. Of note, poor glycaemic control per se increases cardiac output by approximately 10% in adults with type 1 diabetes, and it is possible that the increase in foetal BNP secretion in infants of mothers with diabetes reflects increased pre- or afterload of the foetal heart, perhaps attributable to foetal hypervolaemia.
A study by Russels et al. also reported increased levels of BNP and proBNP in the umbilical cord blood of offspring from women with type 1 diabetes mellitus. In this study, Troponin T, a marker of acute myocardial damage, and proBNP were measured in umbilical cord blood at delivery in 45 women with type 1 diabetes mellitus and 39 healthy women. In addition, foetal echocardiography was performed every trimester in a subset of women. In offspring of patients with diabetes, levels of proBNP and Troponin T positively correlated and were both elevated. The increase was mostly marked in offspring of women with type 1 diabetes mellitus, who had poor glycaemic control during early pregnancy. ProBNP was also increased in the umbilical cord blood of neonates with third-trimester interventricular septal hypertrophy. Indeed, the only infant with clinically recognised cardiomyopathy had high levels of both proBNP and Troponin T.
These recent studies, therefore, underline the assumption that cardiac dysfunction might contribute to stillbirths in pregnancies complicated by diabetes.
Role of glycaemic control
It is likely that strict glycaemic control will reduce the number of stillbirths in women with type 1 or type 2 diabetes. In Denmark, the rate of stillbirths was examined in the period 1993–1999 and found to be 20 out of 1000 deliveries. In that period, the mean HbA1c in the third trimester was 7.1% in women with serious adverse pregnancy outcome (including stillbirth) versus 6.7% in women with uncomplicated pregnancies. Our Center for Pregnant Women in Copenhagen participated in the study and had comparable results. During the following years, the levels of glycaemic control have improved considerably, and in the period 2000–2009 only 5 out of 712 deliveries ended in stillbirths, corresponding to a stillbirth rate of 7 out of 1000 deliveries ( Fig. 1 , unpublished data).
Based on the findings listed in this review, strict glycaemic control is probably the most important factor for prevention of stillbirth. In addition, it is wise to refrain from smoking, and have special attention focused on women with diabetic nephropathy and on the women who develop pre-eclampsia.
Preventive measures
The single most important factor to reduce the risk of stillbirth is to achieve and maintain good glycaemic control during pregnancy to avoid foetal hypoxia. It is beyond the scope of this article to give specific guidelines for this (for a review, please see References ).
Furthermore, anti-hypertensive treatment in women with microalbuminuria or diabetic nephropathy reduces the risk of pre-eclampsia and pre-term delivery, and thereby probably also the risk of stillbirth.
Due to lack of evidence, there is no generally accepted way to perform antenatal testing to identify the infants susceptible to stillbirth before it happens. However, the often-used methods include ultrasound examinations of the foetal growth rate, kick counting and non-stress testing of foetal cardiac function:
- (1)
Pregnant women with pregestational diabetes are examined frequently with ultrasound. In the first half of pregnancy, the purpose is particularly to identify congenital malformations. Later, observation of foetal growth is important to diagnose intrauterine growth restriction most often seen in women with diabetic nephropathy, chronic hypertension or pre-eclampsia and to diagnose excess growth, as these foetuses also are at increased risk of stillbirth.
- (2)
Many centres ask the pregnant women to perform daily kick counting in a more or less organised way. Despite lack of solid scientific evidence, many clinicians, including ourselves, have the clinical experience that it is of value to keep the pregnant women alert to possible changes in the foetal kick pattern.
- (3)
Retrospective studies have indicated that frequent non-stress testing of foetal cardiac function can identify foetuses at high risk of stillbirth, and delivery of these infants may decrease the stillbirth rate, though this has been questioned by others. However, currently, most centres apply non-stress testing 1–2 times weekly from 32 to 34 weeks of gestation onwards.
- (4)
Ultrasound Doppler examination of the umbilical and uterine arteries has also been used in an attempt to prevent stillbirths. However, the evidence for routine use is relatively poor. Some studies propose a beneficial effect, while others did not find this.
Although no general agreement exists concerning when, how and how often antenatal testing should be performed, it certainly seems that antenatal testing of some kind improves the perinatal outcome of these pregnancies.
In Copenhagen, the antenatal testing of women with pregestational diabetes includes ultrasound examinations of the foetal growth rate at 28, 34 and 37 weeks, once weekly non-stress testing from 33 to 34 weeks and kick counting from 28 weeks onwards. High-risk pregnancies can be followed with more frequent ultrasound examinations for foetal growth and with non-stress testing twice a week from 32 weeks onwards. Ultrasound Doppler examination of the umbilical and uterine arteries is mainly reserved for cases with growth restriction or pre-eclampsia. Using this strategy, in combination with strict glycaemic control during pregnancy and anti-hypertensive treatment when needed, our stillbirth rate in the past decade is closer to the rate in the background population ( Fig. 1 ).
