Pregnancies in women with diabetes [type 1, type 2, or gestational diabetes mellitus (GDM)] are associated with an increased risk of poor obstetrical and perinatal outcome including stillbirth and intrapartum death 1–3. Maternal diabetes is associated with fetal cardiomyopathy and up to 40% of infants born to women with diabetes may have some degree of fetal cardiomyopathy 4. The cardiac enlargement, because of asymmetrical septal hypertrophy, is usually benign and regresses within the first 6 months of life. Rarely, however, the cardiomyopathy causes severe problems in utero and during the neonatal period 4–7.
In adults, ventricular strain including hypertrophy causes a change in the shape of the T wave on the ECG recordings. Fetal ECG in combination with cardiotocography (CTG) can be used to evaluate the ST segments and detect changes and is an intrapartum fetal monitoring method (STAN). Studies on this technology have showed improved fetal outcome in comparison with the use of conventional CTG alone 8,9. However, recent meta-analyses have shown a reduction in instrumental vaginal deliveries and fetal blood sampling, but not a significant reduction in metabolic acidosis at birth 10,11.
Yli et al. 12 observed that ST depression on the fetal ECG was more prevalent in deliveries complicated by diabetes. The changes were unrelated to asphyxia and the authors suggested that the findings reflect an altered ability of the fetal heart to respond to fetal distress 12.
B-type natriuretic peptide (BNP) is an amino acid peptide released from cardiac myocytes as a response to cardiac stress. BNP is released as pro-BNP, which is then cleaved into the active BNP and an N-terminal fragment. The biological roles of BNP in adults include regulation of the extracellular fluid volume and blood pressure by increasing the natriuresis and inhibiting the renin–angiotensin–aldosteron axis 13–15. BNP probably also exerts important protective autocrine effects on the heart by inhibiting fibrosis and hypertrophy 16,17. The plasma concentrations of BNP and pro-BNP increase in patients with heart failure, including those with hypertrophic cardiomyopathy 18,19.
Fetal BNP acts as a vasodilator in the placental circulation 20. Children with congenital heart disease and newborns with severe fetal distress have increased plasma BNP concentrations 21,22. We and others have found increased pro-BNP concentrations in umbilical cord blood from newborns of women with type 1 diabetes with suboptimal metabolic control 23,24. In addition, cord blood pro-BNP concentrations were associated positively with established markers of perinatal stress such as low cord blood pH and a low Apgar score 23,24. On the basis of this, we hypothesized that pro-BNP concentrations in newborns of women with diabetes may reflect cardiomyopathy and that these abnormalities may be associated with the fetal ECG changes observed during the stress of labor and delivery in women with diabetes. This complex hypothesis has not been addressed previously.
The purpose of this explorative study was to investigate possible physiological relations between serological and morphological markers of cardiac dysfunction and abnormal changes on fetal ECGs during labor and delivery in pregnancies complicated by maternal diabetes.
Materials and methods
A total of 99 pregnant women with diabetes delivering after 37 completed gestational weeks in cephalic presentation were prospectively included at the Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen. Thirty women had type 1 diabetes, nine had type 2 diabetes, and 60 had GDM. All women provided informed written consent, and the study protocol was approved by the local ethics committee (KR 01283644). Basic demographic data on the women, obstetric data from the labor, and neonatal data were retrieved from medical charts and databases within the Department of Obstetrics, Rigshospitalet. GDM was diagnosed after a risk factor-based screening procedure as described previously 25.
As soon as possible, during vaginal labor, the midwife places a scalp electrode on the fetus’ head and connects to the STAN monitor (Neoventa Medical AB, Molndal, Sweden). The technology supplies an automatic analysis of the fetal ECG and detects elevation and depression of the ST segment as well as a calculation of the T/QRS ratio. Significant ST changes are named ST events and are based on the change in the T/QRS ratio over time. ST segment elevations are classified as either episodic (<10 min) or baseline ST events (>10 min), whereas ST segment depressions are called biphasic ST events (8).
Within 72 hours of delivery, an echocardiography was performed on the neonates by two of the authors (K.G. Halse or S. Hertel) using a GE Vingmed Vivid FiVe (GE Healthcare, Wauwatosa, Wisconsin, USA) with a 5 MHz probe with color doppler. The examinations included a parasternal long axis view M-mode recording of the left ventricle, measuring end diastolic septal diameter and left ventricle posterior wall diameter, as well as the ejection fraction 26. The results are presented as the mean values of three measurements. All pregnant women underwent a type 2 ultrasound examination (a systematic examination with ultrasound in order to detect structural fetal abnormalities in, for example, the brain, heart, abdomen, kidney, and spinal cord) for malformations at 18–19 gestational week. Furthermore, women with type 1 and 2 diabetes were examined by fetal echocardiography in week 21 of pregnancy 27.
The umbilical cord was routinely doubly clamped immediately after delivery, and arterial and venous blood was drawn for the measurement of pH. Acid–base analysis was carried out in a Radiometer ABL 5 (Radiometer Medical, Brønshøj, Denmark).
Umbilical venous blood for pro-BNP and BNP measurements was collected into EDTA-containing tubes (1.5 g/l). The tubes were immediately placed on ice, centrifuged, and stored at −20°C for 1–3 days and then at −80°C until analysis. Venous blood was chosen for practical reasons as pro-BNP levels have been shown to be similar in umbilical cord arterial and venous plasma 28,29. The pro-BNP concentrations were analyzed using a processing-independent assay where trypsin digestion of the plasma proteins is used to release the NH2-terminal fragment of pro-BNP before using a radioimmunoassay with antibodies directed against the NH2-terminus of pro-BNP 26. The intra-assay coefficients of variation of the pro-BNP assay were 12% at 13 pmol/l, 7% at 75 pmol/l, and 5% at 130 pmol/l (n=10) 29. The BNP concentrations were analyzed using a commercially available immunoassay kit (Shionogi, Osaka, Japan) that quantifies the bioactive BNP-32 peptide and has no cross-reactivity with atrial natriuretic peptide. According to the manufacturer, the inter-assay variation is 9.4% at 8.3 pmol/l and 12% at 168.9 pmol/l 13.
Data are presented as the mean (SD) for Gaussian-distributed variable and the median (interquartile range) for variables with a skewed distribution. Pro-BNP data were non-Gaussian-distributed and log-transformed before statistical analysis. For comparison between groups, we used unpaired analysis as appropriate (Student’s t-test, Mann–Whitney U-test, or one-way analysis of variance). Correlations between continuous variables were tested by linear regression analysis. A P-value less than 0.05 was considered statistically significant. For statistical analysis, we used GraphPad Prism 4 (Graph Pad Software Inc., La Jolla, California, USA).
Women with type 2 diabetes or GDM tended to be heavier and the metabolic control in late pregnancy was different in the three groups (Table 1). The basic characteristics of women are presented in Table 1. Sixty-three (64%) women had a vaginal delivery, 16 (16%) had an elective delivery, and 20 (20%) had an emergency Cesarean section (Table 2). For practical reasons, for example heavy workload on the labor ward, complete data could not be collected for all the women included.
Data from women with type 1, type 2 diabetes, and GDM were pooled and analyzed together as no differences were found between the three groups in the echocardiographic measurements, pro-BNP, or STAN events (Table 1). Seventy-five newborns were investigated by echocardiography (Table 2).
Umbilical cord blood pro-BNP concentrations were higher in infants with an interventricular septal thickness above the median compared with infants with an interventricular septal thickness below the median (P=0.025; n=52), (Fig. 1). Further, umbilical cord blood pH was lower in the group with umbilical cord blood pro-BNP concentrations above the mean compared with those with umbilical cord blood pro-BNP concentrations below the mean (P=0.036, n=64) (Fig. 2). This result is in agreement with previous findings 23,30.
Fifty-three (54%) women were subjected to STAN monitoring during labor. STAN events were observed in six of the eight deliveries leading to an emergency Cesarean section. In 16 (36%) of the 45 women who delivered vaginally, STAN events during labor were observed. A total of 41 deliveries were STAN monitored during labor and also subjected to analysis of umbilical cord blood pro-BNP concentrations. We found no association between STAN events and interventricular septal thickness and no association between STAN events and pro-BNP (data not shown). Furthermore, no associations were found between the late pregnancy HbA1c and interventricular septal thickness nor the pro-BNP concentration.
To the best of our knowledge, this is the first study on a possible relation between neonatal serum markers of cardiac function, structural measurable changes, and fetal ECG changes during the stress of birth. The umbilical median cord blood pro-BNP concentrations were higher in neonates with an interventricular septal thickness above the median compared with those with an interventricular septal thickness below the median. This finding suggests an association between elevated pro-BNP concentrations at birth and fetal cardiomyopathy in diabetic pregnancies. Moreover, and in agreement with our previous findings 23, an inverse association was observed between umbilical cord blood pH and umbilical cord blood pro-BNP concentrations.
A trend toward an association between fetal ECG changes during birth and increasing neonatal interventricular septal thickness was observed. However, as only half of the women were monitored with STAN during labor, the statistical power thus could not be measured.
The offspring of women with diabetes are known to be at a risk of fetal and neonatal cardiac hypertrophy 6,7. An asymmetrical interventricular hypertrophy is considered to develop in the third trimester of pregnancy and has been shown to disappear within 6 months postnatally in most cases. However, fatal cases with intrauterine fetal death in the third trimester or perinatal death have been reported 7,31. Whether the surviving children are more likely to develop cardiac hypertrophy later in life remains unresolved.
In our previous study, pregnancies complicated by type 1 diabetes had higher umbilical cord blood pro-BNP levels compared with the control group of healthy pregnant women 23. This is in agreement with the recent findings of Girsen et al. 30. Previous studies have also shown that a pro-BNP increase in umbilical cord blood is associated with perinatal cardiac stress reflected in umbilical cord blood pH 21,22. Russell et al. 24 observed that pro-BNP levels correlated positively with interventricular septal thickness measured by ultrasound in the third trimester of pregnancy. In our study, the echocardiographic examinations were performed within 72 h after delivery, and the same positive association between pro-BNP levels and interventricular septal thickness was found. We did not find any association between late pregnancy HbA1c and interventricular septal thickness nor pro-BNP concentrations in agreement with a recent study 5. This might be because good metabolic control in late pregnancy was achieved in the majority of the women in our study (Table 1).
The offspring of women with type 1 diabetes are at a risk of prediabetes/diabetes, overweight, and the metabolic syndrome 32,33. The predictive value of pro-BNP, neonatal interventricular septal thickness, and fetal echocardiography during labor for later development of these conditions would be of considerable interest to study in the future.
The low number of women in our study is a limitation and might have influenced the statistical power negatively, especially in terms of the fetal ECG changes. Furthermore, there was a huge overlap between individual results among different groups as can be seen in Figs 1 and 2. Thus, although the observed statistical differences indicated interesting pathophysiological associations, our results cannot be used clinically because of the huge overlap. Further studies in larger groups with a long-term follow-up and a control group are needed to answer questions on the possible correlation between fetal ECG changes during birth and the long-term prognosis of the cardiac findings.
Increased cord blood pro-BNP was found to be associated with echocardiographic signs of cardiomyopathy, probably reflecting an altered functionality of the fetal heart in pregnancies complicated by maternal diabetes.
The authors appreciate the help from the midwifes in the Department of Obstetrics, Rigshospitalet, Copenhagen, in collecting the umbilical cord blood samples. This study was supported by grants from The Danish Diabetes Association and the Danish Medical Research Council.
Conflicts of interest
Isis Amer-Wahlin was a consultant to Neoventa Medical, the manufacturer of STAN monitors during the last few months of writing of this manuscript. During the collection of data and analysis, she was working as a senior lecturer in the Department of Obstetrics, Rigshospitalet, Copenhagen. For the remaining authors, there are no conflicts of interest.
1. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS.Effect of treatment of gestational diabetes mellitus on pregnancy
outcomes.N Engl J Med2005;352:2477–2486.
2. Jensen DM, Damm P, Moelsted-Pedersen L, Ovesen P, Westergaard JG, Moeller M, et al..Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study.Diabetes Care2004;27:2819–2823.
3. Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P.Poor pregnancy
outcome in women with type 2 diabetes.Diabetes Care2005;28:323–328.
4. Vela-Huerta MM, Vargas-Origel A, Olvera-Lopez A.Asymmetrical septal hypertrophy in newborn infants of diabetic mothers.Am J Perinatol2000;17:89–94.
5. Aman J, Hansson U, Ostlund I, Wall K, Persson B.Increased fat mass and cardiac septal hypertrophy in newborn infants of mothers with well-controlled diabetes during pregnancy
6. Abu-Sulaiman RM, Subaih B.Congenital heart disease in infants of diabetic mothers: echocardiographic study.Pediatr Cardiol2004;25:137–140.
7. Sardesai MG, Gray AA, McGrath MM, Ford SE.Fatal hypertrophic cardiomyopathy
in the fetus of a woman with diabetes.Obstet Gynecol2001;98Pt 2925–927.
8. Amer-Wahlin I, Hellsten C, Noren H, Hagberg H, Herbst A, Kjellmer I, et al..Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomised controlled trial.Lancet2001;358:534–538.
9. Westerhuis ME, Visser GH, Moons KG, Zuithoff N, Mol BW, Kwee A.Cardiotocography plus ST analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum monitoring: a randomized controlled trial.Obstet Gynecol2010;115:1173–1180.
10. Potti S, Berghalla V.ST waveform analysis versus cerdiotocography alone for intrapartum fetal monitoring: a meta-analysis of randomized trials.Am J Perinatol2012;29:657–664.
11. Schuit E, Amer-Wahlin I, Ojala K, Vayssiére C, Westerhuis ME, Marsal K, et al..Effectiveness of electronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at> 36 weeks of gestation: an individual participant data metaanalysis.Am J Obstet Gynecol2013;208:187.e1–187.e13.
12. Yli BM, Kallen K, Khoury J, Stray-Pedersen B, Amer-Wahlin I.Intrapartum cardiotocography (CTG) and ST-analysis of labor in diabetic patients.J Perinat Med2011;39:457–465.
13. Goetze JP.Biochemistry of pro-B-type natriuretic peptide-derived peptides: the endocrine heart revisited.Clin Chem2004;50:1503–1510.
14. Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, Kastrup J, et al..Increased cardiac BNP expression associated with myocardial ischemia.FASEB J2003;17:1105–1107.
15. Goetze JP, Gore A, Moller CH, Steinbruchel DA, Rehfeld JF, Nielsen LB.Acute myocardial hypoxia increases BNP gene expression 1.FASEB J2004;18:1928–1930.
16. Woods RL.Cardioprotective functions of atrial natriuretic peptide and B-type natriuretic peptide: a brief review.Clin Exp Pharmacol Physiol2004;31:791–794.
17. Kousholt BS, Larsen JKR, Bisgaard L, Burnett JC, Hasenkam JM, Goetze JP.Natriuretic peptide infusion reduces myocardial injuri during acute ischemia/reperfusion.Cardiovasc Endocrinol2012;1:4–12.
18. De Lemos JA, McGuire DK, Drazner MH.B-type natriuretic peptide in cardiovascular disease.Lancet2003;362:316–322.
19. Hirata Y, Matsumoto A, Aoyagi T, Yamaoki K, Komuro I, Suzuki T, et al..Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload.Cardiovasc Res2001;51:585–591.
20. Cameron VA, Ellmers LJ.Minireview: natriuretic peptides during development of the fetal heart and circulation.Endocrinology2003;144:2191–2194.
21. Kunii Y, Kamada M, Ohtsuki S, Araki T, Kataoka K, Kageyama M, et al..Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease.Acta Med Okayama2003;57:191–197.
22. Fleming SM, O’Gorman T, O’Byrne L, Grimes H, Daly KM, Morrison JJ.Cardiac troponin I and N-terminal pro-brain natriuretic peptide in umbilical artery blood in relation to fetal heart rate abnormalities during labor.Pediatr Cardiol2001;22:393–396.
23. Halse KG, Lindegaard ML, Goetze JP, Damm P, Mathiesen ER, Nielsen LB.Increased plasma pro-b-type natriuretic peptide in infants of women with type 1 diabetes.Clin Chem2005;51:2296–2302.
24. Russell NE, Higgins MF, Amaruso M, Foley M, McAuliffe FM.Troponin T and pro-B-type natriuretic peptide in fetuses of type 1 diabetic mothers.Diabetes Care2009;32:2050–2055.
25. Jensen DM, Molsted-Pedersen L, Beck-Nielsen H, Westergaard JG, Ovesen P, Damm P.Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study 1.Am J Obstet Gynecol2003;189:1383–1388.
26. Skinner J, Alverson D, Hunter S.Echocardiography for the neonatologist. ISBN 4430548082000.Philadelphia:Churchill Livingstone.
27. Nielsen LR, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER.Hypoglycemia in pregnant women with type 1 diabetes: predictors and role of metabolic control.Diabetes Care2008;31:9–14.
28. Hammerer-Lercher A, Mair J, Tews G, Puschendorf B, Sommer R.N-terminal pro-b-type natriuretic peptide concentrations are markedly higher in the umbilical cord blood of newborns than in their mothers.Clin Chem2005;51:913–915.
29. Goetze JP, Kastrup J, Pedersen F, Rehfeld JF.Quantification of pro-B-type natriuretic peptide and its products in human plasma by use of an analysis independent of precursor processing.Clin Chem2002;48:1035–1042.
30. Girsen A, Ala-Kopsala M, Makikallio K, Vuolteenaho O, Rasanen J.Increased fetal cardiac natriuretic peptide secretion in type-1 diabetic pregnancies.Acta Obstet Gynecol Scand2008;87:307–312.
31. Eidem I, Vangen S, Hanssen KF, Vollset SE, Henriksen T, Joner G, Stene LC.Perinatal and infant mortality in term and preterm births among women with type 1 diabetes.Diabetologia2011;54:2771–2778.
32. Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, Damm P.High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia.Diabetes Care2008;31:340–346.
33. Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, et al..Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes.J Clin Endocrinol Metab2009;94:2464–2470.
Keywords:© 2013Wolters Kluwer Health Lippincott Williams Wilkins
cardiomyopathy; echocardiographic changes; fetal distress; maternal diabetes; pregnancy