Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lauenborg, J.
Right arrow Articles by Damm, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lauenborg, J.
Right arrow Articles by Damm, P.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Diabetes Care 26:1385-1389, 2003
© 2003 by the American Diabetes Association, Inc.

Epidemiology/Health Services/Psychosocial Research
Original Article

Audit on Stillbirths in Women With Pregestational Type 1 Diabetes

Jeannet Lauenborg, MD1, Elisabeth Mathiesen, MD, PHD2, Per Ovesen, MD, PHD3, Jes G. Westergaard, MD, PHD4, Pia Ekbom, MD2, Lars Mølsted-Pedersen, MD, PHD5 and Peter Damm, MD, PHD1

1 Obstetric Clinic, the Juliane Marie Center, National University Hospital, Rigshospitalet, Copenhagen, Denmark
2 Department of Endocrinology, National University Hospital, Rigshospitalet, Copenhagen, Denmark
3 Department of Obstetrics and Gynecology, Aarhus University Hospital, Skejby, Denmark
4 Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark
5 Department of Obstetrics and Gynecology, Copenhagen University Hospital, Glostrup, Denmark


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 APPENDIX
 References
 
OBJECTIVE—To audit stillbirth cases in women with type 1 diabetes to search for specific characteristics in order to improve antenatal care and treatment

RESEARCH DESIGN AND METHODS—Retrospectively identified cases of stillbirths in women with type 1 diabetes during 1990–2000 were analyzed regarding characteristics of the mother, the pregnancy, glycemic control, and the stillborn. The cause of stillbirth was categorized as explainable, likely, or without obvious cause.

RESULTS—We found 22 women with 25 stillbirths among 1,361 singleton births by women with type 1 diabetes. In seven stillbirths the cause was categorized as explainable and in six as likely. In 12 cases no obvious cause was found; however, glycemic control was suboptimal in 9 of these cases. A total of 14 women reported daily smoking, and 10 of 19 with low education were unemployed.

CONCLUSIONS—Women experiencing stillbirth were characterized by a high incidence of suboptimal glycemic control, diabetic nephropathy, smoking, and low social status.

Abbreviations: AGA, appropriate for gestational age • GA, gestational age • LGA, large for gestational age • SGA, small for gestational age


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 APPENDIX
 References
 
Women with pregestational diabetes still have a five times increased risk of stillbirth compared with women with normal pregnancies (1). In the general population the risk of stillbirth in Denmark is 4.5 for every 1,000 deliveries (2), and stillbirths account for half of the cases of perinatal mortality, many of them being unexpected as well as unexplained (3–5). The literature on stillbirths by women with pregestational type 1 diabetes is very limited, and to our knowledge this is the only recent study focusing specifically on pregnancies ending in stillbirths in women with type 1 diabetes. The aim of the study was to audit stillbirth cases in women with type 1 diabetes to search for specific characteristics in order to improve antenatal care and treatment.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 APPENDIX
 References
 
The stillbirths were defined as intrauterine death after 24 weeks gestation and were identified retrospectively among 1,361 singleton births of women with pregestational type 1 diabetes. The women were followed during the period of 1990–2000 at three large tertiary centers in Denmark (Rigshospitalet Copenhagen, Aarhus University Hospital, and Odense University Hospital) that specialize in diabetes and pregnancy. These centers take care of approximately two-thirds of pregnant women with type 1 diabetes in Denmark.

Data were collected from the medical records with details on maternal age, White class (6), age at onset of diabetes, duration of diabetes, smoking habits, occupation, gestational age at the first visit to the center, gestational age at diagnosis of stillbirth, HbA1c before pregnancy (within 2 months before conception), HbA1c in early pregnancy (before 14 weeks of gestation) and in the last trimester (after 28 weeks’ gestation), health during pregnancy, attendance to planned antepartum visits, nonstress testing, birth weight of the stillborn, and results from the autopsy report. Autopsy of the stillborn was routinely performed after permission from the mother and included microscopical analysis of placenta but not microbiological culture. Weekly antenatal testing with a nonstress test was routine in all three departments from approximately week 34. Information about the educational level and unemployment among the general Danish female population aged 20–40 years was obtained from the National Bureau of Statistics (Danmarks Statistik).

The causes of stillbirth were categorized as explainable (clear-cut explanation), likely, or without obvious explanation. Sub-optimal glycemic control was defined as HbA1c >7.5% (corresponding to 4 SD above mean) according to the recommendations from the American Diabetes Association (7). The reference range for HbA1c in the background population of Copenhagen was 4.1–6.4% and was used as standard. The reference range from Aarhus and Odense was 4.4–6.4 and 5.4–7.4%, respectively. HbA1c from these two centers was corrected to be able to compare HbA1c values (see APPENDIX). HbA1c was analyzed by antibody immunoassay (8) in the majority of pregnancies.

Gestational age (GA) was determined by early ultrasonography before 20 weeks’ gestation in all cases except two, where the last menstrual period was used due to late enrollment. Birth weight in relation to GA and sex was calculated using a Danish linear growth curve (9). These curves are made for newborns with GA >=28 weeks’ gestation. In five cases with GA <28 weeks, birth weight was compared with data for normal fetal growth evaluated by longitudinal ultrasound examinations (10). Small for gestational age (SGA) was defined as birth weight below the 10th percentile, large for gestational age (LGA) as birth weight above the 90th percentile, and appropriate for gestational age (AGA) as birth weight between the 10th and 90th percentile. Birth weight in standard deviations from the mean in the background population was calculated (10).

The results are presented as medians and ranges. If a woman had more than one stillbirth in the study period, only the first stillbirth was included in the calculations of the medians, while all cases were included in the overall analysis.

The results were compared with a reference group of 236 consecutive pregnant type 1 diabetic women without stillbirths, followed at the center in Copenhagen in the years 1996–1999 (11). This group was chosen because it is well characterized, and no detailed data were available for the total population of pregnant women with type 1 diabetes in the three departments for the period 1990–2000. {chi}2 test and Fisher’s exact test were used as appropriate for comparisons of frequencies.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 APPENDIX
 References
 
Of 22 women with type 1 diabetes, 25 stillbirths (1.8% of all singleton births by women with type 1 diabetes) were identified; 3 of the women had 2 stillbirths. Details for the individual stillbirths are presented in Table 1. An explainable cause was found in seven cases: chorioamnionitis, ketoacidosis, placental abruption, and severe intrauterine growth retardation. A likely cause was found in the six cases with autopsy records describing severe malformations in four cases, multiple placental infarctions in one, and thrombosis in the umbilical cord in one. In the remaining 12 cases of stillbirth no obvious explanation was found. However, in 9 of these 12 cases glycemic control in pregnancy was suboptimal. Overall, HbA1c in pregnancy was considerably higher in women with stillbirths compared with the reference group (Fig. 1, Table 1) with 64% in stillbirth group versus 33% in reference group having suboptimal glycemic control early in pregnancy (P = 0.004). Late in pregnancy, suboptimal glycemic control was present in 67% in the stillbirth group and in 4% in the reference group (P < 0.001).


View this table:
[in this window]
[in a new window]
  		Table 1— Characteristics for women with type 1 diabetes and stillbirth categorized according to possible cause of stillbirth

 


View larger version (15K):
[in this window]
[in a new window]
  		Figure 1— Hemoglobin A1c late in pregnancies resulting in stillbirths compared to reference group.

 
The incidence of major malformations was 10 times higher (P < 0.001) than in the reference group (Table 1), and all cases of stillbirths with malformation were found in the groups with explainable and likely causes. Of the 22 women, 6 (27%) suffered from diabetic nephropathy. The prevalence of diabetic nephropathy was only 5% in the reference group (P < 0.001). Preeclampsia was diagnosed in 18% of the women (case 6, 11, 19, and 20a) versus 12% in the reference group (not significant). Approximately half of the stillborns were large for gestational age; however, this was similar to the reference group.

In 20 cases the woman had been examined within the last week of the stillbirth. Among the five cases with examination beyond 1 week, three stillborns were severely macerated, indicating that the fetus had been dead for >3 days. In two of these cases the women reported fetal movements within 3 days (both stillborns AGA). The two women with diabetic ketoacidosis had not attended the hospital for >1 month before presenting with a stillbirth. In only seven cases a nonstress test was performed within 1 week from the diagnosis of stillbirth. Six tests were normal and one test in a growth-retarded fetus at 30 weeks’ gestation was suspicious without indicating acute intervention. The six normal tests were all performed in the cases without an explainable cause of intrauterine death.

A total of 19 women had an occupation corresponding to no or only short education, and 10 of them were unemployed. The unemployment rate for the general Danish female population at age 20–40 years was 4.8–15.5%. There was no data available for reference group regarding social status. Daily smoking was reported by two-thirds of the women with stillbirth and by one-third in reference group (P = 0.001).


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
APPENDIX
 References
 
Suboptimal glycemic control before and in early pregnancy is known to be associated with high rates of congenital malformations and spontaneous abortions (12–14), and strict glycemic control before and throughout pregnancy seems to improve fetal outcome (15–17). In accordance with this, the glycemic control did not improve during pregnancy in the stillbirth group in contrast to the reference group resulting in markedly higher HbA1c values in late pregnancy. Furthermore the malformation rate was high. Overall suboptimal glycemic control during pregnancy was present in 67% of the pregnancies resulting in stillbirth. Suboptimal glycemic control during pregnancy (HbA1c > 7.5%) was the only "medical" finding in 36% of the stillbirths. This is in accordance with the study of Hanson et al. (18) who found a poor glycemic control as the only explanation in 5 of 10 cases of stillbirth in women with type 1 diabetes. Glycemic control in both early and late pregnancy was poorer in the stillbirth group when compared with reference group. In the stillbirth group HbA1c did not decline during pregnancy as in the reference group. The difference in metabolic control between the stillbirth group and the control group were therefore greatest in late pregnancy around the time of stillbirth. Early as well as late suboptimal glycemic control may predispose to fetal distress, due to fetal hyperinsulinemia, acidosis, and hyperlacticemia, as maternal hyperglycemia and elevated HbA1c are risk factors for fetal asphyxia, possibly leading to intrauterine death (19–21).

One-third of the women in the stillbirth group had diabetic nephropathy, which was six times higher than that in the reference group (11). In women with diabetic nephropathy, perinatal mortality is increased (22).

The proportion of unemployed women was four times higher in the stillbirth group than in the general Danish female population. Furthermore, the majority of the women in the stillbirth group were characterized by low educational level, and together with a high unemployment rate this expresses a low social status, which has also been associated with unexplained stillbirth and perinatal mortality (23,24). On the other hand, daily smoking, known to be related to social status, was reported by two-thirds of the women compared with less than one-third of the women in the reference group. In addition, smoking is a well-known risk factor for placental complications as found in four of the stillbirths (25,26).

Despite a routine with weekly nonstress testing from ~34 weeks’ gestation, only 28% of our cases had a test performed within the last week before the diagnosis of stillbirth. This is partly explained by the fact that nine stillbirths occurred before 34 weeks’ gestation. Nevertheless, a normal nonstress test cannot exclude an intrauterine death occurring within a few days after the test has been performed (27,28). The retrospective nature of the study design did not give the opportunity to decide whether some of the not-performed nonstress tests were due to flaws in the clinical setup or due to poor patient compliance. The lack of fetal surveillance together with the lacking improvement in glycemic control during pregnancy, the high rate of smokers, and the low social status indicate that this group has limited compliance, corresponding to the term "neglectors" introduced by Mølsted-Pedersen and Pedersen in 1967 (29).

In conclusion, our study identified the following characteristics of women with type 1 diabetes experiencing intrauterine death after 24 weeks’ gestation: HbA1c >4 SD above the range for the normal population, previous stillbirth, diabetic nephropathy, current smoking, and low social status. Our study indicates that more attention should be focused on these women during pregnancy, especially with respect to optimizing their glycemic control.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 APPENDIX
References
 
Correction of HbA1c was done by the following formula: (X - meanL)/1 SDL * 1 SDC + meanC, where X is the HbA1c to be corrected, meanL is the mean from either Odense or Aarhus (6.4 and 5.4%, respectively), 1 SDL the SD from Odense or Aarhus (= 0.5 for both Odense and Aarhus), 1 SDC the SD from Copenhagen (= 0.575), and meanC the mean from Copenhagen (= 5.25). The corrections were done on the assumption that the values follow a normal distribution and that the reference range is the mean ± 2 SD.


   Footnotes
 
Address correspondence and reprint requests to Jeannet Lauenborg, Obstetric Clinic, the Juliane Marie Center, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ö, Denmark. E-mail: lauenborg{at}dadlnet.dk.

Received for publication 8 November 2002 and accepted in revised form 25 January 2003.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 APPENDIX
 References
 

  1. Casson IF, Clarke CA, Howard CV, McKendrick O, Pennycook S, Pharoah PO, Platt MJ, Stanisstreet M, van Velszen D, Walkinshaw S: Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study. BMJ 315:275–278, 1997[Abstract/Free Full Text]
  2. Danish National Board of Health Sundhedsstatistikken: The Medical Birth Register: Summary of Birth Statistics 1994 and 1995. No. 6. Copenhagen, Denmark, Munksgaard, 1997
  3. Gardosi J, Fagan D: Causes and prevention of antepartum stillbirth. In Textbook of Perinatal Medicine. 1st ed. Kurjac A, Ed. London, New York, The Parthenon Publishing Group, 1998, p. 846–850
  4. Kohler L: Infant mortality: the Swedish experience. Annu Rev Public Health 12:177–193, 1991[Medline]
  5. Pedersen J, Pedersen LM, Andersen B: Assessors of fetal perinatal mortality in diabetic pregnancy: analysis of 1,332 pregnancies in the Copenhagen series, 1946–1972. Diabetes 23:302–305, 1974[Medline]
  6. White P: Pregnancy and diabetes, medical aspects. Med Clin North Am 49:1015–1024, 1965
  7. American Diabetes Association: Preconception care of women with diabetes. Diabetes Care 24:S66–S68, 2001
  8. Svendsen PA, Christiansen JS, Soegaard U, Welinder BS, Nerup J: Rapid changes in chromatographically determined haemoglobin A1c induced by short-term changes in glucose concentration. Diabetologia 19:130–136, 1980[Medline]
  9. Greisen G, Michaelsen KF: Perinatal growth: a practical perinatal growth curve. Ugeskr Laeger 151:1813–1815, 1989[Medline]
  10. Larsen T, Petersen S, Greisen G, Larsen JF: Normal fetal growth evaluated by longitudinal ultrasound examinations. Early Hum Dev 24:37–45, 1990[Medline]
  11. Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Mølvig J, Mathiesen ER: Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 24:1739–1744, 2001[Abstract/Free Full Text]
  12. Hanson U, Persson B, Thunell S: Relationship between haemoglobin A1C in early type 1 (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia 33:100–104, 1990[Medline]
  13. Kitzmiller JL, Gavin LA, Gin GD, Jovanovic-Peterson L, Main EK, Zigrang WD: Preconception care of diabetes: glycemic control prevents congenital anomalies. JAMA 265:731–736, 1991[Abstract]
  14. Suhonen L, Hiilesmaa V, Teramo K: Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 43:79–82, 2000[Medline]
  15. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 174:1343–1353, 1996[Medline]
  16. McElvy SS, Miodovnik M, Rosenn B, Khoury JC, Siddiqi T, Dignan PS, Tsang RC: A focused preconceptional and early pregnancy program in women with type 1 diabetes reduces perinatal mortality and malformation rates to general population levels. J Matern Fetal Med 9:14–20, 2000[Medline]
  17. The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 45:1289–1298, 1996[Abstract]
  18. Hanson U, Persson B: Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 10:330–333, 1993[Medline]
  19. Bradley RJ, Nicolaides KH, Brudenell JM, Campbell S: Early diagnosis of chronic fetal hypoxia in a diabetic pregnancy. Br Med J (Clin Res Ed) 296:94–95, 1988
  20. Madsen H, Ditzel J: Blood-oxygen transport in first trimester of diabetic pregnancy. Acta Obstet Gynecol Scand 63:317–320, 1984[Medline]
  21. Bradley RJ, Brudenell JM, Nicolaides KH: Fetal acidosis and hyperlacticaemia diagnosed by cordocentesis in pregnancies complicated by maternal diabetes mellitus. Diabet Med 8:464–468, 1991[Medline]
  22. Kitzmiller JL, Combs CA: Management and outcome of pregnancies complicated by diabetic nephropathy. In Diabetes and Pregnancy. Dornhorst A, Hadden DR, Eds. Chichester, UK, New York, Wiley, 1996, p. 167–206
  23. Froen JF, Arnestad M, Frey K, Vege A, Saugstad OD, Stray-Pedersen B: Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986–1995. Am J Obstet Gynecol 184:694–702, 2001[Medline]
  24. Olsen O, Madsen M: Effects of maternal education on infant mortality and stillbirths in Denmark. Scand J Public Health 27:128–136, 1999[Medline]
  25. Raymond EG, Cnattingius S, Kiely JL: Effects of maternal age, parity, and smoking on the risk of stillbirth. Br J Obstet Gynaecol 101:301–306, 1994[Medline]
  26. Wisborg K, Kesmodel U, Henriksen TB, Olsen SF, Secher NJ: Exposure to tobacco smoke in utero and the risk of stillbirth and death in the first year of life. Am J Epidemiol 154:322–327, 2001[Abstract/Free Full Text]
  27. Diamond MP, Vaughn WK, Salyer SL, Cotton RC, Fields LM, Boehm FH: Antepartum fetal monitoring in insulin-dependent diabetic pregnancies. Am J Obstet Gynecol 153:528–533, 1985[Medline]
  28. Girz BA, Divon MY, Merkatz IR: Sudden fetal death in women with well-controlled, intensively monitored gestational diabetes. J Perinatol 12:229–233, 1992[Medline]
  29. Pedersen LM, Pedersen J: Causes of perinatal death in diabetic pregnancy: a clinico-pathological analysis. Acta Med Scand 476 (Suppl.):175–181, 1967

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Diabetes CareHome page
L. R. Nielsen, U. Pedersen-Bjergaard, B. Thorsteinsson, M. Johansen, P. Damm, and E. R. Mathiesen
Hypoglycemia in Pregnant Women With Type 1 Diabetes: Predictors and role of metabolic control
Diabetes Care, January 1, 2008; 31(1): 9 - 14.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
K. G. Halse, M. L.S. Lindegaard, J. P. Goetze, P. Damm, E. R. Mathiesen, and L. B. Nielsen
Increased Plasma Pro-B-Type Natriuretic Peptide in Infants of Women with Type 1 Diabetes
Clin. Chem., December 1, 2005; 51(12): 2296 - 2302.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
T. D. Clausen, E. Mathiesen, P. Ekbom, E. Hellmuth, T. Mandrup-Poulsen, and P. Damm
Poor Pregnancy Outcome in Women With Type 2 Diabetes
Diabetes Care, February 1, 2005; 28(2): 323 - 328.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
L. R. Nielsen, P. Ekbom, P. Damm, C. Glumer, M. M. Frandsen, D. M. Jensen, and E. R. Mathiesen
HbA1c Levels Are Significantly Lower in Early and Late Pregnancy
Diabetes Care, May 1, 2004; 27(5): 1200 - 1201.
[Full Text] [PDF]

Home page
 Obstet GynecolHome page
S. G. Gabbe and C. R. Graves
Management of Diabetes Mellitus Complicating Pregnancy
Obstet. Gynecol., October 1, 2003; 102(4): 857 - 868.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lauenborg, J.
Right arrow Articles by Damm, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lauenborg, J.
Right arrow Articles by Damm, P.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum