ISSN: 2377-4304OGIJ

Obstetrics & Gynecology International Journal
Commentary
Volume 4 Issue 4 - 2016
Review of Stillbirths among Antepartum Women with Gestational and Pre-Gestational Diabetes
Shadi Rezai1*, Carolyn Withers Cokes2, Sri Gottimukkala3, Ramses Posso Penas1, Annika Chadee1, Ekaterina Chadwick1 and Cassandra E Henderson1*
1Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, USA
2St. George’s University, West Indies
3Department of Obstetrics and Gynecology, Houston Methodist Hospital, USA
Received: May 05, 2016 | Published: May 12, 2016
*Corresponding author: Shadi Rezai, Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, 234 East 149th Street , Bronx, NY, 10451, USA, Email:

Cassandra E. Henderson, Director of Maternal Fetal Medicine, Lincoln Medical and Mental Health Center, 234 East 149th Street , Bronx, NY, 10451, USA, Email:

Citation: Rezai S, Cokes CW, Gottimukkala S, Penas RP, Chadee A,et al (2016) Review of Stillbirths among Antepartum Women with Gestational and Pre-Gestational Diabetes. Obstet Gynecol Int J 4(4): 00118. DOI: 10.15406/ogij.2016.04.00118

Abstract

Background: The literature is replete with reports describing the effect of diabetes on pregnancy outcomes, particularly the risk of stillbirth. The goal of this review is to explore the relationship between maternal diabetes and fetal demise.

Aim: To review the risk of stillbirths in pregnancies complicated by Type 1, Type 2, and gestational Diabetes Mellitus.

Discussion: Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2D), and gestational Diabetes Mellitus (GDM) identified during pregnancy have been independently associated with an increased risk of stillbirth compared to pregnancies not affected by these conditions. Published guidelines for prevention and management of GDM are lacking, but the existing evidence indicates that achieving glycemic targets during pre-conception is associated with decreased rates of stillbirth.

Conclusion: Diabetes is an independent risk factor for stillbirth that is amenable to achieving glycemic targets. Evidence-based recommendations for antenatal screening glycemic management are warranted to achieve reduction in stillbirth rates for gravidas with pre-gestational and gestational DM.

Keywords: Adverse outcome; Congenital malformations; Gestational diabetes; Diabetes; Maternal morbidity; Pre-gestational diabetes; Pregnancy; Perinatal mortality; Still births; Type 1 Diabetes; Type 2 Diabetes

Background

There has been extensive research into the effects of diabetes mellitus (DM) on pregnancy outcomes, and in particular on risk of stillbirth [1,2]. This article aims to bring together those studies to discuss the relationship between antepartum DM and stillbirth.

DM is an umbrella term for several different pathological conditions in which blood glucose is elevated, with a variety of etiologies. Type 1 diabetes mellitus (T1D) is caused an immune-mediated condition in which the beta cells of the pancreas are destroyed and thus unable to produce insulin [3]. Type 2 diabetes mellitus (T2D) is a condition in which the beta cells of the pancreas may have impaired function, but the primary defect is that of insulin resistance. There are numerous etiologies of this condition, including obesity, as well as secondary causes such as hemochromatosis and PCOS [2]. Gestational diabetes mellitus (GDM) is defined as DM associated with pregnancy. GDM is present in about 2-5% of pregnancies in the U.S. [2,4]. Due to current screening guidelines, GDM is generally not diagnosed until after 24 weeks of gestation [2]. Regardless of etiology, DM during the antepartum period is associated with the following risks to the fetus: neonatal death, preterm delivery, congenital anomalies, large for gestational age infants, shoulder dystocia, Erb’s palsy, APGAR < 7 at 5 minutes, and admission to intensive care [5,6].

Stillbirth is generally defined as an intrauterine fetal death at 20 weeks or more gestation. According to an ACOG bulletin on managing stillbirth, published in 2009, 1 out of 160 births are stillborn [7]. Approximately, 26,000 fetal deaths at 20 weeks or more gestation were reported in the United States in 2006, which translates to 6.05 stillbirths per 1,000 births [8]. Many attempts have been made to classify causes of stillbirth, and known causes include unfavorable genetics, infection, fetal maternal hemorrhage, antiphospholipid syndrome, thrombophilias, and the subject of this review: diabetes mellitus [9].

Discussion

An audit on stillbirths among women with T1D in Denmark confirmed that suboptimal glycemic control, both pre-conception and antepartum, is associated with cases of stillbirth [10]. A similar study in Australia confirmed these findings, that pregestational, maternal T1D is associated with an increased risk of stillbirth [11]. A retrospective cohort study of 182 antepartum women with T2D showed a two-fold risk of stillbirth among affected women [12].

Less is known about the relationship of GDM with risk of stillbirth. T2D and GDM have similar pathophysiology, and thus some proven risk of stillbirth attributed to T2D may be extrapolated to GDM, but there is little evidence to support this. The underlying reasons for this lack of evidence are not clear, but a recent study by Hutcheon et al. [13], in which national data on GDM and stillbirth was re-categorized and then reanalyzed, the risk for stillbirth among women with GDM was significant [13]. Other studies have shown that, when compared to pregnancies not affected by DM, a diagnosis of DM during pregnancy portents a 4.5-fold risk of stillbirth [14].

The pathogenesis of high stillbirth rates among pregnancies complicated by diabetes is unknown, but likely to be multifactorial. One theory is that many cases are due to chronic hypoxia and associated acidosis. In addition, cardiac defects are not infrequently identified in infants born to women with T1D [15]. Schaefer-Graf et al. [16] reported that increased maternal hyperglycemia was associated with co-morbid fetal genetic syndromes and congenital abnormalities that are also independently associated with fetal death [16]. While congenital anomalies may be the cause of some stillbirths, these anomalies are not the only cause of stillbirth occurring in pregnancies affected by DM. A study by Tennant et al. [17] compared the risk of stillbirth for gravidas with pregestational diabetes with and without a congenitally anomalous fetus and found a 4.5 fold stillbirth risk even in the absence of fetal malformation [17].

As far as management of DM during pregnancy, in a meta-analysis of 70 studies on screening and management of diabetes during pregnancy, the only timing intervention associated with a significant decrease in rate of stillbirths rates occurred during the preconception period. That is, achieving glycemic targets prior to conception, as opposed to waiting until pregnancy confirmation or even later in pregnancy [18]. These results are particularly salient in light of the finding by Schaefer-Graf et al. [16] that elevated risk of congenital anomalies was associated with maternal hyperglycemia at the time of entry into prenatal care. This findings indicate that maternal hyperglycemia early on in pregnancy (e.g. prior to the time of entry into prenatal care) seems to be the root of the associated adverse perinatal outcome [16]. Thus, stillbirth appears to be a direct risk of maternal hyperglycemia, irrespective of the fact that maternal hyperglycemia is also associated with an increased risk of congenital anomalies, and in addition, congenital anomalies themselves are sometimes to blame for cases of stillbirth. In other words, among gravidas with DM, regardless of whether fetal anomalies are present or not, the risk of stillbirth exists [16,17].

The aforementioned meta-analysis by Syed et al. [18] also found a slightly greater reduction in risk of stillbirth when intensive diabetic control was instituted versus conventional control [18]. A randomized trial conducted to study the benefits of treating mild GDM versus providing only usual prenatal care found a lower rate of complications among the treated group; however, this study was not able to evaluate for stillbirth as an outcome [19]. Due to the fact that risk for stillbirth among antepartum women with any type of DM is elevated, as well as evidence that other studies on the topic failing to support this finding may have been flawed, recommendations to attempt strict glycemic control among antepartum women that include those with GDM is reasonable [20].

Glycemic control antepartum is a relatively contested topic. Findings that sub-optimally controlled hyperglycemia, in particular prior to conception, is associated with increased risk of stillbirth [10] are not generally based on large studies, and many studies do not examine GDM that occurs before 24 weeks due to the structure of screening for DM currently in place. An additional caveat to these findings is that the cases in which stillbirth occurred may have been due to hyperglycemia that was harder to control (for various pathophysiological reasons) versus suboptimal glycemic control due to a lack of intervention. More applied research is needed particularly in programming aimed at strict pre-conception glycemic control, even among women at risk of GDM, and not just those already diagnosed, to determine whether this would decrease risk of stillbirth among these women.

Additional considerations in management of antepartum women include optimal time of delivery, which was specifically assessed as part of a large, retrospective study comparing the risks of delivery to the risks of expectant management by gestational age among pregnancies affected by GDM. For both study groups, the risks of earlier delivery (at 36 weeks) were found to surpass the risks of expectant management. This risk-benefit ratio reversed at 38 weeks. In examining the study results further, based on number needed to treat analysis, the authors concluded that among women with GDM, the benefits of delivery exceed those of expectant management appreciably at 39 weeks and beyond, and thus planned delivery at 39 weeks is optimal for antepartum patients with GDM [21].

Evidence-based guidelines for antepartum management of DM vary situationally. Earlier studies showed that early delivery may be indicated in some patients with vasculopathy, nephropathy, unmet glycemic targets, or a prior stillbirth. In contrast, gravidas whose glycemic targets are achieved may be may be managed by obstetric indications, continuing to full term as appropriate by antenatal testing [22]. Recommendations to address this increased risk among antepartum women with DM, include increased frequency of prenatal care visits to ensure glycemic targets are met, as well as twice weekly reactive non-stress testing (NST) beginning in most cases between 32 and 34 weeks of gestation [23].

Conclusion

After a review of the current literature available regarding the risk of stillbirth among antepartum women with DM of any type, it is clear that the risks among this population are higher compared to women without this condition [9-15].

Prevention of the devastating outcome that is stillbirth is not relevant solely because of the severity of the outcome, but also because of the relatively high incidence. There appears to be a dearth of evidence confirming the timeline for when stillbirth is preventable, and much of the research that negates findings that managing DM reduces risk of stillbirth is based on interventions later in the antepartum period, which is likely too late. This is supported by the finding that pre-conception interventions where glycemic index was tightly controlled were associated with lower risk of stillbirth than cases where the intervention of tight glycemic control was not instituted until later on in pregnancy [16-18].

Potential opportunities to reduce the risk of stillbirth among antepartum women with DM include a focus on pre-conception glycemic targets, frequent fetal testing in the third trimester, and consideration of delivery at 39 weeks of gestation for women [18,21]. In addition, consideration of earlier screening among women at risk of GDM is worth revisiting. The U.S. Preventive Services Task Force (USPSTF) cites a lack of evidence to support earlier screening as the reason for not recommending it, rather than evidence demonstrating that it is not actually useful in preventing negative fetal outcomes [24]. Thus, further research is needed in this area, to determine when screening for gestational diabetes would provide the optimal benefit.

Lastly, in terms of managing fetal monitoring during the antepartum period [25], the finding that normal results of once weekly non stress test (NST) beginning at 32-34 weeks of gestation do not preclude a stillbirth within 7 days among antepartum women with DM prompted the recommendation for twice weekly NST in these cases [23], which is well-supported. It is important, given the relative prevalence of DM during pregnancy, not to discount the potential severity of its effects.

Acknowledgment

The authors would like to thank Ms. Judith Wilkinson, Medical Librarian at Lincoln Medical and Mental Health Center Science Library for providing the reference articles.

References

  1. Penney GC, Mair G, Pearson DW (2003) Outcomes of pregnancies in women with type 1 diabetes in Scotland: a national population-based study. BJOG 110(3): 315-318.
  2. Gestational diabetes mellitus (2013) Practice Bulletin No. 137. American College of Obstetricians and Gynecologists. Obstet Gynecol 122: 406-416.
  3. American Diabetic Association (2013) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 36 Suppl 1: S67-S74.
  4. DeSisto CL, Kim SY, Sharma AJ (2014) Prevalence Estimates of Gestational Diabetes Mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010. Prev Chronic Dis 11: E10.
  5. Hawdon JM (2011) Babies born after diabetes in pregnancy: what are the short- and long-term risks and how can we minimize them?. Best Pract Res Clin Obstet Gynaecol 25(1): 91-104.
  6. Horvath K, Koch K, Jeitler K, Matyas E, Bender R, et al. (2010) Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ 340: c1395.
  7. Committee on Practice Bulletins (2009) ACOG Practice Bulletin No. 102: management of stillbirth. Obstet Gynecol 113(3): 748-761.
  8. MacDorman MF, Kirmeyer SE, Wilson EC (2012) Fetal and perinatal mortality, United States, 2006. Natl Vital Stat Rep 60(8): 1-22.
  9. Silver RM, Varner MW, Reddy U, Goldenberg R, Pinar H, et al. (2007) Work-up of stillbirth: a review of the evidence. Am J Obstet Gynecol 196(5): 433-444.
  10. Lauenborg J, Mathiesen E, Ovesen P, Westergaard JG, Ekbom P, et al. (2003) Audit on stillbirths in women with pregestational type 1 diabetes. Diabetes Care 26(5): 1385-1389.
  11. Engel PJ, Smith R, Brinsmead MW, Bowe SJ, Clifton VL (2008) Male sex and pre-existing diabetes are independent risk factors for stillbirth. Aust N Z J Obstet Gynaecol 48(4): 375-383.
  12. Dunne F, Brydon P, Smith K, Gee H (2003) Pregnancy in women with Type 2 diabetes: 12 years outcome data 1990-2002. Diabet Med 20(9): 734-738.
  13. Hutcheon JA, Kuret V, Joseph KS, Sabr Y, Lim K (2013) Immortal time bias in the study of stillbirth risk factors: the example of gestational diabetes. Epidemiology 24(6): 787-790.
  14. Wood SL, Jick H, Sauve R (2003) The risk of stillbirth in pregnancies before and after the onset of diabetes. Diabet Med 20(9): 703-707.
  15. Mathiesen ER, Ringholm L, Damm P (2011) Stillbirth in diabetic pregnancies. Best Pract Res Clin Obstet Gynaecol 25(1): 105-111.
  16. Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, et al. (2000) Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol 182(2): 313-320.
  17. Tennant PW, Glinianaia SV, Bilous RW, Rankin J, Bell R (2014) Pre-existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-based study. Diabetologia 57(2): 285-294.
  18. Syed M, Javed H, Yakoob MY, Bhutta ZA (2011) Effect of screening and management of diabetes during pregnancy on stillbirths. BMC Public Health 11 Suppl 3: S2.
  19. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, et al. (2009) A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 361(14): 1339-1348.
  20. Robson S, Nolan C (2013) Diabetes and stillbirth, O&G Magazine 15(4): 36-38.
  21. Rosenstein MG, Cheng YW, Snowden JM, Nicholson JM, Doss AE, et al. (2012) The risk of stillbirth and infant death stratified by gestational age in women with gestational diabetes, Am J Obstet Gynecol 206(4): 309.e1-309.e7.
  22. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH (1993) Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 169(3): 611-615.
  23. ACOG Committee on Practice Bulletins (2005) ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105(3): 675-685.
  24. U.S. Preventive Services Task Force (USPSTF) (2008) Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 148(10): 759-765.
  25. Dudley DJ (2007) Diabetic-associated stillbirth: incidence, pathophysiology, and prevention. Obstet Gynecol Clin North Am 34(2): 293-307.
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