Historical literature reports risk of fetal demise after diabetic ketoacidosis (DKA) in pregnancy as high as 25–60% (1,2). However, estimates have generally been based on small sample sizes, with limited investigation of other fetal outcomes or risk factors associated with poor fetal outcomes. We aimed to provide an updated assessment of the incidence and risk factors for fetal demise and other adverse outcomes in women with DKA during pregnancy.
This retrospective cohort study included pregnancies between 1996 and 2015 with at least one DKA event in women with type 1 diabetes at one of three teaching hospitals in Boston. Data were collected through medical record review. Pregnancies were excluded if information on birth status (live or demise) and gestational age at birth or demise were unknown.
Among the 77 DKA events in 64 pregnancies in 62 women included in the study, fetal demise, preterm birth, and neonatal intensive care unit (NICU) admissions occurred in 15.6%, 46.3%, and 59% of pregnancies, respectively. Mothers presented in DKA between 5 and 38 weeks of gestation. Fetal demise occurred at the time of or within 1 week of the DKA event and between 1 and 11 weeks afterward in 60% and 40% of cases, respectively.
Maternal ICU admission (P = 0.024) and higher serum osmolality (P = 0.045) during the DKA event were associated with increased risk of fetal demise (Table 1). Maternal smoking (P = 0.0005) and higher pre-DKA HbA1c levels (P = 0.032) were associated with higher risk of preterm birth. Maternal smoking (P = 0.0077), preeclampsia during pregnancy (P = 0.031), higher anion gap during the DKA event (P = 0.019), and preterm birth (P = 0.0003) were associated with higher risk of NICU admission.
Table 1.
Risk factors for fetal demise in pregnancies complicated by DKA
| Pregnancies with live births | Pregnancies with fetal demise | P value | |
|---|---|---|---|
| Total pregnancies, N | 54 | 10 | |
| DKA events, n | 65 | 12 | |
| Multiple pregnancies, n | 2 | 0 | |
| >1 DKA event, n | 7 (13.0) | 2 (20.0) | 0.6222 |
| Gestational age at DKA event (all events), weeks, mean (SD) | 24.7 (9.2) | 19.5 (11.8) | 0.2825 |
| Gestational age at DKA event, weeks, mean (SD) | 24.7 (9.3) | 21.3 (12.1) | 0.6571 |
| Maternal age, years | 0.2677 | ||
| <20 | 3 (5.6) | 1 (10.0) | |
| 20–35 | 41 (75.9) | 9 (90.0) | |
| >35 | 10 (18.5) | 0 (0) | |
| Race† | 0.4748 | ||
| White | 32 (60.4) | 4 (44.4) | |
| Hispanic | 12 (22.6) | 2 (22.2) | |
| Black | 9 (16.98) | 3 (33.3) | |
| Mother's marital status, single vs. not† | 26 (49.1) | 6 (60.0) | 0.7323 |
| Median income by zip code, USD, mean (SD)*† | 64,924 (21,510) | 54,069 (17,526) | 0.0949 |
| Preexisting diabetes | 51 (94.4) | 10 (100) | 1 |
| Insulin injection† | 1 | ||
| None (new-onset type 1 diabetes) | 4 (7.6) | 0 (0) | |
| Injection | 37 (69.8) | 8 (80.0) | |
| Pump | 12 (22.6) | 2 (20.0) | |
| Fetal sex‡ | 0.4543 | ||
| Unknown (demise before sex known) | 0 (0) | 2 (20.0) | |
| Male | 35 (64.8) | 4 (40.0) | |
| Female | 19 (35.2) | 4 (40.0) | |
| Decade of DKA occurrence | 0.6774 | ||
| 1996–1999 (4 years) | 6 (11.1) | 0 (0) | |
| 2000–2009 (10 years) | 28 (51.9) | 7 (70.0) | |
| 2010–2015 (6 years) | 20 (37.0) | 3 (30.0) | |
| Presence of diabetic gastroenteropathy | 11 (20.4) | 2 (20.0) | 1 |
| ICU admission during DKA hospitalization** | 2 (3.7) | 3 (30.0) | 0.0240 |
| Ever smoked | 12 (22.2) | 4 (40.0) | 0.2517 |
| Chronic hypertension | 8 (14.8) | 0 (0) | 0.3373 |
| Preeclampsia | 12 (22.2) | 0 (0) | 0.1863 |
| Gestational hypertension | 4 (7.4) | 0 (0) | 1 |
| Contributing factors | |||
| Nonadherence | 19 (35.2) | 3 (30.0) | 1 |
| Gastrointestinal symptoms | 9 (16.7) | 1 (10.0) | 1 |
| Beta sympathomimetics | 1 (1.9) | 0 (0) | 1 |
| Pump failure | 4 (7.4) | 2 (20.0) | 0.2337 |
| Infection | 5 (9.3) | 0 (0) | 1 |
| Glucocorticoid use | 1 (1.9) | 0 (0) | 1 |
| Other | 6 (11.1) | 2 (20.0) | 0.5999 |
| Unknown | 13 (24.1) | 2 (20.0) | 1 |
| Gravida, mean (SD) | 2.8 (1.8) | 2.2 (1.5) | 0.2510 |
| Para, mean (SD) | 1.1 (1.4) | 0.8 (1.0) | 0.7287 |
| Maximum anion gap, mEq/L, mean (SD)† | 21.0 (4.7) | 20.8 (3.8) | 0.9520 |
| Maximum BUN, mg/dL, mean (SD)† | 12.4 (4.2) | 12.1 (4.8) | 0.8054 |
| Maximum creatinine, mg/dL, mean (SD)* | 0.74 (0.25) | 0.9 (0.4) | 0.1003 |
| Maximum glucose, mg/dL, mean (SD)*† | 323.3 (118.3) | 431.8 (180.0) | 0.1120 |
| Maximum osmolality, osmol/kg, mean (SD)**† | 295.8 (7.0) | 301.8 (10.1) | 0.0448 |
| Maximum potassium, mmol/L, mean (SD) | 4.4 (0.7) | 4.5 (0.5) | 0.3081 |
| Minimum potassium, mmol/L, mean (SD)*† | 3.5 (0.3) | 3.7 (0.3) | 0.0733 |
| Minimum phosphate, mg/dL, mean (SD)† | 2.4 (0.9) | 2.3 (1.1) | 0.7066 |
| Pre-DKA HbA1c, mean (SD)† | 0.4732 | ||
| % | 8.1 (1.9) | 9.0 (3.1) | |
| mmol/mol | 65.5 (20.3) | 75.0 (10.0) |
Data are n (%) unless otherwise indicated.
Fisher exact test P < 0.20.
Fisher exact test significant with P < 0.05.
Missing: one each maximum blood urea nitrogen (BUN), maximum glucose, maximum osmolality, minimum potassium, pre-DKA HbA1c, median income, insulin injection, and marital status; two each maximum anion gap and race; 13 minimum phosphate.
P value only includes male vs. female, excludes two fetuses with unknown sex due to early gestational age at fetal demise. USD, U.S. dollars.
The risk of fetal demise after DKA during pregnancy has decreased over time but remains substantially higher than the baseline risk (2–3%) in women with type 1 diabetes (3). Risks of preterm birth and NICU admissions were also elevated compared with the general population of pregnant women with diabetes (33% [4] and 47% [5], respectively). Factors associated with increased risk of fetal demise were primarily characteristics of the DKA event severity (e.g., maternal ICU admission and higher serum osmolality), lending support to a direct causal relationship. Factors associated with increased risk of preterm birth and NICU admissions, on the other hand, were more indicative of the mother’s overall health status and health behaviors. This finding suggests that the observed increased risk of preterm birth among women with DKA during pregnancy could be due to the higher prevalence of risk factors in this population.
DKA during pregnancy poses a risk to the fetus both at the time of the event and following. Further research is needed to identify effective methods for prevention, early recognition, and timely treatment of DKA in pregnancy to mitigate risk of fetal demise and other adverse fetal outcomes.
Article Information
Funding. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number T32HD057780.
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. F.J.R.M., E.W.S., M.S., F.M.B., and A.T. contributed to the study concept and design. M.M., A.C., F.M.B., and A.T. contributed to the acquisition of data. F.J.R.M., E.W.S., M.S., and A.T. contributed to the analysis and interpretation of data. F.J.R.M. drafted the manuscript. F.J.R.M. and M.S. contributed to the statistical analysis. A.T. supervised the study. All authors contributed to the critical revision of the manuscript for important intellectual content. A.T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017.
References
- 1.Shimizu I, Makino H, Imagawa A, et al. Clinical and immunogenetic characteristics of fulminant type 1 diabetes associated with pregnancy. J Clin Endocrinol Metab 2006;91:471–476 [DOI] [PubMed] [Google Scholar]
- 2.Lufkin EG, Nelson RL, Hill LM, Melton LJ 3rd, O’Fallon WM, Evans AT 3rd. An analysis of diabetic pregnancies at Mayo Clinic, 1950-79. Diabetes Care 1984;7:539–547 [DOI] [PubMed] [Google Scholar]
- 3.Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A. Maternal and fetal risk factors for stillbirth: population based study. BMJ 2013;346:f108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75–84 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cordero L, Treuer SH, Landon MB, Gabbe SG. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med 1998;152:249–254 [DOI] [PubMed] [Google Scholar]