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Obstetrics & Gynecology 2002;99:537-541
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Clinical Outcomes of Pregnancy in Women With Type 1 Diabetes

Roy Taylor, MD, Choy Lee, MD, D. Kyne-Grzebalski, RGN, S. M. Marshall, MD and J. M. Davison, MD

From the Departments of Medicine and Obstetrics, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.

Address reprint requests to: Roy Taylor, MD, Department of Medicine, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom; E-mail: roy.taylor{at}ncl.ac.uk.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To evaluate predictors of neonatal hypoglycemia and macrosomia in 107 consecutive pregnancies in type 1 diabetic women.

METHODS: We conducted a case record analysis of singleton type 1 diabetic pregnancies between January 1994 and January 1999 following institution of standardized management.

RESULTS: The duration of diabetes in the women was 12.9 ± 6.8 years, and 44 were primigravidas. The mean HbA1c throughout pregnancy was 7.2 ± 0.8%. There was no relationship between neonatal blood glucose (checked before the second feed) and HbA1c at any point in pregnancy or mean pregnancy HbA1c (R = 0.20, P > .1). However, there was a negative correlation between neonatal blood glucose and maternal blood glucose during labor (R = -0.33, P < .001). When maternal blood glucose during labor was greater than 8 mM (144 mg/dL), neonatal blood glucose was usually less than 2.5 mM (mean 1.7 ± 0.4 mM or 31 mg/dL). There was no relationship between mean HbA1c and birth weight (R = 0.02, P > .1) or between maximum insulin dose and birth weight (R = 0.09, P > .1). Fetal abdominal circumference measured by ultrasound at 34 weeks correlated strongly with birth weight (R = 0.72, P < .001).

CONCLUSION: Neonatal hypoglycemia correlates with maternal hyperglycemia in labor, not with HbA1c during pregnancy. Macrosomia does not correlate with HbA1c during pregnancy.

Although the principles of good antenatal diabetes care in women with type 1 diabetes have been established for some time, consistent application of these principles to all patients is not straightforward. Thus, it is critical to monitor the care delivered and overall outcomes in relation to blood glucose control actually achieved. Such data can allow examination of currently accepted beliefs.

Previous audits of outcome for all type 1 diabetic women attending a large obstetric diabetes clinic over two consecutive 5-year periods resulted in several changes in local practice, particularly in respect of blood glucose control during labor.1,2 A modest relaxation of the targets for control during labor (from 3–6 mmol/L to 4–8 mmol/L) was introduced to minimize maternal hypoglycemia during labor. Our data on neonatal hypoglycemia indicated that the change in target range would not increase risk of this problem. Previous recommendations have not been based upon clinical outcome data.3–5 Similarly, it is widely believed that macrosomia reflects the degree of blood glucose control during pregnancy, although there is some evidence to the contrary.6,7

The present reports focuses upon observations made on 107 consecutive singleton pregnancies in type 1 diabetic women between 1994 and 1999 to define the relationships between maternal blood glucose control and neonatal hypoglycemia and macrosomia.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Information was obtained from records on 107 type 1 diabetic women who received antenatal care and subsequently delivered singleton pregnancies at the Royal Victoria Infirmary, Newcastle upon Tyne, between January 1, 1994 and January 31, 1999. Two sets of twins were born to type 1 diabetic mothers, and these were not included in the analysis to avoid violation of statistical requirements. All women were managed by a single team of obstetricians and diabetologists in a Joint Obstetric Medical Clinic. All women were seen monthly until 28 weeks’ gestation, every 2 weeks between 28 and 36 weeks’ gestation, and weekly thereafter until delivery. More frequent visits were arranged if blood glucose control was not optimal, and women were telephoned frequently by one diabetes specialist nurse.

The HbA1c and total insulin requirements were checked at each visit. All women had an ultrasound scan for fetal anomalies at 19 weeks’ gestation. The estimated due date was derived from this scan. This was followed by serial growth scans from 28 weeks’ gestation and every visit thereafter. Ultrasound growth parameters included abdominal circumference and an estimated fetal weight. Our policy is to electively deliver all type 1 diabetic women between 38 and 39 weeks’ gestation. Maternal blood glucose during labor was controlled by a standardized combined glucose, insulin, and potassium infusion as previously described.2 Neonates were fed as soon as practical after delivery. The presecond feed blood glucose and details of symptomatic neonatal hypoglycemia were collated. Neonatal whole blood glucose was measured using a Yellowsprings glucose analyzer (Yellow Springs, OH). The HbA1c was measured monthly by Biorad (Hemel Hempstead, UK) high performance liquid chromatography (coefficient of variation 1.3% at mean HbA1c of 10.0%, and 1.9% at mean HbA1c of 5.8%). The HbA1c assay was standardized upon that used in the diabetes complications and control trial central laboratory at the University of Minnesota, with an upper limit of normal of 6.1%.8

Data are given as mean ± standard deviation. Differences between means were tested by Student t test, and correlations were tested by Pearson correlation coefficient using the Minitab statistical package (Minitab Inc., State College, PA).


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean age of the group was 28.6 ± 5.2 years (range 17–40), and mean duration of type 1 diabetes was 12.9 ± 6.8 years (range 1–26). Diabetic retinopathy was present in 23 women and prepregnancy proteinuria in nine women. A total of 106 women were white. The number of primigravidas was 44 (41.1%), and the number of multigravidas was 63 (58.9%). The mean gestation at first visit was 71.2 ± 25.3 days (10.2 ± 3.6 weeks). The mean gestation at delivery was 258 ± 13 days with 32 (29.9%) deliveries before 259 days’ gestation. Labor was induced in 57 women, and the vaginal delivery rate in this group was 68.5% compared with 55.5% after spontaneous labor. In the induced group, 23 achieved spontaneous vaginal delivery, 16 required nonrotational forceps, and 18 required cesarean deliveries. By comparison, in the spontaneous labor group (n = 27), five had spontaneous vaginal deliveries, ten required nonrotational forceps, and 12 required cesarean deliveries. Overall, the cesarean delivery rate was 49.5%; 19 were elective and 34 emergency.

The mean HbA1c at first visit was 8.0 ± 1.4% and mean HbA1c throughout pregnancy was 7.2 ± 0.8%. Prepregnancy daily insulin requirement was 52.3 ± 20.5 units and during pregnancy averaged 74.1 ± 33.0 units. Insulin requirements remained constant until around 20 weeks (59 ± 25 units per day), when there was a steady increase until 30 weeks’ gestation (87 ± 42 units per day).

The insulin regimen used was that which was most suited to the individual woman to achieve best possible control. Short-acting insulin before each meal together with intermediate-acting insulin before bed was used by 65 women. The remaining women took short- and intermediate-acting insulin before breakfast together with the same before evening meal (n = 18) or short-acting before dinner and intermediate-acting before bed (n = 24).

The mean blood glucose in labor was 6.3 ± 2.2 mM and was maintained steady up to delivery (Figure 1Go). Blood glucose levels were observed to be less than 3mM on 19 occasions involving 13 women and less than 2.5 mM on six occasions involving five women.



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  		Figure 1. Blood glucose control during labor displayed as mean ± standard deviation (with range indicated by dots) zeroed on time of delivery. The shaded area represents the target range for blood glucose in labor.

Taylor. Pregnancy in Type 1 Diabetes. Obstet Gynecol 2002.

 
Blood glucose was less than 2.5 mM in 50 neonates and was less than 2.0 mM in 18 neonates. Neonatal blood glucose was measured before the second feed in all but 18 neonates in whom earlier measurement was indicated by symptomatic hypoglycemia. The relationship between mean maternal blood glucose in labor and neonatal blood glucose is shown in Figure 2Go. There was a significant correlation between neonatal blood glucose and mean maternal blood glucose in labor (R = -0.33, P < .001). This was also so for neonatal blood glucose and maternal blood glucose in the hour before delivery (R = -0.29, P < .01). When maternal blood glucose was within the target range for control during labor (4.0–8.0 mM), there was no relationship with neonatal blood glucose, whereas if maternal blood glucose was greater than 8 mM (144 mg/dL), neonatal blood glucose was less than 2.5 mM (mean 1.7 ± 0.4 mM, 31 mg/dL) in all but two women (Figure 2Go). If maternal blood glucose was greater than 9 mM (162 mg/dL), neonatal blood glucose was always less than 2.5 mM (45 mg/dL).



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  		Figure 2. Relationship between neonatal blood glucose before the second feed and mean maternal blood glucose in labor. The dotted lines show the upper limit of the target range for maternal control during labor (vertical line) and 2.5 mmol/L for neonatal blood glucose (R = -0.25, P < .005).

Taylor. Pregnancy in Type 1 Diabetes. Obstet Gynecol 2002.

 
There was no correlation between neonatal blood glucose and HbA1c throughout pregnancy (R = 0.2, P > .1), first trimester (R = 0.18, P > .1), second trimester (R = 0.15, P > .1), or third trimester (R = 0.18, P > .05). Mean HbA1c was identical in mothers who had hypoglycemic neonates compared with the others (6.6 ± 1.2% for both).

Figure 3Go shows the increase in ultrasound-estimated abdominal circumference from 28 weeks to term. At 28 weeks, mean abdominal circumference in the diabetic group was 248 ± 15 mm, significantly different from a normal comparable group reported by Altman and Chitty9 (239 ± 13, P < .01). By 34 weeks, the difference had increased further, attaining the 90th centile for normals (Figure 3Go). The close correlation between the abdominal circumference measured by ultrasound at 34 weeks’ gestation and birth weight was significant at 34 weeks’ (R = 0.72, P < .001), 36 weeks’ (R = 0.71, P < .001), and 37 weeks’ (R = 0.76, P < .001) gestation, respectively. The relationship was much weaker at 28 weeks’ gestation (R = 0.31), although still statistically significant (P < .05).



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  		Figure 3. Rate of increase in fetal abdominal circumference measured by ultrasound. Data are shown as mean ± standard deviation and the mean (dashed line) and 5th and 95th centiles (dotted line) for infants of nondiabetic mothers.

Taylor. Pregnancy in Type 1 Diabetes. Obstet Gynecol 2002.

 
At term, 39 neonates (36.4%) were heavier than the 90th centile for gestational age. There was no relationship between the mean maternal HbA1c and birth weight (R = 0.02, P > .1) (Figure 4Go), and this remained so when mean HbA1c for each trimester was considered separately (R = 0.02, 0.03, and 0.17, respectively). There was also no significant correlation between estimated fetal weight and mean maternal HbA1c at 28 weeks’ (R = 0.01), at 34 weeks’ (R = 0.15), and at 36 weeks’ (R = 0.13) gestation. Maximum insulin requirement was not related to birth weight (R = 0.09, P > .1).



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  		Figure 4. Lack of relationship between birth weight and mean pregnancy HbA1c (R = 0.06, P = .57).

Taylor. Pregnancy in Type 1 Diabetes. Obstet Gynecol 2002.

 
Blood pressure at first visit was 116 ± 15/70 ± 9 mmHg (systolic range 90–170, diastolic range 50–98). At 12, 28, and 36 weeks, creatinine clearance was 96 ± 27, 95 ± 28, and 92 ± 32 mL per minute, and 24-hour protein excretion was 173 ± 123, 482 ± 126, and 872 ± 177 mg per 24 hours. Hemoglobin concentrations at the same time points were 12.7 ± 1.0, 11.4 ± 1.2, and 11.1 ± 1.0 g/dL, respectively.

Eight women had babies with congenital anomalies (four cardiac, one caudal regression, one pulmonary, one ophthalmic, and one cranial) giving an anomaly rate of 7.2%. The HbA1c averaged 8.4 ± 0.8% at first visit in this group of women, slightly but not significantly higher than the rest of the group (7.9 ± 1.4%). Two unexplained antenatal stillbirths occurred (one at 37 weeks’ and the other at 29 weeks’ gestation). Two neonatal deaths occurred in babies born at 39 weeks (one following an abruption during labor and the other was after surgery for a congenital heart anomaly). Hence, 103 out of 107 fetuses survived the neonatal period.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The most striking finding of this analysis was that maternal blood glucose control in pregnancy had no bearing on the incidence of neonatal hypoglycemia, but maternal blood glucose during labor influenced neonatal blood glucose if over 8 mmol/L. Although previous studies have shown that marked hyperglycemia during labor was associated with neonatal hypoglycemia,10 there are few data reflecting modern management of diabetes during labor. A second important finding is the lack of relationship between macrosomia and degree of blood glucose control achieved as assessed by HbA1c.

The target range for blood glucose control during labor has been established by collation of outcome data from our unit over the 10 years before the present study period.1,2 Previous recommendations were not based upon outcome data, including the St. Vincent Task Force target of 4.0–6.0 mmol/L,3 and textbook recommendations of 3.3–6.1 mmol/L4 and 4–6 mmol/L.5 In the present study, a target range of 4–8 mM was used. The previously described simple regimen for control of blood glucose during labor1,2 was applied by the midwives. Use of a system that avoids the need for frequent changes of infusion rate and for two separate intravenous lines is of great practical benefit. It is clear from Figure 2Go that maternal blood glucose levels over 8 mM (144 mg/dL) are predictive of low neonatal blood glucose levels but, within the target range neonatal blood glucose, can be either normal or low. This emphasizes the lack of a complete explanation for the occurrence of neonatal hypoglycemia in some infants. The normal range for neonatal blood glucose is low, and 5% of normal neonates have levels of less than 1.7 mmol/L within the first few hours of life.11,12 The general phenomenon of severe hypoglycemia in infants of diabetic mothers may reflect a simple shift in the blood glucose distribution as a whole in our population, perhaps as a consequence of islet cell hyperplasia. The maternal blood glucose threshold in pregnancy for triggering this is likely to be close to the normal range. Additionally, intermittent hyperglycemia could bring about islet cell hyperplasia, and this would not be reflected by HbA1c.13

The rate of macrosomia is similar to that reported in other studies of women with type 1 diabetes.14,15 Discrepant findings have been reported with respect to blood glucose control in early pregnancy and macrosomia. It has been reported that in subgroups of women with very tight blood glucose control from before pregnancy through parturition, rates of macrosomia remain high and unchanged in type 1 diabetes.6 In contrast, Rey et al reported macrosomia to be associated with higher HbA1c levels in first and third trimesters.16 A further study observed a greater HbA1c in mothers having babies of birth weight more than one standard deviation over the mean, a difference that was maximal in the first trimester.17 We observed no tendency for HbA1c in early pregnancy to reflect more closely the risk of macrosomia compared with HbA1c in later pregnancy. In early pregnancy, those women who later delivered babies greater than one standard deviation above the mean birth weight (n = 16) had a mean HbA1c of 8.3 ± 1.3% compared with 7.9 ± 1.4% for the rest of the group (n = 93, P = .27). The magnitude of the difference was similar throughout pregnancy, although multiple testing produced apparently significant P values at 24 and 30 weeks (P < .05 for both). Although this requires further study, the frequency of intermittent high blood glucose levels during diabetic pregnancy with excellent HbA1c levels may provide a simple explanation.13 The HbA1c levels reflect an average measure of control, which may not reflect relatively frequent, short duration high levels of maternal plasma glucose sufficient to cause fetal hyperglycemia and hyperinsulinemia in the fetus where insulin acts as a growth factor via insulin-like growth factor 1 receptors.18 In view of the episodic, spiking pattern of growth hormone secretion required to produce optimal stimulation of growth, it is likely that the intermittent hyperglycemia and resultant intermittent fetal hyperinsulinemia will have effects on fetal growth out of proportion to the duration of elevation of maternal blood glucose.

Delivery before 37 weeks occurred in 29.9% of infants, an observation close to the 38% observed by Sibai et al.19 The overall cesarean delivery rate of 49.5% reported here is very similar to the 51% observed in type 1 diabetic women by Remsberg et al from a series of 42,071 births in South Carolina.20 Of the ten cases identified to have fetal abdominal circumference greater than one standard deviation above the mean of the diabetic population at 34 weeks’ gestation, four had elective cesarean deliveries, four required emergency cesarean deliveries, one had a successful spontaneous vaginal delivery, and there was one unexplained intra-uterine death. Shoulder dystocia occurred during the latter delivery.

In summary, this analysis of the effects of our management policy in type 1 diabetes has identified safe limits for maternal blood glucose control during labor with respect to avoiding both maternal and neonatal hypoglycemia. If maternal blood glucose is over 8 mM (144 mg/dL), then neonatal blood glucose levels will be low. The level of control of blood glucose actually achieved during labor requires ongoing monitoring to ensure that the benefits of the current guidelines are realized.


   Footnotes
 
The Northern Regional Maternity Survey Office kindly provided corroborative data on congenital abnormalities.

PII S0029-7844(01)01790-2

Received September 17, 2001. Received in revised form November 26, 2001. Accepted December 11, 2001.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Njenga E, Lind T, Taylor R. Five year audit of blood glucose control during labour in insulin dependent diabetes. Diabet Med 1992;9:567–70.[Medline]

2. Carron-Brown S, Kyne-Grzebalski D, Mwangi B, Taylor R. Effect of management policy upon 120 type 1 diabetic pregnancies: Policy decisions in practice. Diabet Med 1999;16:573–8.[Medline]

3. British Diabetic Association. Pregnancy and neonatal care subgroup to the St. Vincent Joint Taskforce for diabetes. London: British Diabetic Association; 1994.

4. Reece EA, Coustan DR, eds. Diabetes mellitus in pregnancy: Principles and practice. New York: Churchill Livingstone; 1988:286.

5. Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Edinburgh: Churchill Livingstone; 1984:96–7.

6. Temple RC, Aldridge VJ, Heyburn PJ, Sampson MJ, Greenwood RH, Durkan M, et al. Fetal macrosomia is not associated with poor maternal glycaemic control in early pregnancy. Diabet Med 1998;15:S10.

7. Small M, Cameron A, Lunan CB, MacCuish AC. Macrosomia in pregnancy complicated by insulin-dependent diabetes mellitus. Diabet Care 1987;10:594–9.[Abstract]

8. Gibb I, Parnham AJ, Lord C, Steffes MW, Bucksa J, Marshall S. Standardization of glycated haemoglobin assays throughout the Northern Region of England: A pilot study. Diabet Med 1997;14:584–8.[Medline]

9. Altman DG, Chitty LS. New charts for ultrasound dating of pregnancy. Ultrasound Obstet Gynecol 1997;10: 174–91.[Medline]

10. Andersen O, Hertel J, Schmilker L, Kuhl C. Influence of maternal plasma glucose on the risk of hypoglycemia in infants of insulin dependent diabetic mothers. Acta Paed Scand 1985;74:268–73.[Medline]

11. Cornblath M, Reisner SH. Blood glucose in the neonate and its clinical significance. N Engl J Med 1965;273: 378–81.

12. Ward Platt MP, Hawdon JM. Hypoglycaemia in the neonate. In: Gregory JW, Aynsley-Green A, eds. Hypoglycaemia. London: Bailiere Tindall; 1993:669–82.

13. Kyne-Grzebalski D, Wood L, Marshall SM, Taylor R. Episodic hyperglycemia in well controlled type 1 diabetic women in pregnancy: A potential cause of macrosomia. Diabet Med 1999;16:702–4.[Medline]

14. Sibai BM, Caritis S, Hauth J, Lindheimer M, VanDorsten JP, MacPherson C, et al. Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. Am J Obstet Gynecol 2000;182: 364–9.[Medline]

15. Russel G, Farmer G, Lloyd DJ, Pearson DWM, Ross IS, Stowers JM. Macrosomy despite well-controlled diabetic pregnancy. Lancet 1994;343:283–5.[Medline]

16. Rey E, Attie C, Bonin A. The incidence of first trimester diabetes control on the incidence of macrosomia. Am J Obstet Gynecol 1999;181:202–6.[Medline]

17. Gold AE, Reilly R, Little J, Walker JD. The effect of glycemic control in the pre-conception period and early pregnancy on birth weight in women with IDDM. Diabet Care 1998;21:535–8.[Abstract]

18. Susa JB, Swartz R. Effects of hyperinsulinemia in the primate fetus. Diabetes 1985;34:S36–S41.

19. Sibai BM, Caritis SN, Hauth JC, MacPherson C, VanDorsten JP, Klebanoff M, et al. Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies. Am J Obstet Gynecol 2000;183:1520–4.[Medline]

20. Remsberg KE, McKeown RE, McFarland KF, Irwin LS. Diabetes in pregnancy and cesarian section. Diabet Care 1999;22:1561–7.[Abstract/Free Full Text]




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