Volume 197, Issue 4 , Pages 404.e1-404.e5, October 2007
Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions
Article Outline
Objective
We aimed to compare glycemic control and pregnancy outcome in type I diabetic patients treated by 2 modes of treatment: multiple daily injections of insulin (MDI) and continuous subcutaneous insulin infusions (CSII).
Study Design
In a retrospective, matched-control study, patients treated by MDI were compared with patients treated by CSII in a ratio of 2:1. Level of glycemic control and pregnancy outcome was compared.
Results
Overall, 90 women were evaluated; of them 30 were treated by CSII and 60 by MDI. No between-group differences were found in maternal age, nulliparity rate, severity and duration of diabetes, prepregnancy body mass index, and weight gain during pregnancy. The rate of diabetic ketoacidosis (DKA) and neonatal hypoglycemia were significantly higher in the CSII group (13% vs 2%, P = .04) and (35% vs 13%, P = .01), respectively. No significant differences were found in pregnancy outcome measures.
Conclusion
In type 1 diabetes, glycemic control and pregnancy outcome are compromised, regardless of treatment modality. CSII may be associated with higher rate of both maternal DKA and neonatal hypoglycemic events.
Key words: glycemic control, insulin pump, pregnancy, type 1 diabetes
Achievement of the desired level of glycemic control at conception and during pregnancy is essential for attaining optimal pregnancy outcome in patients with type 1 diabetes. Although major progress took place in recent years in the treatment of women with type 1 diabetes during pregnancy, in most national audits, pregnancy outcome is associated with an increased risk of congenital malformations, perinatal mortality, obstetric complications, and neonatal morbidity.1, 2, 3, 4, 5, 6, 7
Recently, subcutaneous insulin infusion (CSII) or insulin pump therapy has been used as an alternative to multiple-dose insulin injection (MDI). It is recognized that both CSII and MDI offer the advantage of frequent dose adjustment, which should lead to optimum blood sugar level attainment. However, insufficient data exist concerning the use of these different methods of insulin administration during pregnancy8, 9, 10, 11, 12, 13 in terms of normalizing blood sugar level, reducing hypo/hyperglycemia, and pregnancy outcome. Thus, we aimed to compare glycemic control and pregnancy outcome in women with type 1 diabetes.
Materials and Methods
Subjects
We conducted a retrospective, matched controlled study of 90 patients with type 1 diabetes who were followed up and treated during pregnancy between 2003 and 2006. For each patient treated with CSII (n = 30), 2 patients treated by MDI were matched (n = 60). Matching criteria included prepregnancy maternal body mass index (BMI; weight in kilograms divided by the square of the height in meters), duration and severity of type 1 diabetes (the presence of microvascular complications), preconception or early pregnancy (prior to 6 weeks of gestation) hemoglobin (Hgb) A1c levels, gravidity, and parity.
For all patients, diagnosis of type 1 diabetes was established at least 1 year prior to the studied pregnancy and allocation for treatment modality (MDI or CSII) was based on patient preference. All women treated with CSII initiated this mode of treatment prior to the studied pregnancy. Women who were transferred from MDI to CSII or vice versa during pregnancy as well as all multiple pregnancies were excluded. The study was approved by the local institutional review board.
Management approach and level of glycemic control assessment
Our department offers patients with diabetes an intensive prepregnancy treatment protocol for a minimum of 3 months, which includes folic acid supplementation (5 mg daily), instruction in self-administration of multiple insulin injections (4-6 daily), or use of the continuous subcutaneous insulin pump. In both treated groups, both recombinant insulin and analogs were used as needed. All women were instructed in the measurement of blood glucose with a memory reflectance meter to ascertain reliable glucose data 7 times daily: after an overnight fast, before meals, 2 hours after meals, and at bedtime. Hgb A1c levels are taken prior to pregnancy or during the first trimester and during the third trimester prior to delivery.
Subjects with proliferative retinopathy are referred for laser treatment when necessary, and those with proteinuria are prescribed angiotensin converting enzyme (ACE) inhibitors. ACE inhibitor treatment is discontinued immediately after a missed period and a positive pregnancy test and was not used during pregnancy. Preexisting hypertension is defined as a systolic blood pressure greater than 140 and/or diastolic blood pressure greater than 90 mm Hg or the need for antihypertensive drugs before pregnancy. Proteinuria is defined quantitatively as absent (less than 20 mg per 24h; grade 0), microalbuminuria (20-300 mg per 24h; grade 1), low (300-3000 mg per 24h; grade 2), and high (greater than 3000 mg per 24h; grade 3)14; nephropathy as the presence of proteinuria or serum creatinine of greater than 1.5 mg/dL; and progression of nephropathy as a significant increase in urinary albumin excretion or deterioration in renal function.
At the initial visit, a detailed history was obtained from all patients. This included a demographic profile, social history, and summary of past obstetrical and medical data. Subjects were counseled by nutritionists about a diet regimen of 3 meals and 4 snacks daily. Gestational age was determined on the basis of the menstrual history and/or first-trimester ultrasound when available.
All patients were treated to attain the same metabolic goals: overall mean blood glucose levels defined as mean blood glucose from diagnosis to delivery of 105 mg/dL or less, fasting blood glucose levels between 60 and 90 mg/dL, and 2-hour postprandial blood glucose levels of 120 mg/dL or less. Patients with mean blood glucose of 105 mg/dL or less were considered well controlled and those with mean blood glucose greater than 105 mg/dL were considered poorly controlled. Women with a prepregnancy BMI of 30 kg/m2 or greater were considered obese. Total pregnancy weight gain was based on the prepregnancy weight and the last weight measured within a week before delivery.
Pregnancy outcome and adverse events
All patients were evaluated on a weekly basis. In each prenatal visit, level of glycemic control was assessed and insulin therapy was modified when needed. Moreover, blood pressure, maternal weight, and the presence of proteinuria were assessed. Fetal testing included non–stress testing starting at 32 weeks of gestation, fetal movement, and velocity (Doppler) studies; fetal growth assessments; and biophysical profile when medically indicated.
Preeclampsia was defined as systolic blood pressure 140 mm Hg or greater and diastolic blood pressure 90 mm Hg or greater and proteinuria on at least 2 occasions, at least 6 hours apart after the 20th week of gestation. Gestational hypertension was defined as hypertension in the absence of proteinuria.15, 16 Preterm labor was defined as delivery prior to 37 weeks of pregnancy.
Hypoglycemic events were defined as: (1) symptomatic hypoglycemic episode when blood glucose was less than 40 mg/dL combined with symptoms, such as confusion, poor coordination, double vision, headache, or combativeness and (2) significant hypoglycemic episode when blood glucose was less than 40 mg/dL in conjunction with an inability of patients to treat their own symptoms.
Infants were considered large for gestational age (LGA) when birthweight was greater than the 90th percentile and small for gestational age (SGA) when birthweight was less than the 10th percentile based on growth standards developed for our population.17 Macrosomia was defined as delivery weight greater than 4000 g. Neonatal respiratory outcomes included the presence or absence of hyaline membrane disease, transient tachypnea (respiratory distress in infants born near term that lasts for about 3 days), and respiratory support. Metabolic complications were defined by the presence of 1 or more of the following: neonatal prefed hypoglycemia (less than 40 mg/dL), polycythemia (hematocrit greater than 60%), hyperbilirubinemia (greater than 12 mg/dL), or hypocalcemia (less than 8 mg/dL).
Statistical analysis
Data analysis was performed with SPSS software (version 13.0, SPSS Inc., Chicago, IL). A Student t test was used to compare continuous variables between the groups, and a χ2 test was used for categorical variables. A P value less than .05 was considered significant.
Results
Selected patient characteristics are presented in Table 1. Both studied groups were characterized by similar maternal age, nulliparity rate, severity and duration of diabetes, prepregnancy BMI, Hgb A1c level, and weight gain during pregnancy (Table 1).
TABLE 1. Clinical characteristics of type 1 diabetic women, by treatment modality
| CSII (n = 30) | MDI (n = 60) | P value | |
|---|---|---|---|
| Maternal age (y) | 29.6 ±5.0 | 29.3±4.9 | .62 |
| Duration of diabetes (y) | 12.3±5.2 | 13.4±4.7 | .32 |
| Prepregnancy BMI (kg/m2) | 24.7±4.1 | 24±4.2 | .45 |
| Obesity (%) | 7(23%) | 13(22%) | .32 |
| Prepregnancy consultation (%) | 16(53%) | 34(56%) | .41 |
| Gravidity | 1.4±0.8 | 1.7±1.0 | .22 |
| Nulliparity rate (%) | 43% | 45% | .45 |
| Weight gain (kg) | 14.0±5.2 | 11.7±5.1 | .11 |
| Hgb A1c (%) | 6.9±0.6 | 7.1±1.7 | .28 |
| Number of prepregnancy DKA episodes (%)⁎ | 2(6.6%) | 3(5.0%) | .31 |
| Prepregnancy retinopathy (%) | 7(22%) | 12(20%) | .48 |
| Prepregnancy proteinuria (%) | 1(3.2%) | — | .34 |
⁎DKA event in the year prior to the current pregnancy. |
Gestational age at delivery, rate of preterm delivery, mean birthweight, and cesarean delivery rate were similar in both groups (Table 2). No differences were found in fetal metabolic complications, but the rate of neonatal hypoglycemia was found to be significantly higher in the CSII group (36% vs 13%, P = .016) (Table 2).
TABLE 2. A comparison in fetal outcome for women with type 1 diabetes treated by CSII or MDI
| CSII (n = 30) | MDI (n = 60) | P value | |
|---|---|---|---|
| Gestational age at delivery (wks) | 36.2±5.1 | 36.1±6.5 | .40 |
| Preterm delivery (less than 37 wks) | 9(30%) | 21(35%) | .33 |
| Birth weight (kg) | 3454±633 | 3488±662 | .48 |
| Macrosomia | 8(26%) | 17(28%) | .55 |
| Cesarean delivery rate (%) | 19(63%) | 36(60%) | .88 |
| LGA (%) | 16(53%) | 24(40%) | .43 |
| SGA (%) | 0 | 1(1.6%) | — |
| Fetal metabolic complications | |||
| Hypocalcemia (%) | 0 | 2(3.3%) | .43 |
| Hyperbilirubinemia (%) | 8(26.6%) | 9(15%) | .11 |
| Polycythemia (%) | 0 | 3(5%) | .26 |
| Hypoglycemia (%) | 11(36%) | 8(13%) | .016 |
| Convulsions (%) | 0 | 2(3.3%) | .43 |
| Respiratory complications (%) | 4(13%) | 7(11%) | .19 |
No differences were found in the rate and severity level of maternal hypoglycemic events, hypertensive complications, or level of glycemic control as reflected by mean blood glucose and Hgb A1c taken prior to delivery (Table 3). Type 1 patients treated with CSII had a significantly higher rate of diabetic ketoacidosis episodes (13% vs 1.6%, P = .04) (Table 3).
TABLE 3. A comparison in maternal outcome for women with type 1 diabetes treated by CSII or MDI
| CSII (n = 30) | MDI (n = 60) | P value | |
|---|---|---|---|
| Maternal hypoglycemia | |||
| Overall hypoglycemic events (%) | 18(60%) | 37(62%) | .51 |
| Symptomatic hypoglycemic episode | 13/18(72%) | 28/37(75%) | — |
| Severe hypoglycemic episode | 5/18(28%) | 9/28(25%) | — |
| Deterioration in retinopathy (%) | 4(13%) | 9(15%) | .55 |
| Deterioration in nephropathy (%) | 7(23%) | 7(12%) | .14 |
| Hypertensive complications (PET and gestational HTN) | 6(25%) | 13(22%) | .17 |
| Number of diabetic ketoacidosis episodes (%) | 4(13%) | 1(1.6%) | .044 |
| Third-trimester Hgb A1c (%) | 6.2±0.4 | 6.3±0.8 | .36 |
| Mean blood glucose (mg/dL) | 123±23 | 128±31 | .17 |
| Well controlled | 52% | 53% | .55 |
Comment
Pregnancy in women with type 1 diabetes mellitus is associated with an increased risk of congenital malformations, perinatal mortality, obstetric complications, and neonatal morbidity.1, 2, 3, 4, 5, 6, 7 Almost 17 years ago, the St. Vincent’s declaration was established, which aimed to approximate pregnancy outcome of women with type 1 diabetes to that of the nondiabetic population, a goal fated to be achieved in 5 years.18 Nevertheless, emerging and growing data imply, though, more than 17 years afterward, that poor pregnancy outcome is obtained among women with type 1 diabetes.3, 4, 5, 6, 7, 19
The goal of management in pregnancy complicated by diabetes is to maintain blood glucose as near to normal as possible. Intensive therapy involves using memory-based self-monitoring blood glucose, multiple injections of insulin or CSII, diet, and an interdisciplinary team effort.
Regardless of the treatment strategy, the purpose of intensified therapy is to achieve the targeted level of glycemic control that diminishes the rate of hypoglycemia and ketosis and maximizes perinatal outcome. Although there is ample evidence associating glycemic control and the occurrence of maternal-fetal complications, association does not prove cause and effect. It does provide the rationale for glucose control, however.
It is recognized that both CSII and MDI offer the advantage of frequent insulin dose adjustment, which should lead to optimum blood sugar level attainment. It is less clear, however, because of the lack of any systematic metaanalysis or randomized studies during pregnancy, which method achieves the best outcome in terms of normalizing blood sugar level and reducing hypo/hyperglycemia to prevent associated complications for both mother and child.
Our study aimed to compare pregnancy outcome and level of glycemic control in patients with type 1 diabetes treated by CSII or MDI. Our main findings included the following: (1) glycemic control is compromised, regardless of treatment modality; (2) maternal and fetal outcomes of pregnant women with type 1 diabetes treated with MDI therapy are compared with those of women treated with CSII; (3) the rate of maternal hypoglycemia events (mild and severe) is similar with MDI and CSII therapy; and (4) CSII may be associated with a higher rate of both maternal diabetic ketoacidosis and neonatal hypoglycemic events.
Suboptimal pregnancy outcome in patients with type 1 diabetes is usually elucidated by the combination of both the low rate of preconception care and the low proportion of patients achieving the desired level of glycemic control. In our cohort, only half of the pregnancies were planned, and only 50% of the women underwent prepregnancy medical consultation. Moreover, approximately half of the women (the same rate as in CSII or MDI therapy) achieved the desired level of glycemic control. Although in both treated groups Hgb A1c levels decreased during pregnancy, the mean blood glucose levels were higher than the levels expected for both groups (Table 3).
These findings may explain the high rate of LGA and macrosomia, fetal metabolic complications, and high cesarean section rate found in our study (Table 2). We speculate that achievement of desired level of glycemic control by higher proportion of our patients (in both treatment modalities) would have been associated with enhanced pregnancy outcome and especially the lower rate of both LGA and macrosomia. The increased rate of neonatal hypoglycemia in the CSII-treated group may be explained by transient maternal hyperglycemia during delivery.
Our findings are in agreement with other studies that found similar pregnancy outcome and the level of glycemic control in both MDI- and CSII-treated patients12, 13, 20; however, other studies have shown that CSII is superior to conventional therapy.9, 21, 22, 23, 24 Notably, these studies were limited by different definitions for pregestational diabetes mellitus, and only a few evaluated the level of glycemic control or firmly defined pregnancy outcome, and the studies usually assessed only 1 aspect of pregnancy outcome (the rate of congenital anomalies). Nevertheless, a recent study has noted that women who initiate insulin pump therapy during pregnancy are highly likely to continue with the pump after they deliver. Moreover, they maintain better glucose control than do patients remaining on multiple insulin injections.12
Maternal hypoglycemia is a common finding in pregnancies complicated by type 1 diabetes. Clinically significant hypoglycemia requiring assistance from another person was reported in approximately 40-70% of pregnant patients with type 1 diabetes.25, 26 With the advantages of CSII in decreasing hypoglycemia and improving glycemic variability, it is logical to assume that CSII would be beneficial for pregnant women with diabetes, especially during the first trimester. In our study, most hypoglycemic events although symptomatic, were mild, and we did not find any difference in the rate of overall maternal hypoglycemic events both symptomatic and severe between CSII- and MDI-treated patients.
Diabetic ketoacidosis has been recognized as a potential complication of insulin pump failure during pregnancy.12, 27 In our study, 4 patients in the CSII group did require hospitalization for mild ketoacidosis (all because of mechanical pump failure), but neither episode adversely affected pregnancy outcome. Thus, the overall risks for ketoacidosis associated with CSII (although increased in comparison with MDI therapy) during pregnancy appear to be small.
Our results represent a single-center experience, in which all patients were treated by the same diabetic protocol and by the same care providers. However, it is a retrospective analysis with a limited number of patients who were not randomly assigned to either pump therapy or conventional treatment. Importantly, although the overall costs of CSII are much higher in comparison with MDI because of the fact that national medical insurance covers these costs, the allocation to treatment modality was performed by patient’s preference. Thus, it is likely that the 2 groups were similar in most socioeconomic and demographic aspects, a fact that reduces potential biases for comparison between the studied groups. Nevertheless, it may be that patients who were treated by CSII are those who had difficulty controlling glucose using MDI in the past.
In conclusion, our study found overall both similar maternal and neonatal outcome in both the CSII- and MDI-treated patients. It is understandable that patient satisfaction and lifestyle flexibility is increased under CSII treatment in comparison with MDI treatment. CSII allows the patients to modify insulin availability hour by hour and avoid multiple injections during the day.
This increased flexibility, especially during pregnancy, may be fueling the upsurge in patient demand for CSII more than any other factor. However, it should be remembered that the risk of diabetic ketoacidosis (a potentially life-threatening outcome for both mother and fetus) is increased in CSII-treated women. Because more women are choosing the CSII for lifestyle issues, there is a potential for more adverse outcome.
Nevertheless, to establish clear benefit of CSII (other than improvement in lifestyle) with regard to pregnancy outcome, a large prospective, randomized study is needed.
References
- . Racial/ethnic trends in fetal mortality in United States, 1990-2000. MMWR Morbid Mortal Wkly Rep. 2004;53:529–532
- . Prospective population based survey of outcome of pregnancy in diabetic women: results of the northern diabetic pregnancy audit, 1994. BMJ. 1997;315:279–281
- Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study. BMJ. 1997;315:275–278
- . Congenital anomalies and first year life surveillance in type 1 diabetic births. Diabet Med. 2002;19:589–593
- . French multicentric survey of outcome of pregnancy in women with pregestational diabetes. Diabetes Care. 2003;26:2990–2993
- . Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328:915–920
- . Scottish Diabetes in Pregnancy Group (Outcomes of pregnancies in women with type 1 diabetes in Scotland: a national population-based study). BJOG. 2003;110:315–318
- Randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. JAMA. 1986;255:631–636
- Continuous subcutaneous insulin infusion versus intensive conventional insulin therapy in type I and type II diabetic pregnancy. Diabet Metab. 1986;12:121–129
- Continuous subcutaneous insulin therapy during early pregnancy. Obstet Gynecol. 1985;66:606–611
- . Use of insulin pumps in pregnancies complicated by type 2 diabetes and gestational diabetes in a multiethnic community. Diabetes Care. 2001;24:2078–2082
- . Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol. 2000;182:1283–1291
- Analysis of outcome of pregnancy in type 1 diabetics treated with insulin pump or conventional insulin therapy. Acta Diabetol. 2003;40:143–149
- Microalbuminuria as an early predictor of hypertensive complications in pregnant women at high risk. Am J Kidney Dis. 1996;28:220–225
- . Diagnosis and management of preeclampsia and eclampsia. American College of Obstetricians and Gynecologists; 2002;Practice bulletin no. 33
- . Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1–S22
- . Birth weight standards in the live-born population in Israel. Isr Med Assoc J. 2005;7:311–314
- Workshop Report. Diabetes care and research in Europe. The Saint Vincent declaration. Diabet Med. 1990;7:360
- Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333:177
- . Continuous subcutaneous insulin infusion during pregnancy. Diabetes Res Clin Pract. 1988;4:257–268
- . Preconception care of diabetes (Glycemic control prevents congenital anomalies). JAMA. 1991;265:731–736
- . Preconceptional treatment with insulin infusion pumps in insulin-dependent diabetic women with particular reference to prevention of congenital malformations. Acta Endocrinol Suppl (Copenh). 1986;277:81–85
- . The effect of continuous subcutaneous insulin infusion and conventional insulin regimes on 24-hour variations of blood glucose and intermediary metabolites in the third trimester of diabetic pregnancy. Diabetologia. 1981;21:534–539
- . Complications and fetal outcome in diabetic pregnancy (Intensified conventional versus insulin pump therapy). Gynecol Obstet Invest. 1988;26:104–112
- . Hypoglycemia: the price of intensive insulin therapy for pregnant women with insulin-dependent diabetes mellitus. Obstet Gynecol. 1995;85:417–422
- . Severe hypoglycemia incidence and predisposing factors in 85 pregnancies of type I diabetic women. Diabetes Care. 1992;15:1034–1037
- . Diabetic ketoacidosis in pregnancy resulting from insulin pump failure: a case report. J Reprod Med. 1993;38:306–308
Cite this article as: Chen R, Ben-Haroush A, Weissmann-Brenner A, et al. Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am J Obstet Gynecol 2007;197:404.e1-404.e5.
PII: S0002-9378(07)00736-3
doi:10.1016/j.ajog.2007.06.007
© 2007 Mosby, Inc. All rights reserved.
Refers to erratum:
- Correction
Volume 197, Issue 4 , Pages 404.e1-404.e5, October 2007
