Insulin pump dosing across gestation in women
with well-controlled type 1 diabetes mellitus
Hilary A. Roeder, MD; Thomas R. Moore, MD; Gladys A. Ramos, MD
OBJECTIVE:We hypothesized that bolus and basal insulin doses in women with type 1 diabetes mellitus who use insulin pumps would in-crease 2-fold to maintain hemoglobin A1c⬍6.5% across gestation.
STUDY DESIGN:This was a retrospective study of 9 women with type 1 diabetes mellitus with preconceptional hemoglobin A1c
ⱕ7.4% using insulin pumps. The primary outcome was absolute and percentage change of basal and bolus insulin from preconcep-tion to delivery.
RESULTS:Total daily dose of insulin increased from 33.3⫾7.8 U/d before conception to 93.5⫾ 27.9 U/d at delivery. Basal rates rose modestly (50% increase, from 16.2⫾6.5 U/d to 24.0⫾9 U/d); bolus
insulin doses quadrupled from 17.1⫾6.1 U/d to 69.5⫾29.6 U/d (P⫽.0001). Bolus insulin increased from approximately 50% of total daily dose of insulin before conception to 75% of total daily dose of in-sulin at 36 weeks’ gestation.
CONCLUSION:In well-controlled type 1 diabetes mellitus, insulin re-quirements increased 3-fold from before conception to 36 weeks’ ges-tation. Most of this requirement was attributed to an increase in bolus rates that are required for control with meals.
Key words:insulin pump, pregnancy, subcutaneous insulin infusion, type 1 diabetes mellitus
Cite this article as: Roeder HA, Moore TR, Ramos GA. Insulin pump dosing across gestation in women with well-controlled type 1 diabetes mellitus. Am J Obstet Gynecol 2012;207:324.e1-5.
T
ype 1 diabetes mellitus (T1DM) is characterized by the loss of pancre-atic beta cells that leads to subsequent absolute insulin deficiency.1This diseaseaffects nearly 1 in 300 individuals by age 18 years,1 and approximately 19.7 in
100,000 children and adolescents are di-agnosed with T1DM per year.2In
preg-nancy, T1DM has been associated with an increased risk of congenital birth de-fects, miscarriage, fetal death, and pre-eclampsia; preconceptional glycemic control and rigorous medication adjust-ments during gestation are associated with reduced complications.3
The achievement of tight glycemic control depends on an understanding of physiologic changes of pregnancy that lead to insulin resistance. This results
from a combination of placental hor-mones that include prolactin, progester-one, human placental lactogen, placental growth hormone, cortisol, leptin, and adiponectin.4,5 Typically, insulin re-quirements follow a characteristic pat-tern in pregnancy, with a decrease in the first trimester and a rise in the second and third trimesters.6-8Increases in insu-lin requirements of 36-114% from pre-conceptional baseline to the second and third trimesters have been reported.6-8
However, those past studies included pa-tients with suboptimal glycemic control before conception and have had various gestational ages (GAs) at study entry.6,7
More patients with T1DM are being treated with insulin pumps to achieve adequate glycemic control. Recent stud-ies have demonstrated that patients can be treated effectively with insulin pumps when compared with multiple subcuta-neous insulin injections.9,10 However, expected changes in basal insulin and bolus insulin requirements in pregnant women who use insulin pumps remain poorly defined. Previous studies have fo-cused on patients with multiple daily in-sulin injections. One study included pa-tients who used insulin pumps,8but the changes that are unique to this group were not evaluated.
We hypothesized that bolus and basal insulin doses in women with T1DM who are treated with insulin pumps and who are in good control (hemoglobin A1c [HbA1c], ⬍7.4%) would increase by
ⱖ2-fold above preconceptional baseline to maintain an HbA1c level of ⬍6.5% across gestation.
M
ATERIALS ANDM
ETHODS This retrospective study was conducted at the University of California San Diego Diabetes in Pregnancy Program among patients who delivered from 2010-2011. The study was approved by the Univer-sity of California San Diego Human Re-search Protection Program before initia-tion. Inclusion criteria were singleton pregnancies with preexisting T1DM man-aged with a continuous insulin pump, pre-conceptional HbA1c level ofⱕ7.4%, pre-conceptional insulin dosing and self-monitored plasma glucose values available for review, and delivery at term. Exclusion criteria included patients who were not us-ing an insulin pump preconceptionally or who were switched to subcutaneous injec-tions after the initiation of care. The inclu-sion criterion of HbA1c level ofⱕ7.4% was chosen because it is associated with similar rates of congenital malformations and spontaneous abortion as innondia-From the Division of Perinatology, Department of Reproductive Medicine, UC San Diego Health System, San Diego, CA.
Received March 12, 2012; revised May 12, 2012; accepted June 14, 2012.
The authors report no conflict of interest. Presented as a poster at the 32nd annual meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Feb. 6-11, 2012. Reprints not available from the authors.
0002-9378/$36.00
© 2012 Mosby, Inc. All rights reserved.
betic women whose data have been re-ported in the Diabetes Control and Com-plications Trial.11
All patients were provided nutri-tional counseling that included recom-mended meal carbohydrate/fat/protein content and meal frequency (3 meals and 3-4 snacks daily). Patients were advised to monitor plasma glucose levels at the following times: in the morning after fasting; preprandially; 1 hour postpran-dially for breakfast, lunch, and dinner; at bedtime, and between 3 and 4AM. Goals for glycemic control were fasting values of 90 mg/dL, preprandial values of 80-120 mg/dL, and 1-hour postprandial val-ues ⬍130 mg/dL. Target values were chosen optimally to balance the risks of fetal macrosomia with maternal hypo-glycemia.12Patients recorded their cap-illary glucose measurements in glycemic control logs, and glucose meters were re-viewed by clinical diabetic educators to verify accuracy. Glucose logs with di-etary recall and actual insulin dosing were evaluated weekly in person or by fax/email by clinical diabetes mellitus educators and by the study investigators. Adjustments to insulin basal and bolus dosing were made by the 2 senior au-thors (T.R.M. and G.A.R.). Insulin
re-quirements were calculated based on units per kilogram weight. Basal and bo-lus insulin dosing (absolute and percent change) was compared between precon-ception and weeks 9, 16, 20, 24, 28, 32, 36, and 38 of pregnancy. During the day, basal rates were generally divided into 5 segments: 0000-0500, 0500-0900, 0900-1600, 1600-2200, and 2200-2400. These segments correspond with typical times of day when insulin requirements in-crease or dein-crease; however, each patient had an individualized regimen that was based on her time of awakening, work/ sleep schedule, and meals. Bolus insulin doses were subdivided by the breakfast, lunch, and dinner meals. HbA1c data were obtained every trimester.
Maternal medical records were re-viewed to obtain demographic data, evi-dence of end-organ disease, glycemic control from preconception through de-livery, HbA1c level, and delivery data. Body mass index was calculated with the documented weights during pregnancy. Height was based on maternal recall. Neo-natal medical records were reviewed to obtain gestational age at delivery and birthweight.
The primary outcome measure was the absolute and percentage change of
basal and bolus insulin requirements from preconception to delivery. Second-ary outcomes included gestational age at peak basal and bolus insulin doses and changes in basal rates and bolus insulin dosing during specific time segments of the day.
Statistical analysis was performed us-ing SPSS software (version 20; SPSS Inc, Chicago, IL). The Studentttest was used for a comparison of continuous vari-ables. Data are presented as mean⫾SD.
R
ESULTSThirty-one women with T1DM were identified during the time period; 9 of these women met inclusion criteria and were included in our analysis. Mean maternal age at diagnosis of T1DM was 13.5 ⫾ 5.8 years (Table 1). The mean preconception HbA1c level was 6.4%⫾ 0.5%, and the mean HbA1c level at de-livery was 5.8%⫾0.6%. The mean pre-conception and first-, second-, and third-trimester body mass index mea-surements were 24.7⫾3.3 kg/m2, 25.4⫾ 3.6 kg/m2, 27.2⫾3.1 kg/m2, and 29.5⫾ 3.1 kg/m2, respectively. Subjects were all white; the mean maternal age was 31.4⫾ 2.2 years, and 3 women were nullipa-rous. No patient had evidence of end-organ damage. Four women had vaginal deliveries; 3 women had primary cesar-ean deliveries, and 2 women had repeat cesarean delivery. Indications for pri-mary cesarean delivery were macro-somic profile on ultrasound, a nonreas-suring fetal heart rate tracing in the setting of severe preeclampsia, and a his-tory of a shoulder dystocia in a previous delivery. Neonates of these subjects were born at 38 weeks 5 days’ (⫾6 days) gestation and weighed 3695 ⫾ 440 g (Table 2).
By the end of gestation, total daily dose of insulin (TDI) nearly tripled; at pre-conception evaluation, the mean dose was 33.3 ⫾7.8 units/day (U/d), which rose to 93.5⫾ 27.9 U/d at the time of delivery. This represents a 181% change in daily insulin requirement. Total units of insulin per kilogram of maternal body weight increased from 0.6 U/kg precon-ceptionally to a maximum of 1.3U/kg at 36 weeks’ gestation. TABLE 1 Demographic information Characteristic Measure Age, ya 31.4⫾2.2 ... Parity, n (%) ... Nulliparous 3 (33) ... Multiparous 6 (67) ... Age at diagnosis, ya 13.5⫾5.8 ... Ethnicity: white 9 (100) ... Hemoglobin A1c, %a ...
Before conception 6.4⫾0.5 (range, 5.8–7.4)
...
Delivery 5.8⫾0.6 (range, 5.3–6.4)
...
Body mass index, kg/m2a
... Before conception 24.7⫾3.3 ... First trimester 25.4⫾3.6 ... Second trimester 27.2⫾3.1 ... Third trimester 29.5⫾3.1 ...
aData are given as mean⫾SD.
Across gestation, the basal TDI in-creased moderately by 48%, from 16.2⫾ 6.5 U/d preconceptionally to 24.0 ⫾ 9 U/d at delivery. The basal insulin dose peaked at 33.2 ⫾ 2.7 weeks’ gestation, with a mean TDI increase of 5.8⫾4.3 U/d from baseline. The basal nadir was at 9 weeks’ gestation when the TDI de-creased by 1.9 U/d from the preconcep-tional baseline, which represents a de-crease of 11.4% (Figure). Analysis of the specific time segments during the day demonstrated that the time of day that re-quired the highest increase of basal insulin was the morning segment (0500-0900), with an 85% (range, 3–150%) increase that was noted from preconception to peak (33.2⫾2.7 weeks’ gestation;Table 3). The time segment that required the smallest in-crease of basal insulin was the late
morn-ing-early afternoon (0900-1600) segment, with an increase of only 8% (Table 3).
In contrast, the insulin bolus doses that were required to maintain glucose values within the target range increased by 306% throughout gestation, from a TDI of 17.1⫾6.1 U/d before conception to 69.5⫾29.6 U/d at delivery (P⫽.0001). Bolus insulin requirement peaked at 34.6⫾2.3 weeks’ gestation, which was not significantly different from the corre-sponding gestational age at which basal in-sulin dose peaked (P⫽.23). At the peak, there was a mean increase in TDI of 48.3⫾ 26.5 U/d. The nadir for insulin boluses was 9 weeks’ gestation, with a mean decrease in TDI of 0.6 U/d, which represents a 3.2% decrease from baseline. Bolus insulin in-creased from 51% of the TDI in the pre-conception period to 73% of TDI at the peak (Figure). The meal that required the largest percentage of change in insulin was breakfast, with a 53% (range, 25–70%) in-crease in bolus insulin requirement from baseline (Table 4).
C
OMMENTRequirements for insulin change through-out gestation13; however, in patients with T1DM who use an insulin pump, peaks and nadirs in basal and bolus insulin have not been well-characterized. In this study, we describe the changes in insulin dosing for a group of patients in excellent glucose control before and throughout pregnancy that permits assessment of changes in in-sulin resistance across gestation.
The novel findings that were observed in our well-controlled subjects with pre-conceptional HbA1c levels of ⱕ7.4% may provide new insights regarding ad-justment strategies for insulin dosing as pregnancy progresses for women with this challenging chronic disease. As pre-viously published by others, we found a decrease in TDI in the first trimester and a rise in the second and third trimes-ters.4,6-8However, we noted that the TDI increased 3-fold during gestation. The bolus insulin that is required to control postprandial glucose excursions con-tributes to most of this dose increase; basal insulin, which is used to control in-terprandial and overnight glucose levels, increases minimally (30% of the change
in TDI). In our examination of glycemic control during the course of the day, the time that required the largest increase in both basal and bolus insulin was the morning segment (0500-0900).
In the third trimester, glucose de-mands of the fetoplacental unit increase in parallel with concomitantly rising in-sulin resistance.14 This phenomenon
correlates with the peaks of both bolus and basal insulin that was observed in our study (33 weeks’ gestation). Human placental lactogen and progesterone contribute to the increased insulin resis-tance during this point in gestation.15
In-creases in bolus insulin accounted for the greatest proportion of the progressive es-calation in TDI that was observed. It should also be noted that, in our patient population, we sought to achieve pre-prandial capillary glucose levels of 80-120 mg/dL. In most of our patients, the values hovered near this threshold (data not shown). As gestation advanced to-ward the peak of basal and bolus insulin requirements at 32-34 weeks’ gestation, increased bolus doses were required to
TABLE 3
Basal increase from before conception to 32 weeks’ gestation Basal segment time Percentage of basal increase (range) 0000-0500 35 (4–114) ... 0500-0900 85 (3–150) ... 0900-1600 8 (–100 to 67) ... 1700-2200 14 (–70 to 86) ... 2200-2400 25 (–50 to 100) ...
Roeder. Insulin pump dosing for T1DM in pregnancy. Am J Obstet Gynecol 2012.
TABLE 4
Bolus increase from before conception Meal Percentage of bolus increase (range) Breakfast 53 (25–70) ... Lunch 50 (14–72) ... Dinner 48 (13–75) ...
Roeder. Insulin pump dosing for T1DM in pregnancy. Am J Obstet Gynecol 2012.
TABLE 2
Neonatal outcomes
Neonatal outcome Measure Gestational age at delivery, wk/da 38/5⫾6 d ... Birthweight, ga 3695⫾440 ... Mode of delivery, n (%) ... Vaginal 4 (44) ... Primary cesarean 3 (33) ... Repeat cesarean 3 (33) ...
Roeder. Insulin pump dosing for T1DM in pregnancy. Am J Obstet Gynecol 2012.
FIGURE
Insulin doses across gestation
Total daily insulin dose increased 3-fold across gestation. Bolus doses of insulin constitute most of the rise; basal rates of insulin change minimally.
PC,preconception.
Roeder. Insulin pump dosing for T1DM in pregnancy. Am J Obstet Gynecol 2012.
control glucose values 1-2 hours post-prandially. At this same time, however, there is increasing vulnerability to hypo-glycemia 3-4 hours after a meal, which moderates the dose of basal insulin that can be delivered between meals without inducing maternal hypoglycemia.
Compared with other specific time segments, the morning was the most in-sulin-resistant time period in this study. For basal insulin, the segment that re-quired the largest insulin increases was at 0500-0900; for the bolus, breakfast was the meal that required the largest in-crease with advancing gestation. This correlates with observations that fasting hyperglycemia is present in almost all in-dividuals with diabetes mellitus.16Early morning hyperglycemia may result from dysregulation of normal circadian hor-monal patterns that lead to increased glucose output from the liver.17 The need for larger morning doses of insulin is also consistent with literature that de-scribes the “dawn phenomenon” and the “Somogyi effect” as possible explana-tions for morning hyperglycemia in dia-betic patients. The dawn effect, which is seen in up to 54% of patients with T1DM,18occurs when endogenous insu-lin decreases or when exogenously ad-ministered insulin the day before is in-sufficient to counteract the morning surge in insulin-antagonistic hormones such as growth hormone, epinephrine, norepinephrine, thyroid hormone, and cortisol.19This effect is associated with normal or high blood glucose levels from 3-5AM. Although the Somogyi effect re-sults in the same morning hyperglyce-mia, it is described as a rebound effect of low blood glucose levels from 3-5 AM. This can occur when a patient is treated with excessive amounts of insulin that are not antagonized properly by hor-mones in the hypothalamic-pituitary-adrenal axis.19In our patients, the So-mogyi effect was encountered rarely because most of the women checked glu-cose levels at 3-4AMseveral times weekly, and basal insulin doses from midnight to 5AMwere adjusted accordingly.
The nadir of basal and bolus insulin occurred in the first trimester at approx-imately 9 weeks’ gestation. Insulin resis-tance is thought to rise progressively
during gestation; thus, the exact cause of the increase in insulin sensitivity at 9 weeks’ gestation, compared with the prepregnant state that was observed in this study, remains unclear. During this time, women may not be eating as much as they were previously, which could de-crease insulin requirements.8Nonobese pregnant women may deplete their sup-ply of glucose and glycogen stores more quickly because of embryo/fetus needs for development. The results of this study can better equip practitioners to counsel their patients with T1DM about how their pregnancy will affect insulin requirements. Many patients with diabe-tes mellitus are concerned or discour-aged by the substantial increases in insu-lin doses that are required for euglycemia as they approach term. This study may help early-pregnant and preconcep-tional women to calibrate their expecta-tions for anticipated changes in insulin dosing. Better counseling before preg-nancy and early in the first trimester may lead to better compliance. Patients who strive for near-perfect glycemic control will better understand the need for higher basal and bolus insulin doses. Pa-tients can be reassured that, in the early-to-mid third trimester, they will reach the peak of their bolus dose at breakfast, and they can be counseled that they will require steep increases in insulin from 5-9AM.
A significant strength of this descrip-tive analysis is studying a homogeneous group of subjects whose disease was well-controlled at baseline. This allowed the examination of the trends of insulin re-quirements in pregnancy without the ef-fects of having to compensate and con-trol for poor concon-trol and a suboptimal HbA1c level. In this group of highly mo-tivated women, results were not biased by noncompliance, differences in age, race, or other confounders and reflect closely the result of the changes in insulin sensitivity/re-sistance in pregnancy alone.
This study does have some limitations. Lack of heterogeneity in the demograph-ics of the subjects may limit applicability to other populations. It is also impossible to characterize each patient’s insulin reg-imen according to rigid time-segments throughout the day because the doses
and rates are customized based on daily routine; it was necessary to generalize the times of day to analyze basal rates for study purposes. The sample size was lim-ited by the necessity of including only subjects whose diabetes mellitus was well-controlled and who used only an in-sulin pump. Additionally, convenient access to all of the patient’s glycemic control was possible only after the imple-mentation of our electronic medical re-cord in recent years. At our institution, many patients opt to use a pump on the initiation of prenatal care because of the potential for tighter glycemic control; however, the patient’s funding, motiva-tion, and other similar factors can in-crease the length of time she is treated with multiple daily injections before crossing over. Such patients were ex-cluded for this study because we limited our description to those who used insu-lin pumps because of the paucity of cur-rent data.
In summary, there are marked changes in insulin requirements throughout preg-nancy that require frequent assessment of patient glucose profiles and insulin adjust-ments. Marked increases in insulin re-quirements are due largely to a rise in in-sulin boluses with only modest increases in basal insulin rates. Early morning remains the period of greatest insulin need, both basal and bolus. An understanding of these changes may aid clinicians and patients to achieve optimized glucose control in preg-nancies that are complicated by T1DM. f REFERENCES
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