Insulin Therapy in Pregnancy

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Lois Jovanovic

Sansum Medical Research Institute, Santa Barbara, California


Before the advent of insulin, few diabetic women lived to childbearing age. Before 1922, fewer than 100 pregnancies in diabetic women were reported; most likely these women had type 2 and not type 1 diabetes. Even with this assumption, these cases of diabetes and pregnancy were associated with a greater than 90% infant mortality rate and a 30% maternal mortality rate. As late as 1980, physicians were still counseling diabetic women to avoid pregnancy. This philosophy was justified because of the poor obstetric history in 30% to 50% of diabetic women. Infant mortality rates finally improved after 1980, when treatment strategies stressed better control of maternal plasma glucose levels, once self-blood glucose monitoring and hemoglobin A ,c (HbA ]c) became available. As the pathophysiology of pregnancy complicated by diabetes has been elucidated and as management programs have achieved and maintained near-normal glycemia throughout pregnancy complicated by type 1 diabetes, perinatal mortality rates have decreased to levels seen in the general population. This review is intended to help clinicians understand the increasing insulin requirements of pregnancy and to design treatment protocols to achieve and maintain normoglycemia throughout pregnancy.


If a mother has hyperglycemia, the fetus will be exposed to either sustained hyperglycemia or intermittent pulses of hyperglycemia. Both situations prematurely stimulate fetal insulin secretion. Fetal hyperinsulinemia may cause increased fetal body fat (macrosomia), and therefore a difficult delivery, or inhibition of pulmonary maturation of surfactant, and therefore respiratory distress of the neonate. The fetus may also have decreased serum potassium levels caused by the elevated insulin and glucose levels, which may lead to cardiac arrhythmias. Neonatal hypoglycemia may cause permanent neurological damage.

There is also a greater prevalence of congenital anomalies and spontaneous abortions among diabetic women who are in poor glycemic control during the period of fetal organogenesis, which is nearly complete by 7 weeks postconception. A woman may not even know she is pregnant at this time, so prepregnancy counseling and planning are essential in women of childbearing age who have diabetes. Because organogenesis is complete so early on, if a woman presents to her healthcare team and announces that she has missed her period by only a few days, there is still a chance to prevent cardiac anomalies by swiftly normalizing the glucose levels (although the neural tube defects are already "set in stone" by the lime the first period has been missed). These findings emphasize the importance of glycemic control at the earliest stages of conception. Ideally, if a diabetic woman plans her pregnancy, then there is time to create algorithms of care that are individualized and a woman can be given choices. When a diabetic woman presents in her first few weeks of pregnancy, there is no time for individualization; rather rigid protocols must be urgently instituted to provide optimal control within 24-48 hours.

After the period of organogenesis, maternal hyperglycemia interferes with normal growth and development during the second and third trimesters. The maternal postprandial glucose level has been shown to be the most important variable in the subsequent risk of neonatal macrosomia. The fetus thus is "overnour-ished" by the peak postprandial. This peak response occurs in over 90% of woman 1 hour after beginning a meal. Therefore, the glucose level at that 1-hour point needs to be measured and treatment designed to maintain glucose in the normal range at that point. Studies have shown that when the postprandial glucose levels are maintained, from the second trimester onward, below 120 mg/dl 1 hour after beginning a meal, the risk of macrosomia is minimized.


Fetal demise associated with pregnancy complicated by type 1 diabetes seems to arise from glucose extremes. Elevated maternal plasma glucose levels should s

always be avoided, because of the association of maternal hyperglycemia with subsequent congenital malformation and spontaneous abortions. To achieve nor-moglycemia, a clear understanding of "normal" carbohydrate metabolism in pregnancy is paramount. Thus, the amount of insulin required to treat type 1 diabetic women throughout pregnancy needs to be sufficient to compensate for 1) increasing caloric needs, 2) increasing adiposity, 3) decreasing level of exercise, and 4) increasing anti-insulin or diabetogenic hormones of pregnancy.

The major diabetogenic hormones of the placenta are human chorionic somatomammotropin (hCS), previously referred to as human placental lactogen (hPL), estrogen, and progesterone. Also, serum maternal Cortisol levels (both bound and free) are increased. In addition, at the elevated levels seen during gestation, prolactin has a diabetogenic effect.

The strongest insulin antagonist of pregnancy is hCS. This placental hormone appears in increasing concentration beginning at 10 weeks of gestation. By 20 weeks of gestation, plasma hCS levels are increased 300-fold, and by term, the turnover rate is about 1000 mg/dl. The mechanism of action whereby hCS raises plasma glucose levels is unclear, but probably originates from its growth-hormone-like properties. hCS also promotes free fatty-acid production by stimulating lipolysis, which promotes peripheral resistance to insulin.

Placental progesterone rises 10-fold above non-pregnancy levels and is associated with an insulin increase in normal healthy pregnant women by two- to fourfold.

Most of the marked rise of serum Cortisol during pregnancy can be attributed to the increase of cortisol-binding globulin induced by estrogen. However, free Cortisol levels are also increased. This increase potentiates the diurnal fluctuations of Cortisol with the highest levels occurring in the early-morning hours.

The rising estrogen levels also trigger the rise in pituitary prolactin early in pregnancy. Prolactin's structure is similar to that of growth hormone, and at concentrations reached by the second trimester (>200 ng/ml) prolactin can affect glucose metabolism. Although no studies have examined prolactin alone as an insulin antagonist, there is indirect evidence that suppressing prolactin in gestational diabetic women with large doses of pyridoxine improves glucose tolerance.

In addition to the increasing anti-insulin hormones of pregnancy, there is also increased degradation of insulin in pregnancy caused by placental enzymes comparable to liver insulinases. The placenta also has membrane-associated insulin-degrading activity. Concomitant with the hormonally induced insulin resistance and increased insulin degradation, the rate of disposal of glucose slows. The normal pancreas can adapt to these factors by increasing the insulin secretory capacity. If the pancreas fails to respond adequately to these alterations, then gestational diabetes results. In a woman with type 1 diabetes, her insulin requirement will rise progressively. Failure to increase her insulin doses appropriately will result in increasing hyperglycemia.


Maternal anti-insulin antibodies may contribute to hyperinsulinemia in utero and thus potentiate the metabolic aberrancy. Although insulin does not cross the placenta, antibodies to insulin do, and may bind fetal insulin; this necessitates the increased production of free insulin to re-establish normoglycemia. Thus, the anti-insulin antibodies may potentiate the effect of maternal hyperglycemia to produce fetal hyperinsulinemia. Human and highly purified insulins are significantly less immunogenic than mixed beef-pork insulins. Human insulin treatment has been reported to achieve improved pregnancy and infant outcome compared with the use of highly purified animal insulins. Recently the insulin analog lispro (which has the amino acid sequence in the |3 chain reversed at position B28, B29) has been reported to be more efficacious than human Regular insulin in normalizing blood glucose levels in gestational diabetic women. This insulin lowered the postprandial glucose levels, thereby decreasing the glycosylated hemoglobin levels, with fewer hypoglycemic episodes and without increasing the anti-insulin antibody levels. Although the safety and efficacy of insulin lispro in the treatment of type 1 and type 2 diabetic women throughout pregnancy have not yet been reported, there have been scattered case reports of infants born with congenital malformations. Regardless of the type of insulin used, the risk for severe malformations in infants of diabetic mothers is greater than that in infants of nondiabetic mothers: 5.2-16.8% versus 1.2-3.7%. This risk is drastically reduced, however, when the mother has excellent blood glucose control and maintains an HbAic below 5%. Thus, the clinician needs to explain to the patient that there are no clinical trials in which insulin analogs have been proven to be without risk, but using the newer insulin analogs may facilitate better glucose control, and normalization of the glucose is paramount if congenital anomalies are to be prevented.


Type 1 diabetic women must increase their insulin dosage to compensate for the diabetogenic forces of normal pregnancy. However, the exact patterns of insulindosage increase are still controversial. Many observers have detected a decline in insulin requirement in the late first trimester of diabetic pregnancies. Jorgen Pedersen, the father of the study of diabetes in pregnancy, was among the first to write about first-trimester hypoglycemia as a symptom of pregnancy and noted that it had long been common knowledge among physicians. Pedersen wrote, "Those physicians who manage diabetic women should be particularly alert for hypoglycemia in women who have recently become pregnant. About the 10th week of gestation there is an improvement in glucose tolerance manifesting itself tX

as insulin coma, milder insulin reaction or an improvement in the degree of compensation. When a reduction in insulin dosage is called for it amounts to an average of 34%." Indeed, he even claimed, "Once in a while pregnancy may be diagnosed on account of inexplicable hypoglycemic attacks." In all 26 cases of insulin coma collected, he found that coma occurred in the first to fourth month, with the majority occurring at months 2 to 3. He also noted that by late gestation, regardless of the metabolic control and duration of diabetes, average daily insulin requirements increased twofold from earlier in pregnancy.

Early-first-trimester overinsulinization might explain a later-first-trimester drop in insulin requirement. One example of this effect may be the significantly greater weight gain seen in the first trimester by diabetic women compared with normal healthy women. Perhaps the drive to increase calorie intake to prevent hypoglycemia in the first trimester may have been the cause of the first-trimester excessive weight gain in the diabetic women.

On the other hand, others have not seen the first-trimester decrease in insulin requirement. There are aJso reports of rising insulin requirement in the first trimester. My colleagues and I have described the declining insulin requirements during pregnancy of a population of well-controlled type 1 diabetic women, possibly lending credence to the notion that first-trimester overinsulinization may be the cause of the hypoglycemia seen by some in the first trimester. Based on our studies of well-controlled diabetic women, we have created an algorithm for care and an insulin-requirement protocol based on gestational week and a woman's current pregnant body weight. The total daily dose of insulin in the first trimester (weeks 5-12) is 0.7 units/kg per day; in the second trimester (weeks 12-26), the total daily dose is 0.8 unit/kg per day; in the third trimester (weeks 26-36), it is 0.9 units/kg/day; and at term (weeks 36-40) the total daily dose of insulin is 1.0 units/kg/day (Table 1). The insulin needs to be divided throughout the day to provide the basal need (the dose of insulin that keeps levels normal in the fasting state) and the meal-related need.

The basal need—usually 50% of the total daily insulin dose (I)—may be delivered using a constant-infusion pump (Table 2) or by multiple doses of intermediate-acting insulin (Table 1). When using a constant-infusion pump, the basal need is calculated as an hourly rate and is delivered such that the calculated rate (]h I divided by 24) is given between 10 a.m. and midnight. The rate is cut in half ('/21 divided by 24 X 0.5) from midnight to 4 a.m., and increased by another 50% O/2 I divided by 24 X 1.5) to counteract the morning rise of Cortisol levels that are potentiated during pregnancy.

When we use multiple insulin injections to provide the basal need, we prefer to use NPH insulin because it has a more predictable absorption pattern than Lente or Ultrájente insulin. Also, the recently developed long-acting insulin analogs (insulin glargine or insulin detemir) have not yet been proven to be safe or efficacious in pregnancy.

Table 1 Initial Calculation of Insulin Therapy for Pregnancy

Fraction of total daily insulin dose (1)

(50% of 1)

Regular/lispro/aspart (50% of I)



4/20 (0.20)


3/20 (0.15)



3/20 (0.15)



I = 0.7 units x present pregnant weight in kilograms for weeks 1-12; 0.8 units x present pregnantweight in kilograms forweeks 12-26; 0.9 units x present pregnant weight in kilograms for weeks 26-36; 1.0 units x present pregnant weight in kilograms for weeks 36-40.

I = 0.7 units x present pregnant weight in kilograms for weeks 1-12; 0.8 units x present pregnantweight in kilograms forweeks 12-26; 0.9 units x present pregnant weight in kilograms for weeks 26-36; 1.0 units x present pregnant weight in kilograms for weeks 36-40.

Our preferred use of NPH is to give one-sixth of the total daily dose of insulin as morning, dinner, and bedtime injections (i.e., NPH dose equals 50% of daily dose divided into three equal injections of NPH given every 8 hours, or at 8 a.m., 4 p.m., and 12 midnight) (Table 1),

The other half of the totaJ daily insulin dose should be a short-acting insulin (human Regular, insulin lispro, or insulin aspart) given before each meal to coo-

Table 2 Basal Insulin-Pump Program Using Human Regular, Insulin Lispro, or Insulin Aspart (basal (B) = V2 total daily insulin dose (I); B/24 = hourly rate)


Basal requirement (hourly infusion rate)


12:00-4:00 a.m.

50% less basal

Maternal Cortisol at nadir

(B/24 X 0.5)

4:00-10:00 a.m.

50% more basal

Highest level of maternal

(B/24 X 1.5)


10:00 a.m.-12:00 a.m.



To refine basal settings, have the patient perform SM8G at the end of each period to determine whether adjustments are needed. For instance, at the 4:00 a.m. test, blood glucose should be 60-90 mg/dl. If blood glucose is out of this range, dial up or down insulin in increments of 0.10 U/hr.

To refine basal settings, have the patient perform SM8G at the end of each period to determine whether adjustments are needed. For instance, at the 4:00 a.m. test, blood glucose should be 60-90 mg/dl. If blood glucose is out of this range, dial up or down insulin in increments of 0.10 U/hr.

Table 3 Pre-Meal Sliding-Scale Dose Calculation Using Rapid-Acting Insulin®

Compensatory insulin

<60 Meal-related insulin dose minus 3% of the total daily insu lin dose

61-90 Meal-related insulin dose, no adjustment necessary

91-120 Meal-related insulin dose plus 3% of the total daily insulin dose

>121 Meal-related insulin dose plus 6% of the total daily insulin dose

' Human Regular insulin, insulin lispro, or insulin aspart.

trol postprandial glycemia (Table 1). This dose of short-acting insulin can be given using the insulin infusion pump or by multiple doses of subcutaneously injected insulin.

The meal-related insulin dose (one-half the total daily insulin requirement) is divided such that 40% of the meal-related dose is given to cover breakfast and the remaining 60% covers the lunch and dinner meals (Table 1). The exact division of this meal-related insulin dose depends on the size of the woman's lunch versus her dinner. Breakfast necessitates the majority of the meal-related dose because the diurnal variation in Cortisol levels is potentiated by pregnancy.

Compensatory doses to adjust for high or low glucose levels are calculated as 3% of total daily insulin requirement (Table 3). Clinicians should note that hyperglycemia will occur if a patient uses only insulin lispro or insulin aspart for the meal-related needs and the woman goes a long time between meals. The dose of NPH insulin may not be sufficient to prevent an escape of the blood glucose before the next dose of insulin is given. To prevent this escape of blood glucose when longer than 3 hours elapses between injections of the rapid-acting insulin analogs of lispro or aspart, the patient should add 3% of her total daily insulin requirement as Regular human insulin to the lispro injection to extend the effectiveness of the short-acting component.


The goal of dietary management for the type 1 diabetic woman is to maintain normoglycemia. Moreover, in either the insulin-requiring gestational diabetic woman or the type 1 diabetic woman, the food and the insulin must match. The diet shown in Table 4 of frequent small feedings is designed to avoid postprandial

Table 4 Total Daily Dietary Calculations for Pregnant Women



Fraction (kcal/24 hr)

% of daily carbohydrate allowed

8:00 a.m.




10:30 a.m.




12:00 noon




3:00 p.m.




5:00 p.m.




8:00 p.m.




11:00 p.m.




The total daily caloric need is calculated based on current pregnant weight to be 30 kcal/kg per day for a woman who is 80-120% of her ideal body weight, 24 kcal/kg per day for a woman 120-150% of her ideal body weight, 18 kcal/kg per day for a woman 150-200% of her ideal body weight, and 12 kcal/kg per day for a woman greater than 200% of her ideal body weight.

The total daily caloric need is calculated based on current pregnant weight to be 30 kcal/kg per day for a woman who is 80-120% of her ideal body weight, 24 kcal/kg per day for a woman 120-150% of her ideal body weight, 18 kcal/kg per day for a woman 150-200% of her ideal body weight, and 12 kcal/kg per day for a woman greater than 200% of her ideal body weight.

hyperglycemia and preprandial starvation ketosis, and to promote an average weight gain of 12.5 kg in accord with the Committee on Maternal Nutrition, National Academy of Sciences. In the obese type 1 diabetic woman, fewer calories per kilogram of total pregnant weight are needed to prevent ketosis yet provide sufficient nutrition for the fetus and mother (Table 4). Recently it has been reported that when overfeeding of the pregnant woman completely suppresses ketone production, there is an increased risk of macrosomia.

Each diabetic woman should have her diet prescribed and the monitoring protocol explained at the same visit. No matter how educated the pregestational woman is about managing her diabetes, metabolism is affected so greatly by pregnancy that reinforcement is necessary. Ideally, education to achieve and maintain normoglycemia should be before conception or as soon as the diagnosis of pregnancy has been made. Usually, it requires 5 to 7 days to teach the patient the requisite goals and skills to normalize her plasma glucose level throughout gestation through the use of insulin adjustments. The training process is best achieved in centers specialized for education of diabetes self-care.


Because normal pregnant women have lower fasting glucose levels than nonpregnant people (fasting 60-90 mg/dl) and postprandial glucose levels should

not exceed 120 mg/dl (or the risk of macrosomia increases exponentially), insulin doses should be adjusted upward if more than 2 days of glucose levels are above preprandial levels of 90 mg/dl or postprandial glucose levels are greater than 120 mg/dl. In order to titrate against the ever-increasing insulin requirements of pregnancy, the basal dose of insulin should be increased by 0.1 units per hour. This insulin increase will be heralded by a rise in the preprandial glucose levels. In addition, the increased insulin requirements are addressed by an increase in meal-related insulin dose. When the postprandial glucose levels are elevated (in 90% of women this peak is reached I hour after beginning a meal), the following day's corresponding pre-meal injection should be increased by an additional 3% of the total daily insulin.

This titration of insulin is based on frequent glucose monitoring and ensures a smooth increase of insulin as the pregnancy progresses to a higher insulin requirement of up to 1.0 unit/kg/day at term (Table 1). Twin gestations will cause an approximate doubling of the insulin requirement throughout pregnancy.

The outpatient visits should be frequent enough to provide the needed consultation, guidance, and emotional support to facilitate compliance. Moreover, tests and therapy should be appropriate for gestational age (Table 5). The healthcare delivery team should put forth an extra effort during pregnancy. Each patient should have telephone access to the team on a 24-hour basis for questions concerning therapy, and visits should be frequent (e.g., 2 weeks apart).

Table 5 Important Tests for Monitoring Concomitant Diseases and Glucose During Pregnancies Complicated by Type 1 Diabetes



Eye examination

Prior to conception and then once each


Kidney function

Prior to conception and once each


Thyroid function

Prior to conception and once each



Prior to conception and once every 2-4


Self-blood glucose monitoring:

Before meals and 1 hour after meals

target capillary whole

blood glucose:

Pre-meal <90 mg/dl

Post-meal <120 mg/dl

Blood pressure and weight

Prior to conception and at each visit


Glycosylated hemoglobin levels are not sensitive enough to detect minor elevations of glucose and cannot be used as a screening tool for gestational diabetes; however, the glycosylated hemoglobin levels can be used as a monitor of "control." Serial determinations (once every 2 weeks) can reinforce the patient's records and are useful when the patient sees her own trends compared with her starting glycosylated hemoglobin level. Treatment decisions should be based solely on the self-monitored glucose levels, with double-checking of this value with a laboratory standard.

The best way to use glycosylated hemoglobin in pregnancy is to create "pregnancy norms." Because the mean plasma glucose level is about 20% lower in pregnancy, the glycosylated hemoglobin levels in normal pregnancy are about 20% lower than nonpregnant levels. When a glycosylated hemoglobin level is markedly elevated above the mean for a nondiabetic pregnant woman in the first 8 weeks of pregnancy, then the risk of a congenital anomaly in the infant rises fourfold above the risk in the general population. Achieving a glycosylated hemoglobin level in the normal range of nondiabetic pregnant women decreases the rates of retinopathy progression, spontaneous abortion, and birth defects to near those in the general population.


With improvement in antenatal care, intrapartum events play an increasingly crucial role in the outcome of pregnancy. The intravenous glucose and insulin may be used to maintain normoglycemia during labor and delivery, but normogly-cemia can be maintained easily by subcutaneous injections. Before active labor, insulin is required, and glucose infusion is not necessary to maintain a blood glucose level of 70 to 90 mg/dl. With the onset of active labor, insulin requirements decrease to zero and glucose requirements are relatively consistent at 2.5 mg/kg/min. From these data, a protocol for supplying the glucose needs of labor has been developed.

The goal is to maintain maternal plasma glucose between 70 and 90 mg/dl. In cases of the onset of active spontaneous labor, insulin is withheld and an intravenous dextrose infusion is begun at a rate of 2.55 mg/kg/min. If labor is latent, normal saline is usually sufficient to maintain normoglycemia until active labor begins, at which time dextrose is infused at 2.55 mg/kg/min. Blood glucose is then monitored hourly, and if it is below 60 mg/dl, the infusion rate is doubled for the subsequent hour. If the blood glucose rises to more than 120 mg/dl, 2 to 4 units of Regular insulin is given intravenously each hour until the blood glucose level is 70 to 90 mg/dl. In the case of an elective cesarean section, the bedtime dose of NPH insulin is repeated at 8 a.m. on the day of surgery and every 8 hours tX

if the surgery is delayed. A dextrose infusion may be started if the plasma glucose level falls below 60 mg/dl, and 2 to 4 units of Regular insulin given intravenously every hour if the blood glucose rises to above 120 mg/dl.


Maternal insulin requirements usually drop precipitously postpartum, and these requirements may be decreased for 48 to 96 hours postpartum. Insulin requirements should be recalculated at 0.6 unit/kg based on the postpartum weight and should be started when the 1-hour postprandial plasma glucose value is above 150 mg/dl or the fasting glucose level is greater than 100 mg/dl. The postpartum caloric requirements are 25 kcal/kg/day, based on postpartum weight. For women who wish to breastfeed, the calculation is 27 kcal/kg/day and insulin requirements are 0.6 unit/kg/day. The insulin requirement during the night drops dramatically during lactation, owing to the glucose siphoning into the breast milk. Thus, the majority of the insulin requirement is needed during the daytime to cover the increased caloric needs of breastfeeding. Normoglycemia should especially be prescribed for nursing diabetic women, because hyperglycemia elevates milk glucose levels.


If blood glucose concentration is normalized throughout pregnancy in a woman with diabetes, there is no evidence that excess attention need be paid to her offspring. However, if normal blood glucose level has not been documented throughout pregnancy, it is wise to monitor the neonate in an intensive-care situation for at least 24 hours postpartum. Blood glucose level should be monitored hourly for 6 hours. If the neonate shows no signs of respiratory distress, hypocalcemia, or hyperbilirubinemia at 24 hours after delivery, it is safe to discharge to the normal nursery.


With the advent of tools and techniques to maintain normoglycemia before, during, and between all pregnancies complicated by diabetes, infants of diabetic mothers now have the same chances of good health as infants born to nondiabetic women. Animal and human studies clearly implicate glucose as the teratogen. These studies and others emphasize the need for preconceptional programs, and the need for support systems to facilitate the maintenance of normoglycemia throughout pregnancy. The morbidity and subsequent development of the infant of the diabetic mother are associated with hyperglycemia. Therefore, the goal of

insulin therapy is to achieve and maintain normoglycemia before, during, and after all pregnancies complicated by diabetes.


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