Diana E. Alexandrescu, MD
Sonal Bhandari, MD
Departments of Pediatrics and Pediatric Endocrinology
SUNY Downstate Medical Center
Brooklyn, NY
Pre Test: (detailed explanations at the bottom):
Q1. You are a 3rd year resident in a NICU taking care of a 2 hour old full term baby boy, born by C section to a 26 year old mother with a 10 year history of Type 1 Diabetes Mellitus (T1DM). Your main concerns in the next following days related to DM include the following, except:
a. Hypoglycemia
b. Hypomagnesaemia
c. Hypothermia
d. Hypocalcemia
e. Polycythemia
f. Hyperbilirubinemia
g. Hypoxemia
h. Hypothermia
i. All are of concern
Q2. You are in your office with the mother of a 2 week old baby girl. The mother says that that she has Type 2 DM (T2DM) and was on Insulin during pregnancy. She wishes to return to her previous Glyburide regimen. The baby otherwise healthy. The mother is eager to breastfeed her baby. Which of the following statements regarding breastfeeding is FALSE?
a. The oral anti-diabetic agents thought to be generally safe during lactation are Glyburide and Metformin..
b. The maternal history of diabetes is a contraindication for breastfeeding
c. Exclusive breastfeeding decreases the risk of obesity and diabetes later in life
d. Mothers with diabetes may have delayed lactation by 2-3 days compared to healthy women
e. All of the statements listed above are TRUE.
Q3. Which one of these nutritional recommendations would you make as the child grows older?
a. Breastfeeding exclusively for 6 months and continued breastfeeding for at least 12 months.
b. Limit juice intake to 10 oz a day when the baby is going to be 1 year old
c. 20% of the diet should consist of carbohydrates
d. After 1 year of age, keep the child on a strict diet to prevent obesity
Q4. TRUE or FALSE: Women with DM during pregnancy have lower nutritional requirements compared to healthy women because they have to maintain a tighter glucose control.
Q5. TRUE or FALSE: The perinatal morbidity and mortality of infants of diabetic mothers reach levels close to those found in general population if a euglycemic state in maintained throughout pregnancy.
Q6. The following are more common for infants born to mothers with Gestational diabetes (GDM), EXCEPT:
a. Macrosomia
b. Hypoglycemia
c. Spina bifida (Neural Tube Deficits or NTDs))
d. Respiratory distress syndrome
e. Diabetes or metabolic syndrome
OBJECTIVES
On completion of this module, residents or health care professionals will:
1. Review the criteria for diagnosis of gestational diabetes
2. Describe briefly nutritional and medical interventions to improve glucose control during pregnancy
a. Describe the carbohydrate metabolism during the pregnancy, and.
b. Changes in carbohydrate metabolism in the early neonatal period
3. Recognize short-term complications of diabetes in pregnancy
a. Differentiate between complications related to pre-gestational and those of gestational diabetes, and
b. Perform the necessary interventions in the early neonatal period
4. Understand the importance of breastfeeding an infant of diabetic mother including the safety and side effects of diabetes medications during pregnancy and lactation
5. Be aware of the long-term consequences of being an infant of a diabetic mother
6. Identify measures to improve the outcome of these infants in the community where they work.
FACILITATOR PREPARATION:
1. Infants of Diabetic Mothers in AAP Textbook of Pediatric Care - Chapter 97: Abnormalities of Fetal Growth, by Suhas M. Nafday, MD, MRCP (Ire), DCH
2. Pregnancy complicated by diabetes mellitus in Fanaroff and Martin's Neonatal-Perinatal Medicine, 8th edition, 2006 - Chapter 15, Martin RJ, Fanaroff AA, Walsh
3. Infant of Diabetic Mother, eMedicine , Potter CF, Kicklighter SD, updated August 2006
4. Diabetes Mellitus complicating pregnancy - Chapter 37, in Normal and Problem Pregnancies, Gabbe Obstetrics, 5th edition, 2007 by Gabbe SG, Niebyl JR, Simpson JL.
Introduction:
In an era faced with the epidemic proportions of obesity and diabetes, any pediatric health practitioner is frequently challenged to offer explanations and solutions. The explanations can be found sometimes in the early development of the fetus and in the characteristics of the environment in which he/she develops. The solutions are also specific to the maturation stage and are mainly aimed to prevent undesirable outcomes.
In this context, the "infant of diabetic mother" is defined as a clinical entity which links a multitude of genetic, biochemical and clinical information in early and late development. To the student it forms a perfect clinical exercise for all the metabolic and endocrine pathways that seems so unattractive in the first years of medical school. To the pediatric residents and other health practitioners, it is a relatively common clinical encounter. Apart from the obvious problems related to diagnosis and management, it offers the valuable opportunity to educate parents and children, to later prevent diabetes and obesity.
Relatively recent data from CDC show that maternal diabetes can be found in 25.3 per 1000 women, with 90% of the cases attributed to gestational diabetes mellitus. Furthermore, more recent national surveillance shows alarming rates for gestational diabetes, reaching to more than 10% of women of childbearing age in some states (1,2).
Since the advent of specialized maternal, fetal and neonatal care, the morbidity and mortality of infants of diabetic mothers (IDMs) has decreased considerably (more than 30 times). Today, the feared complications of diabetes during pregnancy, such as still birth, devastating cardiac malformations or the neurodevelopmental consequences of hypoglycemia, are rare. Near-normal glucose control can be achieved throughout pregnancy with careful prenatal screening and supervision, nutritional interventions and insulin therapy. These interventions decrease the morbidity and mortality rates of IDMs to rates that are comparable to those observed in the general population. Failure to achieve this euglycemic state will result in increased perinatal morbidity.
The facilitator should present the case to the group. Careful and thorough discussion of the cases is encouraged. The cases are provided with short explanations. More complete observations completing the objectives are at end of module.
Always begin by having residentsanswer the question, make the list, etc.
Case 1:
You are called to the Operating Room for the emergency C Section of a full term baby, noticed to have late decelerations in external fetal monitor. You discuss the case briefly with Dr. Smith, the on-call obstetrician. The mother, age 34, has been in labor for the last 14 hours, with no progression of cervical dilation or fetal stance for the last 6 hrs. She came for obstetrical evaluation only 3 weeks prior and she was diagnosed with gestational diabetes at that time. In the last weeks her blood glucose has been averaging around 140-150, but she has not taken the insulin as prescribed.
The baby is placed under the radiant warmer and is dried. He is vigorous and only requires mild stimulation. His birth weight is 4560 grams (10 lbs 2 oz). No signs of respiratory distress are detected and the baby is put on mom's breast for feeding. 30 minutes later the baby is taken to the Observation unit. The nurse tells you that the baby's glucose is 34 mg/dl.
Q1. List the potential immediate complications:
A1. Complications in Infants of Diabetic Mothers
Complications:
- Birth trauma (shoulder dystocial, abdominal organ injury, brachial plexus injury, clavicular fracture, cephalohematoma, diaphragmatic paralysis, facial nerve palsy, ocular hemorrhage, external genitalia hemorrhage, subdural hemorrhage)
- Asphyxia
- Hypoglycemia
- Hyperbilirubinemia
- Macrosomia
- Polycythemia and hyperviscosity
- Respiratory distress syndrome, transient tachypnea of newborn, meconium aspiration, air-leak syndromes, diaphragmatic paralysis
- Congenital anomalies (caudal regression, small left colon syndrome, hypertrophic obstructive cardiomyopathy, septal hypertrophy, double-outlet right ventricle, truncus arteriosus, anencephaly, spina bifida, hydrocephalus)
- Neurologic instability (short and long term)
- Hypocalcemia, hypomagnesemia
- Organomegaly
- Renal vein thrombosis, transient hematuria
Modified from - Infants of Diabetic Mothers in AAP Textbook of Pediatric Care - Chapter 97: Abnormalities of Fetal Growth, by Suhas M. Nafday, MD
Q2. What are the immediate interventions for this baby?
A2. The baby is macrosomic, with a weight above the 90th percentile for gestational age. Although the baby breastfeeds in the first minutes of life, he goes on the develop hypoglycemia. Breastfeeding in the first hour of life is highly recommended and it is thought to improve the bonding between mom and baby, the future feeding behavior and also, in the particular case of the IDM, will decrease the possibility of hypoglycemia. Frequently, breastfeeding at this time is technically difficult because of the constraints of the operating room, the possibility of general anesthesia administered to the mother and the clinical condition of the baby. This requires a highly motivated medical team, able to adapt the strict rules of the OR and the required medical interventions, and to accommodate the needs of both mother and baby.
The case continues:
In the Observation Unit, the infant is found to have a blood sugar of 34 mg/dl and to be very jittery. He is administered a Dextrose 10% IV infusion calculated to give maintain a glucose infusion rate of 6-8 mg glucose/kg/min. An adequate infusion is essential because the resultant hyperglycemia results in increase release of insulin and rebound hypoglycemia. The baby's blood sugar corrects with the dextrose 10% infusion and his feeds are increased gradually as the Dextrose 10% infusion rate is lowered. He does well and goes home with mom 4 days after delivery.
Q3. What nutritional advice should the mother have for infant feeding in the immediate post partum period?
A3. The mother should be encouraged to breast feed exclusively the baby for at least 6 months, irrespective of her current treatment with Glyburide, Metformin or Insulin. These medications are permitted using Guidelines for mediocations used during pregnancy and lactation.
Q4. Of what benefit would this advice be for the mother?
A4. Breastfeeding has been showed to have beneficial effects on the baby as well as the mother. The mother may have lower insulin or anti-diabetic agents requirement, but the mother still needs to monitor her blood glucose regularly and have an adequate nutritional intake.
Apart from the medical benefits, breastfeeding also improves the bonding experience for mothers and babies, creating a sense of security and lower anxiety for both of them.
The Case continues:
2 weeks later, you see the same mom and baby in your office. She tells you about her stressful social situation. During her pregnancy she was homeless without any support from her family. Since the delivery of her beautiful baby boy she has decided to "put her life in order". She now lives in a shelter and is taking night classes in a community program. The baby gained 6 oz from the birth weight and he is exclusively breast fed.
Mom is worried now about the long term complications for the baby of her uncontrolled GDM and asks you what she can do to prevent them.
Q5. List long term complications:
A5. Again, always begin by having residents make the list.
The baby is gaining weight appropriately for the age and he is also breastfed, which is excellent. The 2 major complications associated with diabetes during pregnancy are obesity/diabetes and neurodevelopmental delays. There are a multiple of hereditary, in-utero programming and post natal environmental factors affecting the likelihood of development of T2 and GDM. The neurodevelopmental consequences are secondary to the hypoglycemia, hypocalcemia, hyperviscosity syndrome with depletion of CND iron stores. A more complete description can be found in Karp RJ. (in press) Health (in) Wachs TD & Bremner G. (Eds) Blackwell Handbook of Infant Development: 2nd Edition. Volume 2: Applied and policy issues. London. Blackwell Publishers.
Q6. What interventions are suggested?
A6. Effective interventions to decrease the risk of obesity and diabetes are the continuation of breastfeeding and avoidance of high-sugar or high caloric foods in an attempt to limit weight gain. As noted in the case study, this family is in need of support. A full description of "wrap around therapy" can be found in part III of the Teacher's Guide in the module on Failure to Thrive by Drs. Wilbur and Frank. The chapter by Karp in Wachs and Bremner includes a description of Calvin Sia's "The Medical Home" as might be applied here.
Case 2
Your colleague, Dr. Smith, has another case for you. Mrs. Alexander is 28 years old and has had Insulin Dependent Diabetes for the last 20 years. She is now 35 weeks pregnant and admitted to the Labor and Delivery Unit due to her high risk pregnancy. She has had diabetic nephropathy and hypertension for several years and has tried to conceive for the last 4 years. So this is a highly desired pregnancy. Although she has had excellent glucose control during pregnancy, Dr. Smith is worried about the baby's low estimated fetal weight and wants you to discuss with mom about the possible/potential complications after delivery. You review the chart and find that her prenatal sonograms did not show any congenital anomalies and her last glycated hemoglobin is 8 %, and you get ready to walk into her room.
Q8. What impact does quality of glucose control have on outcome?
A8. Good control of diabetes prior to conception can reassure you and the mother that the risk of congenital malformations is low or close to that of the general population. Moreover, her prenatal sonograms failed to show any anomalies.
Q9. What factors may be out of reach for physicians providing prenatal care?
A9. Small for gestational babies are usually born to mothers with long standing diabetes and vasculopathies. This is thought to be caused by decreased supply of nutrients through a placenta with affected vasculature. As their macroscopic counterparts, SGA babies are prone to hypoglycemia in the first hours of life, but it usually occurs 4-6 hours after delivery and it is caused by decreased glycogen stores, rather than by hyperinsulinism.
A potential danger/complication for the baby in this case is the respiratory distress syndrome (RDS), related to prematurity (35 weeks gestation) due to decreased surfactant production. You can explain to the mother the usual RDS management in the Neonatal Intensive Care Unit (use of surfactant, ventilatory support, clinical course).
The case continues:
The baby is delivered via C-section 1 week later. She is initially vigorous, but develops grunting and sub-costal retractions in the first 10 minutes of life. Her weight is 2010 gr. After mom kisses her, you put her on nasal CPAP and transfer her immediately to the Neonatal ICU.
Q10. What other complications, apart from hypoglycemia, you have to be aware of in managing this baby in the NICU?
A10. The baby is born small for gestational age, a known complication of maternal vasculopathy. She developed signs of respiratory distress syndrome: tachypnea, retractions, grunting. She is managed with nasal positive pressure support and improves rapidly.
Other possible complications are delayed hypoglycemia due to low glycogen stores, hypocalcemia, hypomagnesemia, polycythemia, thrombocytopenia, hypothermia. Due to the low glycogen stores, small for gestational age babies of diabetic mothers are at risk for delayed hypoglycemia - 6-8 hours after delivery.
The baby's polycythemia resolves only with hydration and she is weaned from NCPAP in the next 3 days. She goes on to develop hyperbilirubinemia and spends another 2 days under phototherapy. She is initially fed expressed breast milk by a nasogastric tube. By one week of life she is able to breast feed and goes home with her mother.
SUMMARY:
In these case studies, we have shown the breadth of problems that might be faced by the infant of a diabetic mother and those of us responsible for the infants care. It is essential to have a comprehensive history in oprder to develop a protocol for care. Differences among infants of mothers with T1-, T2- and GDM may appear at first to be subtle. In reality, however, they are not as placental function and timing of insult from the nutritional or "fuel mediated teratogenisis" are critical. As with all nutrition related care, an overview that includes issues affecting social environment are equally important. Specific responses to the listed objectives follow in the Appendix material.
APPENDIX
Objective 1: Review the criteria for diagnosis of gestational diabetes.
Gestational diabetes is defined as a state of impaired glucose tolerance, first discovered during pregnancy. Most of the times the fasting glucose level is within normal limits, but further stress on the function of the beta pancreatic cells, reveals abnormal levels. The Fifth International Workshop-Conference on Gestational Diabetes Mellitus devised in 2007 a screening strategy for detecting GDM. Changing the previous recommendation of universal screening of pregnant women, the current strategy applies to women older than 25 years, with family history of type 1 or 2 diabetes, severe obesity, and part of specific ethnic groups (Native American, Hispanic, and African -American, Asian or Pacific Islands ancestry). (3)
The screening test can be done either as a 1 step or 2 step procedures, depending on the risk of GDM. The first step is a 50 grams Glucose Challenge Test with a serum glucose measurement at 60 minutes. If the glucose level is higher than 130-140 mg/dl, a 3 hour Oral Glucose Tolerance Test, using 75 or 100 grams will follow. If 2 abnormal results are obtained, treatment for GDM is started. The screening is usually done between 24-28 weeks of gestation, or earlier if the suspicion of GDM is high.
Table 1. Diagnosis of GDM by OGTT
100-g Glucose Load (mg/dL) 75-g Glucose Load (mg/dL)
Fasting 95 95
1 hour 180 180
2 hour 155 155
3 hour 140 -
Adapted from (3)
Objective 2: Describe briefly nutritional and medical interventions to improve glucose control during pregnancy.
Prevention of hyperglycemic episodes and rigorous control of blood glucose is the mainstay of treatment in both gestational and pre-gestational diabetes. Among the recommendations are:
- achievement of optimal blood glucose control and normal Hob A1c for women with pre-gestational diabetes, before conception
- non-weight bearing, low impact physical exercise for 30 minutes a day
- dietary recommendation in conjunction with a nutritionist to create an individualized medical nutrition therapy include: increase dietary soluble fibers, mild carbohydrate restriction, caloric intake of 25-35 Kcal/kg/day of present pregnant weight, adjusted to provide a lower weight gain for obese women and a greater weight gain for under-weight women.
- Insulin or Glyburide, when the above measures fail. Of the oral hypoglycemic agents, Glyburide is the only one proven in clinical trials as it is to be minimally transferred across the placenta thus minimizing the risk of neonatal hypoglycemia.
- All these measures should be targeted for capillary blood glucose of <96 mg/dl fasting, <140 mg/dl at 1 hour, <120 mg/dl at 2 hours after starting the meal. (3)
Objective 2a: Be able to describe the carbohydrate metabolism during the pregnancy.
Glucose is the major substrate utilized by the fetus for energy supply and it crosses the placenta via a carrier-mediated transport down a concentration gradient. Thus the fetal glucose levels are at 70-80% of the maternal value.
Maternal insulin cannot cross the placenta. Although fetal insulin is synthesized by the developing pancreatic cells as early as 8 weeks, a response to maternal high glucose levels is minimal in first half of the pregnancy.
In a normal pregnancy, in the first trimester of pregnancy, the increased levels of estrogen, progesterone and cortisol are thought to cause hyperplasia of pancreatic beta islet cells and better insulin sensitivity of the tissues. This contributes to an anabolic state with formation of fatty acids and increased maternal fat stores. The fasting glucose levels decrease and reach a nadir by the 12th week of gestation. A lower insulin requirement for women with pre-gestational diabetes is commonly observed during early pregnancy and it is attributed to an increase in insulin sensitivity, particularly in women with insulin resistance prior to conception.
In the second trimester, insulin resistance develops gradually and leads to a physiologic "diabetogenic" state. Hormones like human placental lactogen, human placental growth factor, and prolactin are classically considered to contribute to the tissue resistance to insulin. More recently, several other substances, alfa TNF and leptin, were added to this category. In normal pregnancies, despite these factors, maternal glucose levels and response to glucose challenge remain within normal limits. A borderline dysfunction of the pancreatic beta cells will lead to even a greater relative insulin resistance and the glucose levels will increase.
As previously mentioned, in the first 20 weeks of gestation, the fetal pancreatic islet cells cannot respond to increased glucose levels. After this period, beta cell hyperplasia occurs as a response to hyperglycemia and higher and higher fetal insulin is produced. This pathway was first described by Pedersen in 1954.
The pathological consequences recognized at birth are the result of fetal hyperglycemia, fetal hyperinsulinemia and a combination of both these factors:
- Insulin exerts its anabolic function, using the available surplus of glucose and other nutrients to form increased stores of fat and glycogen. This leads to selective organomegaly. The brain and the kidney are spared, but cardiomegaly and hepatomegaly occur.
- Insulin is the main growth factor in utero and by both these 2 actions it promotes the increase in fetal weight.
- Insulin increases the fetal metabolic rate and oxygen consumption leading to a relative hypoxemia. Moreover, glycated Hob A1 has higher affinity for oxygen. This results in polycythemia. In order to support the expanding hematocrit, iron stores are diverted from vital organs such as brain and heart. The functional consequences of fetal iron distribution and selective organ iron deficiency are still being investigated. It is thought that early postnatal iron deficiency results in myopathies and altered neurodevelopment (19, 22).t. (reference)
- Insulin decreases surfactant production in the last weeks of pregnancy, interfering with fetal lung maturation and predisposing the newborn to respiratory distress syndrome
- Insulin was proven in rats to produce dysplasia of ventromedial hypothalamic nucleus, responsible for satiety, thus setting the basis for obesity later in life. (5)
Objective 2b: Be able to describe the changes in carbohydrate metabolism in the early neonatal period.
Once the supply of maternal supply of nutrients is cut off at the time of delivery, a rapid fall occurs in the levels of glucose, aminoacids, fatty acids and electrolytes. At the same time there is an acute increase in circulating epinephrine, norepinephrine and glucagon and a decrease in insulin. These hormonal changes stimulate glycogenolysis and gluconeogenesis, leading to a steady state of glucose production and maintenance of normal plasma glucose concentration.
In normal conditions, the glycemia reaches a nadir at 30-90 minutes after delivery, but later rapidly increases to a steady state by 2-3 hours of life. In the case of the newborn of a diabetic mother, hyperinsulinemia persists longer after delivery, with high insulin to glucagon ratio, inhibiting glucose production. Moreover the high insulin stimulates glucose uptake by the peripheral tissues, such as muscle and fat.
Objective 3: Recognize short term complications of diabetes in pregnancy.
Macrosomia
Classically recognized as a complication of diabetes in pregnancy, macrosomia has been variably defined as birth weight higher than 4 - 4.5kg, or more than the 90th percentile for gestational age. It occurs in 26 % of infants born to diabetic mothers and 10% of normal pregnancies.
Apart from the obvious difference in weight, infants of diabetes mothers have a higher absolute fat mass and decreased lean body mass. These differences present even if the weight is normal at birth. The fat is preferentially distributed in the shoulders and interscapular area. (Rudolph)(13)
In addition, the liver and heart are often enlarged and the skeletal length is proportional to the weight. There is no increase in size of the brain or kidney, because their growth is not dependent on insulin. Thus, infants of diabetic mother usually have higher weight and length, but normal head circumference for age.
The explanation for these changes lies in the characteristics of carbohydrate metabolism discussed above. High maternal glycemia is considered to be the main factor that drives the increase production of insulin and thus, maternal glucose control in the last trimester best predicts the birth weight. But apart from glucose, other nutrients such as fatty acids and amino acids are transferred through the placenta in increasing quantities. Insulin exerts its role as an anabolic hormone and uses the existent surplus of nutrients to increase fat deposition, especially during the last trimester of pregnancy.
Macrosomia is the most feared complication as it can lead to several of birth injuries as described below. (see table).
Birth injuries for IDM
Brachial plexus injury
Clavicular fracture
Diaphragmatic paralysis
Cephalhematoma
Facial palsy
Ocular hemorrhage
Subdural hemorrhage
Abdominal organ injury
Table 2. List of potential birth injures in newborns of diabetic mothers - adapted from: "Concepts of neonatal care of the infant of diabetic mother", Cowett R.M, Ital J Pediatr 2004; 30;25-31 (17)
Small for gestational age
Intrauterine growth restriction is directly related to the severity of maternal diabetes. Maternal vascular disease decreases uterine artery blood flow and causes uteroplacental insufficiency. This not only leads to decreases the availability supply of nutrients but also results in fetal hypoxemia. Furthermore, preeclampsia and ketoacidosis may further decrease the uterine blood flow and cause fetal death in severe cases.
Hypoglycemia
There is a controversy involving the definition of hypoglycemia. Neonatal hypoglycemia is defined by different resources as a blood glucose level less than 35-40 mg/dl in a preterm or term neonate. It is present in up to 40% of cases and it is more common in macrosomic infants. (21) .
As previously shown, a drop in newborn glucose level is normal in the first 30-90 minutes after delivery, but no absolute threshold of physiologic hypoglycemia has been defined.
In the face of persistent neonatal hyperinsulinemia this fall is prolonged and deeper. The degree of neonatal hypoglycemia is influenced by maternal glucose control during the latter half of pregnancy and during labor and delivery. Prior poor maternal glucose control results in beta cell hyperplasia and persistent release of high levels of insulin following delivery. Poor maternal glucose control during delivery, by either insufficient insulin or fluids containing high amounts of dextrose, leads to increase fetal insulin release, whose effects persist after delivery.
Hypoglycemia in LGA infants usually occurs 1-2 hours after delivery. In contrast, small for gestational age infants develop hypoglycemia 6-12 hours after delivery due to limited glycogen stores. and he/she can develop. . Clinically, hypoglycemia can manifest as lethargy, poor feeding, apnea or jitteriness. If the hypoglycemia is prolonged, the myocardial contractility decreases and congestive heart failure follows shortly. Moreover, neonatal hypoglycemia can cause permanent neurological damage. (11)
Although there is no absolutely proven threshold that protects newborn from the adverse effects of hypoglycemia, most authors agree that to maintaining neonatal glycemia at a level above 40 mg/dl is protective. (2,13,21)
Hypocalcemia
Neonatal hypocalcemia is defined as calcium levels less than 7 mg/dl. The mechanism responsible for this is not clear, but seems to be due to neonatal hypoparathyroidism. It is hypothesized that changes in maternal metabolism leads to an increased release of PTH, resulting in increased release of calcium in the maternal circulation and thus a higher transport of calcium through the placenta. The resulting higher levels of calcium in fetal circulation delays normal parathyroid function development. (Tsang 1975). The severity of maternal diabetes has been directly correlated to the severity of hypocalcemia. (6)
The nadir of calcium concentration is reached at 24-72 hours of life. Infants can be asymptotic or present with jitteriness, lethargy or seizures. No intervention is necessary if it the infant remains asymptomatic, since hypocalcemia usually improves spontaneously.
Hypomagnesemia
Hypomagnesemia in a neonate is defined as a level less than 1.52 mg/dl. As with hypocalcemia, low magnesium levels are correlated with the severity of maternal disease. Increase magnesium losses in urine due to glycosuria, leads to a diminished supply to the fetus. Moreover, low fetal magnesium levels inhibit the release of PTH, which further decreases calcium levels. Hypocalcemia in the presence of hypomagnesemia cannot be corrected, unless magnesium correction is also instituted.
Polycythemia
As described or explained above, increased red blood cell mass increases in the face of fetal hypoxemia and hyperinsulinemia. It is present seen in approximately 20-30% of infants of diabetic mothers and may present clinically as a reddish discoloration of the skin, known as "ruddy appearance". The draw on iron stores leads to a paradoxical depletion of iron stores and iron deficiency without anemia, a recognized cause for developmental delay. (See Karp RJ in Wachs and Bremner)
Hyperbilirubinemia
High indirect bilirubin levels are frequently seen in infants of diabetic mothers. Although several mechanisms have been studied, the cause of hyperbilirubinemia remains unclear. Polycythemia raises bilirubin levels resulting in neonatal jaundice. However, severe hyperbilirubinemia can occur even in the absence of polycythemia.
Hypothermia
Hypothermia can occur in the first hours of life as the only clinical sign of hypoglycemia. Another reason may be the relatively larger body surface area, which makes them more vulnerable.
Thrombocytopenia
Thrombopoesis is diminished as a result of the "crowding-out" of bone marrow by the excessive of erythrocytes precursors.
Renal vein thrombosis
This is a rare complication seen in IDMs and may be related to polycythemia, hypotension or a hypercoagulable state. Renal vein thrombosis is seen even in the absence of increased red blood cell mass. It causes hematuria, flank mass, hypertension or embolic phenomena.
Respiratory distress syndrome
The incidence of respiratory distress syndrome has decreased drastically in the last 30 years with better management of diabetes and evaluation of fetal lung profile by amniocentesis. The current research shows that insulin directly blocks the effect of cortisol to increase surfactant and can interfere with substrate bioavailability for its production. (12)
As most infants of diabetic mothers undergo C section, transient tachypnea of the newborn and persistent pulmonary hypertension are important differential diagnoses in the early neonatal period.
Objective 3a: Differentiate between complications related to pre-gestational and those of gestational diabetes.
Whether diabetes is present at the time of conception or occurs in the second or third trimester has different impact of the developing fetus. Most of the clinical conditions observed after birth are common to both pre-gestational and gestational diabetes - macrosomia, hypoglycemia and electrolyte imbalance, respiratory distress syndrome, etc. The congenital malformations are almost exclusively found in infants born to mothers with diabetes type 1 or 2, and are 2-4 times more common than in the general population.
Poor control of maternal diabetes in the first trimester is the hallmark of congenital anomalies and Hob A1c level can be used as a predictive marker. The higher the hemoglobin A1c value in early pregnancy, the Mothers with values less than 7% have no greater risk of having an infant with congenital anomalies than mothers without diabetes. (21) If the Hob A1c is between 7.5 and 8.5, the risk is 5%. If the values are higher than 10%, 22% of the babies will have one or more congenital anomalies. (FPR DIANA ref needed)
The first 8 weeks of intrauterine life represent the key period of organogenesis, when any insult can result in adverse outcomes. There is not one single factor responsible for the array of malformations seen, but hyperglycemia is considered the major culprit. As mentioned above, the fetal pancreas cannot secrete insulin to counteract the increased supply of glucose through the placenta, leaving the fetus vulnerable. The exact mechanism by which hyperglycemia acts on the developing fetus are poorly understood (inhibition of glycolysis, alterations in neural tube closure, induced yolk sac dysfunction). Other factors thought to cause harm are the ketones, somatomedin inhibitor, arachidonic acid deficit and free oxygen radicals. (12)
The congenital malformations seen in pre-gestational diabetes can affect:
- central nervous system - anencephaly, open spina bifida, holoprosencephaly
- heart - ventricular septal defect, transposition of great vessels, coarctation of aorta, aortic stenosis
- skeletal structures: sacral agenesis or caudal regression syndrome are thought to be the most characteristic finding in diabetic embryiopathy
- renal or urologic anomalies - agenesis or obstructive lesions
Objective 3b: Know the necessary interventions in the early neonatal period.
Hypoglycemia
The treatment guideline for hypoglycemia varies from one institution to another and most of the interventions are still controversial. Generally, if the baby is asymptomatic and the blood glucose level is higher than 35 mg/dl, early feeding with breast milk, formula or dextrose in water are initiated and the blood glucose is monitored closely.
When the glucose level is lower than 25-35 mg/dl in a symptomatic or asymptomatic baby, parenteral dextrose infusion is recommended.
A symptomatic baby (see above for clinical signs) is treated with dextrose infusion irrespective of the glucose level.
If the baby is otherwise stable and serial blood glucose measurements are reassuring, the rate of dextrose infusion is gradually lowered as the baby feeds more and more.
Hypocalcemia and Hypomagnesemia
Symptomatic infants need to receive 10% calcium gluconate intravenous infusion. Magnesium is usually added since hypocalcemia will not correct in the setting of a low magnesium level.
Polycythemia
For asymptomatic infants with polycythemia, close monitoring is the only required intervention. If the baby develops signs of polycythemia or hyperviscosity, a partial exchange transfusion can be done. The risks of polycythemia related symptoms have to be closely weighted against the huge risks of the partial exchange transfusion.
Hyperbilirubinemia
Close monitoring of blood bilirubin levels is sometimes required. Phototherapy or exchange transfusions follow the general guidelines for hyperbilirubinemia.
Respiratory distress syndrome
Prenatal lung maturity testing by amniotic fluid analysis is done for most of the pregnant diabetic women. However, some infants need to be delivered even if their lung profile is immature.
Objective 4: Understand the importance of breastfeeding an infant of diabetic mother.
Breast feeding has long been recognized as the best feeding method of the newborn in the first year of life. In this respect, the particular case of infants of diabetic mothers makes no difference from the norm.
The beneficial effects of breastfeeding are recognized for mothers with gestational or pre-gestational diabetes, as well as for their babies. The Fifth International Workshop-Conference on GDM, cites studies that have shown lower rates of postpartum diabetes and better fasting glucose levels in breastfeeding women with GDM and a protective effect with lower diabetes rated in healthy women who breastfeed.
A multitude of clinical studies and meta-analyses of babies born to mother with diabetes confirmed that breastfeeding decreases the incidence of obesity and diabetes in childhood and later in life. (7)
But for the mother with diabetes the decision to breastfeed can be a difficult one and the health care practitioner needs to acknowledge and address these issues.
The mother with type 1 diabetes faces an increased risk of infection, unstable metabolism and increased risk of ketoacidosis. Although she may need less insulin than during pregnancy, her risk of hypoglycemia is higher. If type 2 diabetes precedes pregnancy, the mother may be concerned with the safety of her oral anti-diabetic agents in lactation.
Issues related to the infant can also influence the decision to stop breastfeeding. In the neonatal period, the infant of diabetic mother can have a poor suck, can be hypotonic or have medical problems that warrant separation from the mother and rapid formula feeding in the first hours of life.
Know the safety and side effects of diabetes medications during pregnancy and lactation Insulin is the first choice medication to manage pre-gestational diabetes or gestational diabetes uncontrolled by diet. The exogenously administered hormone, as well the endogenous insulin, does not cross the placenta and hence does not pose a risk for the fetus.
Of the suphonylureas, Glyburide is the only agent considered safe in pregnancy. It has is minimally transferred across the placenta and is not associated with neonatal hypoglycemia. (3)
Metformin can cross the placenta and to date there is insufficient evidence to support its use in GDM.
Acarbose and thiazolidinediones have not been fully evaluated for their safety in pregnancy.
Generally, insulin and most oral anti-diabetic agents are considered generally safe during lactation. Mothers need intense follow-up for any side effects that may appear. In each case, but their side effects for the mother have to be closely followed the risk of such effects. e.g., maternal hypoglycemia.
Objective 5: Be aware of the long term consequences of being an infant of a diabetic mother.
Adding to the direct sequelae of early neonatal complications, the long term follow up of children born to mothers with diabetes revealed two important outcomes:
Several studies have shown an increased risk of obesity for IDMs, especially if they were macrosomic at birth. Although the precise mechanisms were not completely elucidated, obesity as a consequence of diabetes in pregnancy is widely accepted. Some of the incriminated factors are genetic factors, fetal beta cell hyperplasia with consequent hyperinsulinemia, behavioral and cultural factors influencing diet.
Moreover, infants of diabetic mothers are also at greater risk for developing metabolic syndrome later in life. (8)
Offsprings of women with insulin dependent diabetes are also at increased risk of developing T1DM later in life. Paradoxically, this risk has been shown to be higher if the father is diabetic, thus showing that genetic factors increase the risk for development of diabetes. (9)
- Neurodevelopmental prognosis
Overall, hypoglycemia in the first day of life poses the highest risk for neurodevelopmental deficits. But even in the absence of low glucose, infants of diabetes mothers have been shown to have delayed motor and cognitive development. More specifically, poorer recognition, memory (10) and lower performance on Stanford - Binet Intelligence scores (11) were noticed.
Acute perinatal events, acidosis, iron deficiency and plasma beta-hydroxybutyrate have also been linked to these long-term delays. (10, 11, 15, 22)
Objective 6: Identify possible measures to improve the outcome of these infants in the communities were they work.
The facilitator should encourage group discussion of possible community interventions.
One possible approach is to start discussion based on prevention measures for the different complications. Example: prevention of neonatal hypoglycemia - close monitoring of blood glucose and early feeding (encouraging breast feeding immediately after birth); prevention of obesity later in life - by breastfeeding education and campaigns, dietary advice, recognizing the psychological and familial factors implicated in food behavior of the mother and child.
Another part of the discussion should be focused on finding the target audience for the proposed interventions. Example: obstetricians for regular OGTT testing of pregnant women, mothers for compliance with the proposed testing and with the diet or medication recommended, pediatric nurses for noticing early signs of hypoglycemia, neonatal intensivists for offering clear guidelines for management of complication, pediatricians for educating health care providers, mothers and children.
References:
1. Diabetes During Pregnancy, United States 1993-1995, MMWR, May 1998; 47(20): 408-414
2. Potter CF, Kicklighter SD, Infant of Diabetic Mother - eMedicine, updated August 2006
3. Metzger B, Buchannan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, Hod M, Kitzmiller JL, Kjos S, Oats JN, Pettitt DJ, Sacks DA, Zoupas C, Summary of Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus - Diabetes Care, Vol 30 (2), July 2007, S251-S260.
4. Strehlow SL, Greenspoon JS, Janzen C, Palmer S - Current Obstetrics and Gynecological Diagnosis and Treatment, 10th edition - Chapter 18 - Diabetes Mellitus and Pregnancy
5. Plagemann A, Harder T, Janert U, Rake A, Ritterl F, Rhode W, Dorner G, Malformations of the hypothalamic nuclei in hyperinsulinemic offsprings of rats with gestational diabetes, Dev Neurosci 1999, 21;58-67
6. Tsang RC, Chen I, Fiedman MA, Parathyroid function of the infant of diabetic mother, J Pediatr 1975, 86;399
7. Mayer-Davis E, Rifas-Shiman SL, Zhou L, Hu F, Colditz G, Gillman MW - Breast feeding and risk of childhood obesity, Diabetes Care 2006; 29; 2231-2237
8. Boney CM, Verma A, Tucker R, Vohr BR: Metabolic syndrome in childhood: association with birth weight, maternal obesity and gestational diabetes mellitus, Pediatrics 2005 Mar; 115(3):e290-6
9. El-Hashimy M, Angelico MC, Martin BC, Krolewski AS, Warram JH, Factors modifying the risk of IDDM in offsprings of an IDDM parent - Diabetes 1995, 44: 295-299
10. deRagnier Ra et al, Neurophysiologic Evaluation of Auditory Memory in health Newborn Infants and Infants of Diabetic Mothers, J Pediatr 2000; 137 (6):777-784
11. Rizzo TA, Dooley SL, Metzger BE: Prenatal and perinatal influences on long term psychomotor development in offsprings of diabetic mothers, Am J Obstet Gynecol 1995; 173:1753-8
12. Gabbe SG, Niebyl JR, Simpson JL, Gabbe: Obstetrics - Normal and Problem Pregnancies, 5th edition, 2007 - Chapter 37 - Diabetes Mellitus complicating pregnancy.
13. Rudolph's Pediatrics, 21st edition, 2003 - Chapter 2.15 - Ogata ES, Infant of Diabetic the Mother.
14. Cordero L, Treuer SH, Landon MB, Gabbe SG, Management of infants of diabetic mothers, Ach Pediatr Adolesc Med, 1998, 152; 249-254
15. Ferris AM, Reece A: Nutritional consequences of chronic maternal conditions during pregnancy and lactation: lupus and diabetes, Am J Nutr 1994, 59 (suppl):465S-473S
16. Weintrob N, Karp M, Hod M, Short and long-range complications in offsprings of diabetic mothers, J Diab Comp 1996; 10:284-301
17. Cowett RM, Concepts of neonatal care of the infant of diabetic mother, Ital J Pediatr 2004; 30:25-31
18. Martin RJ, Fanaroff AA, Walsh M - Fanaroff and Martin's Neonatal-Perinatal Medicine, 8th edition, 2006, Chapter 15 - Pregnancy complicated by diabetes mellitus
19. Nold JL, Georgieff MK, Infants of diabetic mothers, Pediatr Cclin N Am 2004, 51:619-637
20. Infants of Diabetic Mothers in AAP Textbook of Pediatric Care - Chapter 97: Abnormalities of Fetal Growth, by Suhas M. Nafday, MD, MRCP (Ire), DCH
21. Gomella TL, Cunningham MD, Eyal FG, Zenk KE - Chapter 66 - Infant of Diabetic Mother in Neonatology: Management, Procedures, On-call Problems, Diseases and Drugs, 5th edition, 2004
22. Rao, R, et al. Perinatal Brain Iron Deficiency Increases the Vunerability of Rat Hippocampus to Hypoxic Ischemic Insult. J Nutr 1999; 129: 199-205
Annotated Pre-Test Answers
A1. Answer C. Among the conditions listed hyperthermia is the only incorrect option. Hypothermia, rather than hyperthermia, is sometimes found in infants of diabetic mothers. The large body size leads to an increase surface area, which in turn causes more heat loss. Moreover, hypoglycemia also contributes to hypothermia.
Hyperthermia is caused by a variety of conditions: thyroid disease, medications, dehydrations, excessive muscle activity and increased environmental temperature, etc., all of which are less likely found in a neonate.
A2. Answer B. Breastfeeding is the preferred modality of feeding the infants of diabetic mothers, irrespective of the maternal diabetes type. Glyburide and Metformin are considered safe during lactation, as these are excreted minimal amounts. For example, the maximum Glyburide dose for the infant was found to be <1.5% and <0.7% of the maternal weight-adjusted dosage.
Exclusive breastfeeding for the first 6 months was positively correlated with a lower risk of diabetes and obesity later in life.
The onset of stage 2 of lactogenesis may be delayed by 2-3 days in women with diabetes - thus occurring 5-6 days after delivery.
A3. Answer A. The American Academy of Pediatrics supports exclusive breastfeeding for approximately the first six months. The current studies show a decrease in the risk of multiple chronic conditions and infectious diseases. It also enhances maternal-child bonding, etc. For further information of this issue please refer to: American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2005;115(2):496-506. aappolicy.aappublications.org/cgi/content/full/pediatrics;115/2/496)
Other general recommendations are limiting juice intake to 4 oz per day and to ensure a balanced diet. Carbohydrates are considered the major source of calories and should account for 45-65% of calories in a healthy diet. Proteins should account for 10-35% and fat for 30% of total daily caloric intake. In children less than 2 years of age AAP recommends a higher fat intake (to 30-40%) to ensure adequate myelination of the nervous system.
Encouraging a healthy diet, rather than a restrictive diet, should be the main recommendation for any child at risk for obesity or diabetes. See comment in Part II Section II on "authoritative" parenting being more effective than "Authoritarian."
A4. Answer False. Women with diabetes during pregnancy have the same nutritional requirements as healthy women. Maintaining good glycemic control during pregnancy should not compromise adequate nutrition. Medical nutrition therapy for gestational diabetes focuses on food choices for appropriate weight gain, normoglycemia, and absence of ketones.
A5. The answer is TRUE. The vast majority of complications seen for infants of diabetic mothers can be prevented with a good blood sugar control during pregnancy. This requires a dedicated medical team and motivated mother.
A6. Answer C. During early gestational life, high glucose levels are thought to cause congenital malformations in infants of mothers with T1DM, such as spina bidifa, NTDs, or other nervous system malformations, congenital heart defects, skeletal or renal malformations.
As GDM occurs during the second half of pregnancy, after the completion of organogenesis, the infants born to mothers with these conditions do not have any major congenital anomalies.
