Preexisting diabetes is a well known risk factor for congenital anomalies since maternal hyperglycemia during time of embryogenesis has a teratogenic effect of the development of the embryo. Disturbance of fetal development causing these disorders must occur during the first 8 weeks of pregnancy. Our study aimed to determine the incidence of congenital anomalies in women with hyperglycemia diagnosed first in pregnancy and to identify clinical predictors for an increased risk for anomalies.
The majority of our study population belonged to the ethnic group of Mexican-American who are characterized by a high degree of glucose intolerance due to insulin resistance.
In pregnancies with type 1 diabetes there is a predominance of organ systems which are frequently affected by congenital anomalies.
The overall rate of major anomalies was slightly higher than in non-diabetic women of our population. The diagnosis of GDM is based on the glucose values obtained by an oral glucose tolerance test. All used definitions were derived from the original criteria from O’ Sullivan and Mahan from 1964. 39 For termination of thresholds for increased morbidity an untreated population of women with glucose intolerance in pregnancy would be needed. The aim of the present study was to determine the impact of borderline glucose intolerance on diabetic fetopathy indicated by neonatal obesity, fetal hyperinsulinism and placenta immaturity. Women with one abnormal value had significantly higher rates of LGA infants and infants with central obesity, of hyperinsulinism and neonatal hyperglycemia compared to women with normal oGTT with a rate similar to women with GDM.
Neonatal glucose testing is routine part of neonatal care in infants of mothers with known diabetes. There was no clinical useful predictor for hypoglycemia unless glucose values of an oGTT in pregnancy were available.
Several groups have been shown that women with glucose intolerance below the existing thresholds for gestational diabetes have a higher rate of macrosomia, cesarean delivery and preeclampsia.
The hypothesis of Pedersen proposed that glucose from the maternal circulation is a major regulator for fetal growth. Existing studies are limited to the investigation of the influence of maternal glycemia and LGA at time of birth.
The complexity of fetal growth occurs at several levels determined by the mother, the placenta and the fetus. In summary, our GDM management that was focused on tight glucose control could not lower the macrosomia rate in obese women. As demonstrated above, the reliability of maternal glycemic values to predict diabetic morbidity in the newborn is limited.
Existing data demonstrate the tight relation of the fetal AC in the third trimester with the LGA status at birth but there is a paucity of data investigating the predictive power of the fetal AC compared to maternal parameters known to influence fetal growth. The fetal AC measurement is an indirect approach to assess fetal morbidity in pregnancies with diabetes based on a clinical manifestation of fetal hyperinsulinism. Both our studies support the importance of the fetal AC in the management of pregnancies with diabetes. Fetal growth in pregnancies complicated by diabetes is related to maternal glycemia but it is controversial to what extend hyperglycemia determines morbidity. Both our studies demonstrated that a management based on relaxed glycemic criteria combined with fetal AC measurements is a safe approach for mother and child independent on the ethnic background of the study population. 23-28 Data from animal and clinical studies have demonstrated a correlation of the degree of maternal hyperglycemia during early pregnancy and the occurrence of malformations in the embryo. Thus, GDM is not considered as risk factor for congenital malformations because it typically develops not before the late second trimester coincident with the decreasing insulin sensitivity at this time. To exclude that our results were valid only for women with presumably undiagnosed preexisting type 2 diabetes, we repeat the analysis in a subgroup of women with normal oGTT (n= 1600) 1- 4 month postpartum. Maternal historical (age, prepregnancy BMI, prior pregnancy with macrosomia, stillbirth or anomalies) and clinical parameter (gestational age at first prenatal visit, first trimester exposure to sulfonylurea agents) and value of the initial fasting glucose and HbA1c were investigated regarding their relation to anomalies.
There was no predominance seen of any organ system affected with increasing fasting glucose values (figure 4). Additionally, we saw the same predominance of anomalies affecting the heart, skeleton and central nervous system in a mixed population of women with GDM and known type 2 diabetes as reported from pregnancies with type 1 diabetes.
Our women with GDM had an unusual wide range of the degree of glucose intolerance partly due to the high level of insulin resistance in the Mexican-American population in Los Angeles.
There is an ungoing discussion for three decade about the thresholds for defining maternal glucose intolerance in pregnancy which resulted in a great variation of glucose values used for the definition of GDM (table 2). 21 But these were based on the subsequent maternal risk for diabetes and did not investigate the risk for fetal or neonatal morbidity.
Our study was performed between 1992 and 1993 at the Department for Obstetrics at the Vivantes Medical Center Neukoelln in Berlin. Central obesity and hyperinsulinism with consecutive neonatal hypoglycemia was even more frequent than in pregnancies with GDM.
Additionally, neonatal glucose testing is recommended in all LGA infants (birth weight> 90th percentile) independently of the diabetic status of the mother.
In the subgroup of infants of mothers with oGTT the 1 hour-glucose value was an excellent discriminator between infants at low, intermediate or high risk for hypoglycemia. 14 A large body of clinical and experimental studies supported that maternal hyperglycemia enhances fetal growth by an excessive glucose supply to the fetus at a time when the fetal pancreas is able to respond by increasing its production of insulin. Our study aimed to examine the correlation of maternal glucose values and fetal growth at different gestational weeks of pregnancies in normal and overweight women with GDM. Both of our presented studies revealed the strong influence of maternal obesity on the risk for accelerated growth.
Maternal hyperglycemia leads via fetal hyperinsulinism to an increase of the insulin sensitive tissue, like the adipose tissue.
Considering the strong influence of non-glucose related parameters, a modified approach in obese women might be more effective to lower the high rate of LGA infants in these women. Normalization of maternal hyperglycemia could lower the rate of adverse outcome in pregnancies with GDM but the rate of macrosomia and neonatal morbidity is still elevated compared to the normal obstetrical population. 7) measured in the early third trimester revealed to be a good predictor for a LGA newborn.
65-68 The level of fetal insulin is supposed to correspond to the level of insulin in the amniotic fluid secondary to the urinary excretion. But since fetal growth is influenced by many other factors beside the fetal insulin levels there is still a concern of over- or under-treatment when insulin therapy is administered solely depending on the fetal AC. The percentiles of the fetal AC corresponded to the level of the fetal insulin indirectely determined by the AF insulin. 1 In agreement with other groups, we could show that the relation of neonatal morbidity and maternal glucose values seems to behave in a continuous fashion. Both institutions take care of a multiethnic population with a rate of approximately 40% women from Turkey, Arabian countries or East Europe.
The measurement of the fetal AC with ultrasound reliably identified fetuses at low risk for accelerated growth.

29-31 Preconceptional care and optimizing of maternal glucose control can reduce the rate of anomalies to the level of the normal population.
Furthermore there is more and more evidence that the relationship between maternal glycemia during pregnancy and neonatal morbidity behaves more like a continuum, with no precise threshold to discriminate between high and low risk fetus.
They investigated the outcome either in women with positive glucose challange test but negative oGTT or in women with only one pathologic value in the oGTT. We involved 325 women with risk factors for GDM who were tested for glucose intolerance by a 75 g oGTT. Severe placental immaturity was seen most frequently in GDM pregnancies but again the rate in IGT was significantly higher compared to normal pregnancies. Excessive growth is the major clinical sign of fetal hyperinsulinism due to maternal hyperglycemia in pregnancy.
They could demonstrate a graded increase in adverse maternal-fetal outcome with increasing maternal carbohydrate intolerance. 43-45 Although the stimulation of insulin secretion starts with 11-15 weeks of gestation 46 , accelerated growth due to maternal diabetes occurs at around 28 weeks, presumable because of the fetal capacity to store triglycerides at that time.
We use the above described population to determine independent predictors for fetal macrosomia at different periods of pregnancies and at birth. At no time in pregnancy, a higher rate of fetal macrosomia was associated with higher maternal glucose values but with obesity. 1 In studies with very strict control the macrosomia rate had been lowered to 10% but this management required intensive insulin therapy in 66-100% of the women. Secondly, we aimed to create a score of the discriminatory parameters and quantitated the predictive power by receiver operator characteristics (ROC) curves analysis. Thus, we investigated the correlation between amniotic fluid insulin (AF insulin) and fetal AC percentiles at time of amniocentesis performed in the third trimester in 121 diabetic women.
The fetal AC ≥ 90th percentile was the strongest predictor for an LGA infant within a wide selection of tested parameters. 38, 42, 73-76Thus, the glucose targets that we aim to achieve during pregnancies are arbitrary and consensus based. In the experimental group insulin therapy was limited to pregnancies with a fetal AC > 70th percentile at entry or in one of the subsequent monthly ultrasound examinations. 27, 32, 33 In women with preexisting diabetes, a great body of data is available to assess the risk for diabetes based on the level of maternal glucose values. It can be speculated that women with severe hyperglycemia at time of diagnosis of GDM might have had hyperglycemia in early pregnancy high enough to impart a risk for malformation to their children.
Study subjects were again retrieved from our database of diabetic women attending the Diabetes Clinic of the Los Angeles County women’s hospital. Macrosomic newborns are at increased risk for neonatal hypoglycemia when after delivery the insulin secretion has to be adapted to the sudden drop in glucose supply. 38 In addition to other studies which were limited to clinical complications known to be increased in diabetes, we could confirmed the influence of borderline glucose intolerance on very specific parameters for diabetic fetopathy.
47 Thus, it is obvious that maternal hypergylcemia is a risk factor for macrosomia, however the regulation of fetal growth is far more complex and is influenced by many factors.
A fetal abdominal circumference > 90th percentile according to gestational age 48 was defined as fetal macrosomia.
We included maternal historical (prior pregnancy with LGA or GDM, prepregnancy BMI and parity) and glycemic parameters at entry (oGTT, HbA1c and mean fasting and postprandial glucose values of the daily profile) and the glucose values of the profiles at the different periods of pregnancy.
Obesity is often associated with elevated lipids and proteins and peripheral hyperinsulinism which had been shown to be related to the risk for macrosomia. 57-59 Furthermore, in gestational diabetes aggressive lowering of the maternal glucose levels may lead to an increased rate of intrauterine growth retardation and an adverse perinatal outcome for small-for-gestational-age newborns. Although this approach offers a direct estimation of the fetal reaction on maternal glycemia, it is not widely accepted because it requires an amniocentesis as an invasive procedure to obtain amniotic fluid. In a second step, we aimed to find a threshold for fetal AC measurements that identifies low vs high risk levels of AF insulin without performing an amniocentesis.
In contrast, as we expected from our previous studies, the maternal glycemic values in this treated population were not predictive. Interestingly, the AC threshold of the 75th percentile found by our study to identify severe hyperinsulinism was identical to the AC threshold which has been recommended for initiating insulin therapy in GDM. 47, 55, 56 In GDM managed by a fetal-growth based approach the neonatal outcome was similar to pregnancies guided solely by maternal glycemia even in selected women with hyperglycemia from a population of Mexican-Americans that is known to have a high rate of severe glucose intolerance.
Congenital anomalies typical for diabetes affect primarily the heart, central nervous system, kidneys and the axial skeleton. So far, there had been very few data to quantify the risk of malformations in these heterogeneous population of women with GDM.
There was no difference in maternal historical or glycemic parameters between mothers of pregnancies with normal infants and infants with minor anomalies thus we combined them for the further analysis. Diagnosed major congenital malformations were categorized by the number and type of affected organ systems. 35 A second analysis in a subgroup of women with normal postpartum oGTT and therefor little chance of having preexisting diabetes confirmed that women who develop severe glucose intolerance first in pregnancy are also at risk for an infant with congenital anomalies.
Diabetes care consisting of diet education and frequent glucose profiles was limited to women with GDM, defined as usual by two pathologic values in the oGTT.
Universal testing in all LGA newborns implicates unnecessary diagnostic in infants at low or no risk for hypoglycemia since only a minority of macrosomia is caused by diabetes. Beside macrosomia and hypoglycemia also hyperinsulinism, trunk obesity and placenta immaturity were significantly more frequent in untreated women with IGT than in normal women. The clinical experience indicates that despite of tight glucose control neonatal macrosomia occurs.
Glucose values at diagnosis - oGTT , entry glucose profile and HbA1c – and the glucose values of the profiles performed at 5 different categories of gestational weeks were compared between pregnancies with and without fetal macrosomia diagnosed at correspondent gestational ages. We found different parameters univariately associated with accelerated growth at different times of pregnancy: LGA in a previous pregnancy, parity, prepregnancy obesity, fasting of the oGTT or fasting glucose at 32GA.
50-52 Lipids and amino acid levels are influenced by the carbohydrate metabolism but there is no linear correlation between the elevation of glucose and non-glucose nutrients.
Attainment of strict control in all women with GDM might result in unnecessary treatment in low-risk pregnancies and absorption of limited resources needed for intensive therapy in high-risk pregnancies. We can only speculate if maternal glycemia would be more discriminative in an untreated population with a wider range of glycemic values. 77 The best evidence that the same maternal glucose values may result in different outcome comes from observations in twins.
34 Insulin therapy could be avoided in 38 % of these women and in 43% of Caucasian women with hyperglycemia investigated in Berlin.
The study population was divided into women with normal oGTT, women with one abnormal value (IGT= impaired glucose tolerance) and women with GDM and neonatal outcome was compared between the groups.
Therefor we investigated the rate of hypoglycemia in LGA newborns of non-diabetic mothers and whether maternal or neonatal risk factors for hypoglycemia could be identified. Our second work related to this topic concentrated on macrosomic infants of non-diabetic mothers.

Thus, the effect of hyperlipidemia and hyperacidemia on fetal growth cannot be eliminated solely by glucose control.
Therefor some researchers were looking for other predictors besides maternal glycemia to identify pregnancies at high risk for morbidity. 78 Applying the strategy of tight glucose control on all women misses the change to target intervention on pregnancies with high risk for morbidity. According to the protocol, the glucose values during pregnancy were lower in the standard group compared to the experimental group. The US-group was started on insulin if fetal AC exceeded the 75th percentile at entry or at any examination thereafter corresponding to a 4 week examination schedule at 20, 24, 28, 32 weeks of gestation. The fasting glucose is an easy accessible clinical parameter since it is part of the diagnostic procedure. Thus, we could only speculated about the degree of hyperglycemia during embryogenesis which is required to cause anomalies.
In 887 LGA infants, we observed hypoglycemia within the first day of life in 16% of the infants with a steep decrease of the incidence after the first two hours.
We could show that the risk of neonatal hypoglycemia in these infants is tightly related to the 1-hour oGTT value of the mother. 49 There was no difference in glucose values either at entry or during pregnancy between pregnancies with or without fetal macrosomia either in lean nor in obese women.
When we looked for other maternal predictors in the second analysis, we found independent predictors that represent the three major determinants of fetal growth. One approach is based on fetal growth 60-62 and limits intensive insulin therapy to pregnancies with accelerated growth of the fetal abdominal circumference (AC). Easy obtainable historical data by itself seem to provide enough information for clinicians to antenatally estimate the risk for an LGA newborn. In a pilot study limited to women with normoglycemia it was demonstrated that a single measurement at entry to therapy could identify a fetus at risk for macrosomia.
The overall rate of insulin use was slightly higher in the US-group compared to the standard approach. Neonatal obesity was defined according percentile rankings obtained by skinfold measurements that had been previously performed in 250 consecutively born infants.
Interestingly, the identified threshold corresponds to the threshold for an abnormal 1-hour value according to the Carpenter and Coustan criteria for GDM.
In contrast, the fetal macrosomia rate was significantly higher in obese compared to lean women at each category of gestational age and at birth. A history of a prior LGA infant representing the genetic influence, maternal obesity reflecting genetic and non-glucose fuels and the fasting hyperglycemia indicating an increased glucose supply to the fetus.
Diabetes associated macrosomia is characterized by an asymmetric growth of the fetal abdomen versus head and long bones due to the stimulation of the insulin sensitive fat tissue by fetal hyperinsulinism (fig.1 ). All predictors in a single or combined fashion are superior in identifying an infant at low risk for excessive growth (NPV) while the sensitivity and specificity did not exceed 77% or 53%, respectively. Intensive insulin therapy could lower the macrosomia rate by 3 fold in this high risk population compared to those who were treated with diet only. The two groups were similar regarding historical data, glycemic data and the rate of fetal AC at entry.
This reflectes the mild degree of glucose intolerance when diagnosis of GDM is based on the low diagnostic criteria for GDM of O’Sullivan. 31 Regardless the final classification of diabetes after pregnancy, our data provide a useful tool to counsel women with hyperglycemia diagnosed first in pregnancy about their risk for major anomalies based on their fasting glucose levels at time of diagnosis. 20 Thus, all mothers of the infants at greatest risk for hypoglycemia had IGT that was not treated because the oGTT did not fulfill the criteria for GDM. In the early pregnancy the influence of genetic factors predominates; about 15% of the variation in birth weight is due to genetic predisposition. The overall macrosomia rate of the study population was reduced without applying insulin to the majority of the women. Delivery by Cesarean section was performed more frequently in the experimental group but this could not be explained by complications related to diabetes.
21 When we excluded women who did not fulfill the Carpenter and Coustan criteria that require higher post challenge glucose values, the insulin use in both study arms was similar. Secondly, our data support the clinical importance of a general screening for GDM since without available oGTT values a risk assessment for hypoglycemia in LGA newborns seems not be possible. 53 It could be shown that an early symmetric accelerated growth is not associated with fetal hyperinsulinism.
For moderately elevated insulin levels the fetal AC offers no reliable tool for risk assessment. Our subsequent studies which will be presented in the following aimed (1) to extend this approach to women with hyperglycemia and (2) to proof the applicability of this strategy in a population with a different ethnic background and without prior stratification according to the maternal glycemia status.
Despite intensive insulin therapy the LGA rate in women with fetal AC > 70th percentile at entry was higher than in women with normal fetal growth. When we looked at the women who were treated differently in the US-group compared to the standard group we realized a better outcome in the US-group: a tendency toward a lower SGA rate in women with hyperglycemia but normal fetal growth and a lower LGA rate in women with euglycemia but accelerated growth.
Additionally, the high chance for anomalies involving multiple organ systems have to be considered since increasing glucose levels had been associated with a higher number of affected organ systems in the infants of our population.
54 In the early third trimester maternal obesity became a strong predictor coincident with the time of fetal adipocyte proliferation and lipid storage. When we analyzed a subgroup of women with GDM according to Carpenter and Coustan criteria (n=161) the results were identical with the exception of a higher rate of insulin use in the standard group. Further prospective studies are needed to develop strategies to identify preconceptionally women without overt diabetes but glucose intolerance sufficient to cause congenital anomalies. Kainer et al, the only group so far that investigated the relation of amniotic fluid insulin and the fetal AC also found the AC measurement to be useful only in identifying high levels of insulin.
In a secondary analysis in women with euglycemia and AC >75th percentile (n=34) the rate of LGA, C-section and neonatal hypoglycemia was lower in the insulin treated US-group compared to corresponding women in the standard-group. A minority of the women would have qualified for routine diabetes testing which is limited to women with age > 45 or other risk factors like prior GDM.
70 Our finding corresponds to the data of Weiss et al who had demonstrated that neonatal morbidity was mostly limited to AF insulin levels which were increased 2 - 3 fold above normal. In those pregnancies with maternal hyperglycemia but AC< 75th percentile (n=35) there was no adverse outcome in the US-group although insulin was withheld. It can be only speculated about the influence of increased attention and motivation under the conditions of a clinical trial and the frequent demonstration of fetal growth by serial ultrasound examinations. 36 But even with routine testing the women who appeared to be at risk would not have been detected considering the existing diagnostic criteria for diabetes outside pregnancy at the time of the study.

Hypoglycemia causes thyroid malfunction
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