Oded Langer, MD, PhD
In its approach toward the shadow of birth, every child has the right not to be stillborn but well born
—Hellman
Key Points
• All types of diabetes in pregnancy when not optimally managed are associated with increased perinatal mortality.
• The pathogenesis of intrauterine fetal death includes maternal hyperglycemia, fetal hyperinsulinemia, and the development of metabolic acidosis rather than fetal hypoxia.
• The vasculopathy accompanying some types of diabetes is associated with fetal growth restriction and hypoxia.
• Awaiting the ideal randomized clinical trial should not preclude fetal testing protocols based on current clinical wisdom and experience.
• Developmental delay in state behavior patterns and lung maturation characterize the infant of the diabetic mother.
• There are conflicting data on the effects of diabetes on fetal state behavior and maturation that need to be considered when fetal evaluation is performed.
• The primary approach in fetal testing in diabetes should be nonstress testing (NST) and fetal movements (FMs).
• The second line of defense should include the biophysical profile (BPP), amniotic fluid volume (AFV), Doppler studies, and level of glycemic control.
• The diagnosis-related group (i.e., hypertension) should always be addressed in the decision-making process for elective delivery in the presence of either abnormal or normal testing results.
• Fetal testing should be performed once weekly from the 26th to 28th week of gestation.
A 42-year-old woman with G1P0 type 2 diabetes (first diagnosed 7 years ago) came to the clinic for the first time at 7 weeks gestation. She had been treated for diabetes with metformin 500 mg bid; HbA1c upon admission was 6%. Routine prenatal care included a 24-hour urine collection for protein (177 mg) at 12 weeks gestation; amniocentesis at 17 weeks; and fetal echocardiogram and fetal anatomy scan normal at 19 weeks. All other routine prenatal care and diabetic exams (e.g., for retinopathy) were normal. Glycemic profile throughout pregnancy was within the targeted levels of glycemic control. Fetal biometric and surveillance testing throughout pregnancy is displayed in Tables 19-1 and 19-2. At 39 and 4 days of gestation, at a routine clinic visit, an estimated fetal weight of 4698 g was identified. BPP was 10/10, and the patient was transferred to labor and delivery for primary cesarean section due to fetal weight estimation. An hour later, no fetal heart tones were heard, and intrauterine fetal death was confirmed by ultrasound. An autopsy report revealed a normal fetus weighing 4658 g with no congenital anomalies but with organomegaly: fetal heart 168%; liver 178%; and brain 110% based on standard chart for fetal weight at autopsy. What went wrong? What could have been done to alter the outcome?
The aforementioned case is a clear demonstration of care provider frustration over unexplained fetal death after seemingly appropriate management of the pregnant diabetic patient. It has become axiomatic, even with scant data to support it, that patients with poor glycemic control and especially fetal macrosomia are associated with higher fetal death rates in the final weeks of pregnancy. However, in diabetic patients who have achieved targeted levels of glycemic control, fetal demise appears to be less common.1 The accepted and “obvious” observations are unfortunately not always the case. For example, in diabetic women with vascular disease and preeclampsia, fetal growth retardation and demise may develop as early as the late second trimester. Several studies reported an association in both gestational diabetes mellitus (GDM) and pre-existing diabetes with higher rates of intrauterine fetal demise and neonatal death.2,3 Another explanation for the high rate of fetal death in pregnancies compromised by diabetes is the high rate of congenital anomalies. Although it has been demonstrated that the rate of anomalies can be decreased in patients who achieved targeted levels of glycemic control, the majority of studies report an incidence of 8% to 9%. This is a three- to fivefold increase in comparison with nondiabetic pregnancies (2%-3%). Certain system anomalies occur at a disproportionately higher rate. Cardiac anomalies and, in particular, ventricular septal defects and complex lesions such as transposition of the great vessels occur about 5 times more frequently, and central nervous system malformation, in particular, neural tube defects and holoprosencephaly occur about 10 times more frequently. The sacral agenesis/caudal dysplasia complex is reported to occur up to 400 times more commonly among fetuses of mothers with diabetes.4-7
TABLE 19-1 Fetal Surveillance Testing
|
GA |
EFW |
Percentile |
AFI |
BPP |
|
24 ± 6 |
918 |
67% |
||
|
29 ± 3 |
1757 |
75% |
21 |
|
|
31 ± 5 |
2171 |
74% |
26 |
|
|
33 ± 3 |
3085 |
>90% |
27 |
|
|
35 ± 3 |
3265 |
>90% |
17 |
8/8 |
|
36 ± 3 |
— |
— |
16 |
10/10 |
|
37 ± 4 |
3660 |
>90% |
15 |
8/10 |
|
38 ± 4 |
— |
— |
21 |
10/10 |
|
39 ± 4 |
4698 |
>95% |
14 |
8/8 |
Abbreviation: BPP, biophysical profile; EFW, estimated fetal weight.
Advances in ultrasound imaging have made it possible to identify major structural/functional anomalies with greater precision and at progressively earlier gestational ages. The detection of major and lethal anomalies in high-risk populations, including pregnancies complicated by diabetes, is now 86% or more.8 After recognizing the importance of reaching the targeted levels of glycemic control prior to conception, what remains is the response to what causes the reported decreased rate of anomalies. Is it improved care? Or, is it the increased rate of elective abortion after early diagnosis using new detection technology in the first and second trimesters?
There is a broad spectrum of opinionated approaches for antenatal fetal surveillance and timing of delivery of diabetic pregnancies among obstetricians and maternal-fetal special- ists.9 This chapter is an overview of fetal testing of the infant of the diabetic mother. Because of the paucity of well-designed studies, many of the proposed approaches are based on expert and consensus opinion. The chapter will address physiological considerations, pathogenesis of fetal death in the neonate of the diabetic mother, and approaches for the prevention of fetal death.
PATHOGENESIS OF FETAL DEMISE
Although the mechanism of intrauterine fetal death in pregnancies compromised by diabetes remains unknown, there are several plausible explanations. Extramedullary hematopoesis is frequently observed in stillborn infants of diabetic mothers, an indication that chronic intrauterine hypoxia was the likely cause of death. Poor glycemic control will result in the stimulation of the fetal pancreas to increase secretion from the beta-cells (fetal hyperinsulinemia), which in turn stimulates hematopoiesis and fetal erythremia. Cordocentesis studies have demonstrated the association of maternal diabetes with erythremia in poorly controlled patients. There is a shift to the left in the maternal oxyhemoglobin affinity and, therefore, reduced red cell oxygen delivery at the tissue level.10 Hyperglycemia results in increased fetal glycosylated hemoglobin; the hemoglobin variant shifts the oxygen dissociation curve to the left. Fetal hyperinsulinemia may increase fetal metabolic rate and oxygen requirements in the presence of several factors such as hyperglycemia, ketoacidosis, and vascular disease; these, in turn, reduce the uteroplacental blood flow and fetal oxygenation.
Alterations in fetal carbohydrate metabolism may also contribute to intrauterine asphyxia. The marked islet cell hyperplasia in the stillborn macrosomic infant of the diabetic mother has prompted investigation of the effects of both insulin and glucose excess on fetal oxygenation. Hyperglycemia, when accompanied by minimal degrees of hypoxemia, can result in lactic acidosis and fetal death in animal models.11,12 Finally, another explanation for fetal demise is fetal hyperinsulinemia that may result in electrolyte imbalance of hypocalcemia and hypokalemia causing fatal cardiac arrhythmia.
Aerobic and anaerobic glycolysis are substrate driven (glucose) and may result in an increase in oxygen demand and tissue hypoxia. In the human fetus, hyperglycemia correlates directly with lactic acid concentration and inversely with pH and oxygen partial pressure.13 The chain of events of fetal hyperglycemia leading to hypoxemia that triggers the anaerobic glycolytic pathway and metabolic acidosis (lactic) is a potentially deadly combination.
Several animal studies demonstrated the association between fetal hyperglycemia/hyperinsulinemia, hypoxia, asphyxia, and fetal death. In twin fetal lambs that were induced to chronic fetal hypoxemia, it was demonstrated that the rate of development of acidemia was accelerated and the reversibility reduced in the lamb receiving glucose infusion when compared to the lamb receiving saline.14In the primate (Macaca mulatta), fetal insulin infusions resulted in metabolic acidemia, profound bradycardia, and acute fetal deterioration ending in death.15
In some species (e.g., sheep), fetal hypoglycemia, often profound, may occur either spontaneously or as an effect of maternal fasting16 and is not associated with adverse fetal consequence. In the primate fetus, including humans, fetal hypoglycemia does not occur spontaneously but rather in the presence of profound maternal hypoglycemia or fetal hyperinsulinemia, either responsive (to hyperglycemia) or experimental. The primate fetus does not tolerate hypoglycemia and deterioration and death soon follow. As demonstrated in Table 19-2, even subjects in good glycemic control will be out of the targeted glucose range a significant amount of time. Furthermore, even in nondiabetic patients, the glycemic profile varies throughout the day and characteristically will be elevated in the evening and at night.17-19 This fluctuation in glycemic profile may expose the fetus to surges of glucose that may cause intermittent hypoxia and fetal hyperinsulinemia. These fluctuations will be even wider in the poorly controlled woman with diabetes especially type 1 and type 2. It is likely that, in these cases, hypoglycemia is a cause of sudden fetal death.
RANDOMIZED TRIALS IN FETAL SURVEILLANCE: DO THE ENDS JUSTIFY THE MEANS?
Was a randomized study design used to justify a given management protocol? This is a recurring question today in the practice of obstetrics and has, in fact, become a knee-jerk reaction in academic forums. Instead, the questions that need to be asked are: Is a randomized study always needed or justified given the research question? Is it ethical to perform a randomized trial after a given test or intervention has already become the standard of care?
Close to 200,000 pregnancies compromised by diabetes occur in the United States annually. These women need the best reassurance for fetal well-being. For the woman with diabetes who has experienced a stillbirth, any strategy that could have prevented this mishap would have been worthwhile, however marginal its effect might have been on the overall rate of perinatal mortality. The actual benefit to be derived from such strategies and their overall cost/benefit ratio are issues that have yet to be studied. “The train has already left the station” decades ago when fetal biophysical testing was introduced and a randomized controlled study would have been a practical and ethical endeavor. Today, after decades of using these modalities, it would be unethical to deny the mother and infant well-established standardized fetal surveillance modalities. Needless to say are the legal implications of failure to test a fetus that is stillborn. Therefore, we are left with second rate options that are to evaluate the efficacy of large-scale epidemiological data or prospective assessment of a given protocol for fetal testing.
A randomized trial is rarely conducted in isolation. Patients usually have different prior risks for adverse outcome. Any test is generally interpreted in conjunction with these prior conditions. Therefore, it is often difficult to isolate the test results as indicative of a specific condition. Although this confounding effect can be partially overcome with the use of regression analysis technique that measures the net effect of a given variable (test), it is still not full proof. Disraeli is credited with saying: “There is a lie; there is a damn lie; and, there is a statistic.”
In general, randomized trials require large sample sizes especially for research questions associated with relatively small prevalence such as stillbirth, neonatal death, shoulder dystocia, and so on. For example, to prove or disprove the effect of a specific strategy on the overall risk of perinatal mortality in diabetes in pregnancy (8-10/1000), an intervention demonstrating a 50% reduction in that risk (to 5/1,000) would require randomization of 10,400 subjects (5200 in each arm), providing 80% power to detect a significant difference at an alpha error level of 0.05. Therefore, it is not surprising that the literature is almost devoid of any prospective studies examining strategies for antenatal fetal surveillance in diabetes in pregnancies. The large number of women required to test the hypothesis if fetal surveillance is of benefit in pre-existing and GDM suggests that the cost may far exceed any benefit in our current testing schemes. Nonetheless, women nowadays expect perfect outcomes from their pregnancies.
TABLE 19-2 Type 2: Glycemic Profile During Pregnancy
|
HbA1C |
MBG |
Percent Reading |
||||||
|
Premeal (%) |
Postmeal (%) |
Bedtime/Sleep (%) |
||||||
|
Above |
Below |
Above |
Below |
Above |
Below |
|||
|
7 wk |
6% |
— |
— |
— |
— |
— |
— |
— |
|
14 wk |
6% |
127 ± 20 |
— |
— |
— |
— |
— |
— |
|
28-29 wk |
— |
88 ± 27 |
33 |
0 |
0 |
0 |
28 |
12 |
|
30-31 wk |
— |
97 ± 32 |
32 |
0 |
16 |
27 |
16 |
19 |
|
32-33 wk |
4.9% |
95 ± 40 |
33 |
10 |
17 |
22 |
29 |
10 |
|
34-35 wk |
4.9% |
88 ± 31 |
15 |
20 |
4 |
13 |
22 |
20 |
|
38-39 wk |
— |
84 ± 30 |
20 |
7 |
38 |
7 |
31 |
39 |
Abbreviation: MBG, mean blood glucose self-monitoring.
Theoretically, only a randomized trial could fairly determine the potential frequency of both stillbirth and hypoxic injury in offspring of diabetic women without other risk factors who do not undergo routine fetal surveillance tests during the third trimester. Unfortunately, the majority of diabetic patients have other risk factors such as obesity, hypertension, nephropathy, and so on. Furthermore, most of the diabetic patients are enrolled in surveillance programs and undergo fetal testing at least once/ twice weekly. Moreover, trials of tests not only test the test but also any intervention that results from an abnormal test result. A physician’s interpretation of a test will determine the intervention protocol he uses, and no two interpretations and protocols are necessarily the same. It is inconceivable that a sufficient number of trials from a big enough sample size will be performed to cover all the possible combinations of tests linked to all blends of plausible treatment options.
THE EFFECT OF MATERNAL DIABETES ON FETAL BEHAVIORAL CHARACTERISTICS
It is well recognized that the infant of the diabetic mother has delayed maturation of the central nervous system, lungs, and state behavior. In turn, one would expect that this delay would be reflected in varying fetal test results. These characteristics should be considered when fetal testing protocols are designed, thus avoiding unnecessary interventions based on false results. Mulder et al.20 in 20 women with type 1 diabetes found a 1- to 2-week delay in the emergence of all normal FM patterns, particularly in women who had poor glycemic control in early pregnancy. Fetal breathing movements, however, were observed at an earlier age than in nondiabetic controls. During the third trimester, fetuses of mothers with diabetes have fewer FMs and FHR accelerations but more breathing movements compared to controls.21-23 In pregnancies complicated by diabetes, Robertson and Dierker24 attributed fluctuations in maternal glucose levels to the disruption in fetal activity during the third trimester. It should be noted that level of glycemia does not affect all behavioral states. In fact, FMs are not influenced by the level of glycemic control, whereas fetal breathing is stimulated and increased by glucose administration to the mother. Thus, the cause of FM on one hand and earlier appearance of FM on the other hand in the infant of the pregnant diabetic woman should be more complex than just fluctuations in glycemic level.25-27 Some authors report increased fetal activity,28-30 whereas others report decreased fetal activity31,32 in the presence of maternal hyperglycemia.
Habituation in the fetus of his behavioral state was suggested in the past few decades. This was done by studying the response of the fetus to music, light, and other stimuli. With the increased popularity of the use of vibroacoustic stimulation during antepartum and intrapartum periods, it was found that a healthy fetus after several repeat stimulations will recognize and stop responding, whereas the “comatose” fetus will continually respond with jerky movements. Doherty and Hepper33 studied habituation patterns in fetuses of diabetic mothers by performing repetitive vibroacoustic stimulation. These fetuses took longer to habituate compared to controls, demonstrating delayed maturation of the central nervous system.
Several studies have examined the effect of maternal diabetes on the FHR pattern. Tincello et al.34 studied computerized fetal heart rate recordings in 26 women with type 1 diabetes throughout the third trimester. They found that these tracings demonstrated delay in fetal maturation compared to uncomplicated pregnancies. The results were reflected in a greater incidence of absent high variability, as well as differences in short-term variability, basal heart rate, accelerations, and frequency of FMs. Similar findings were reported by others.35 Weiner et al.36 compared FHR patterns in women with well-controlled GDM or pre-GDM and nondiabetic controls. They found that FHR variability and frequency of accelerations were significantly reduced in the diabetic pregnancies and increased at a lower rate during the third trimester compared to controls.
Comparable to the controversy that occurs regarding the effect of maternal hyperglycemia on FMs and fetal breathing, is the issue of fetal heart maturation. The use of fetal activity patterns based on fetal behavioral states, in conjunction with FHR assessment, may provide a window of opportunity to begin to institute fetal surveillance on a sound physiological foundation. Nijhuis et al.37 first described the concept of fetal states. It was demonstrated that fetuses, like neonates and adults, have sleep/wake cycles with characteristic patterns of rapid eye movements, breathing movements, and gross body movements. The FHR demonstrates accelerations coinciding with gross body movements during the wake cycles. As mentioned earlier, hypoxic fetuses will demonstrate the absence of fetal activity patterns, no fetal heat rate acceleration, and redistribution of the blood supply. There is conflicting evidence if maternal ingestion of glucose can affect NST testing results. Zimmer et al.38 found that administration of glucose to nondiabetic women at 37 to 40 weeks gestation was followed by a decrease in FHR reactivity. Holden et al.39 also demonstrated that there was no increase in FHR acceleration following administration of glucose to the mother. In contrast, others have found increased reactivity,40,41 increased mean FHR,42 or no difference43 after glucose ingestion.
The conflicting evidence in studies addressing fetal heart rate characteristics and maternal glycemia suffer from several drawbacks such as small sample sizes. The sleep activity cycle was not addressed in the majority of studies. Thus, it may be the change in the sleep activity cycle and not the administration of the glucose that increased/decreased FHR. In fact, a common practice in many centers is to encourage the patient to eat something in the presence of a nonreactive NST of 20 to 40 minutes duration rather than attempt to wake the baby (acoustic stimulation) or to continue to record FHR for 90 to 120 minutes.
Furthermore, a yet unanswered question is what will be the response of the fetus to chronic maternal glycemia throughout the day on an ambulatory basis.
Hypoglycemia does not appear to have an adverse effect on fetal biophysical measures. We reported in three type 1 diabetic women who were in hypoglycemic comas the disappearance of FM, fetal bradycardia, and absence of FHR acceleration. When the maternal glucose levels were slowly corrected, the fetal behavioral states were restored.44 Reece et al.45 performed insulin-induced hypoglycemic clamp studies in pregnant women with type 1 diabetes, lowering the blood glucose concentration to 45 mg/dL. During hypoglycemia, there was a nonsignificant increase in fetal limb and body movements and no changes in fetal breathing movements or FHR. However, the level of hypoglycemia in the study should be considered, at best, mild hypoglycemia in respect to the maternal condition. The fetus in these conditions can make an appropriate adaptation without further damage. Other authors reported that insulin-induced maternal hypoglycemia was associated with increased frequency and amplitude of FHR accelera- tions46 and fetal activity.
Delayed lung maturation in the diabetic fetus has for decades been considered the result of the maternal disease. The mechanism of this delay is poorly understood. The maternal hyperglycemia and resultant fetal hyperinsulinemia were suggested as the cause for delayed lung maturation. In general, the timing of fetal pulmonary maturation is linked to the level of maternal glucose control in diabetic pregnancies. Adequate glucose control may lower the risk of fetal pulmonary immaturity to that of the nondiabetic population. Poorly controlled diabetic women are associated with delayed appearance of phosphatidylglycerol. However, after 37 weeks gestation, no significant neonatal pulmonary disease occurred.47,48 It was reported in a case-controlled study that the delay in lung maturation is 1 to 1.5 weeks in diabetic pregnancies. This delay coincides with the delay reported for FMs.49
In summary, there are conflicting data on the effects of diabetes on fetal state behavior and maturation. These potential differences between diabetic and nondiabetic infants need to be considered when fetal evaluation is performed and decisions for delivery are being made to prevent unnecessary iatrogenic damage.
ANTEPARTUM FETAL SURVEILLANCE: WHAT AND HOW TO TEST
Not long ago, the obstetrician’s main objective was to monitor that the woman was carrying a live fetus and that she be able to distinguish FM. The typical question would have been: “Is your baby moving?” And “Let’s listen to his/her heart,” as he/she applied the fetoscope. Today, with the development of biophysical testing (ultrasound, FHR monitoring, Doppler studies), a window into the uterus has been opened for obstetrician observation of fetal intrauterine life.
Tests of fetal condition are applied during the second and third trimesters, the period of greatest risk of fetal demise. The goals of antepartum fetal surveillance programs are to eliminate intrauterine death, to detect as early as possible fetal compromise and congenital anomalies and prevent unnecessary premature delivery. Although these techniques have not been subjected to randomized clinical trials, they have been incorporated into patient care protocols. Although programs vary in their use and timing of testing techniques, what remains uniform is a commitment to the use of fetal testing in pregnancies compromised by diabetes with an emphasis upon normalization of maternal glucose levels. The primary clinical value of current antepartum fetal monitoring tests is the low false-negative rate and their ability to reassure the clinician that the fetus with normal test results is unlikely to die in utero. Therefore, in a metabolically stable patient, such testing allows prolongation of pregnancy with continued fetal maturation.
Biochemical Methods
Historically, biochemical tests such as estriol and human placental lactogen (HPL) were used to evaluate fetal well-being; however, they remain historical references since they are no longer in use. The key and only essential biochemical marker of perinatal risk in diabetic pregnancies is the maternal glucose concentration. It may be argued that most of the dramatic reduction in perinatal morbidity and mortality among diabetic patients is a direct consequence of glucose monitoring and control. Self-monitoring blood glucose using reflectance meters coupled with intensified therapy now provides excellent control in the ambulatory outpatient setting.50
Prenatal testing options have grown in number and complexity over the years. Current options include maternal serum and ethnic-based carrier screening, ultrasound, and diagnostic testing; there are, in addition, evolving technologies in microarray and noninvasive prenatal testing. In 2007, the American College of Obstetricians and Gynecologists recommended that screening and diagnostic testing for aneuploidy be made available to all pregnant women, regardless of maternal age. Information discussed with patients should include detection and false-positive rates, advantages/disadvantages, and the associated limitations of each test. Although many health-care professionals are offering testing options, information presented to patients can vary based on provider experience, knowledge, personal bias, and length of clinical encounter.
First Trimester Testing
In the first trimester, the evaluation of the fetus of a diabetic mother should include a transvaginal ultrasound examination to rule out gross congenital abnormalities and crown-rump length (CRL) measurements for dating. A complementary abdominal ultrasound examination for congenital malformations needs to be performed at approximately 20 to 23 weeks gestation. Abdominal circumference (AC), fetal weight estimation, body composition, and cardiac evaluation (echocardiography) will enhance identification of the constitutionally large or small infant. During the third trimester, serial sonographic measurements need to be performed to assist in the selection of the treatment modality and the detection of deviant fetal growth.
Well-designed research protocols are needed to maximize efficacy and safety. At the same time, we need to be realistic. Instead of more research, we need to endorse better research. Ultrasound biometry in the detection of aberrant development of the fetus of the pregnancy affected by diabetes is a major triumph in medical technology. The weight prediction formulae targeted to take account of the different body habitus of the fetus in diabetic pregnancy are well established. However, there is still a need to develop formulae with greater accuracy and predictability to minimize errors and unnecessary intervention.
Diabetic fetal macrosomia can be identified in the third trimester. In contrast, some authors have suggested that first trimester testing will identify fetuses that are small for gestational age (SGA). Traditionally, measurements of the CRL have been considered one of the most precise dating methods (±4-7 days) until the 12th week of gestation. After this date, measurement becomes less accurate because of variable degrees of fetal flexion. The CRL is obtained by measuring the long axis of the embryo.
Pedersen and Molsted-Pederson51 studied 99 diabetic women. In 38 women, the embryos’ CRLs were more than 6 days below the mean for gestation. Seven of these fetuses (27%) with “early growth restriction” were later diagnosed as being anomalous. However, the use of CRL for predicting fetal anomalies remains questionable since almost one in three nonanomalous embryos of women with diabetes had early growth restriction. In contrast, several studies demonstrated no association between CRL and fetal anomalies.52,53 Therefore, although a fetus may be growing in an abnormal restricted environment that may lead to adult disease, there is no reproducible evidence indicating that an early growth delay is associated with malformed infants.
Second-Trimester Biometry
To date, there are numerous logarithmic formulae for estimating fetal weight, but there is a lack of uniformity and accuracy in measurement. Virtually all EFW formulae systematically overestimate birth weight. The imprecision of the formulae to account for fat deposits in fetuses and difficulties in measuring the AC of fetuses of diabetic mothers may provide another explanation for the inaccuracies in EFW. However, most formulae are better at predicting macrosomia than predictions based on gestational age alone. In infants of women with poorly controlled diabetes, there is a characteristic enlargement of the majority of the organs but not of the brain. Increased weight of insulin-sensitive tissues, including the liver, pancreas, heart, lungs, and adrenals, has been demonstrated in the infants of diabetic mothers (e.g., an increase in liver size of 179%). Based on this finding, it has been suggested that morphometry be used to measure fetal liver length.54
It was found that the increase in liver length was evident as early as the 18th week of gestation and became more marked with increased duration of pregnancy. Furthermore, individual liver length measures did not always remain constant when they were followed serially throughout pregnancy. This approach may provide an early fetal marker in addition to maternal markers (level of glycemia) for initiation of pharmacological therapy in the pregnancy affected by diabetes. Neonatal fat contributes approximately 12% to 14% of total birth weight; it accounts for about 50% of the variance. However, the amount of fetal fat in the subcutaneous locations used in anthropometric models may account for 40% to 80% of total fetal fat. A serial ultrasound assessment is more predictive than a single ultrasound examination for assessing fetal growth and health. Assessment of fetal growth and clinical decision making for management should not be viewed in isolation. Other methods that characterize the abnormal diabetic fetus are heart, body composition, and liver size—all of which assist in differentiating between the constitutionally and abnormally large fetus. In addition, clinical factors such as glycemic profile and obesity should be included in the overall assessment to maximize a successful delivery.54
Determination of fetal morphology can be made already in the second trimester with ultrasound technique. The initial scan between 16 and 18 weeks gestation yields accurate information (±7 days) regarding gestational age (if not obtained in the first trimester). At this age, morphometric screening for central nervous system and major gastrointestinal anomalies are reliable with cardiac and renal anomalies less easily diagnosed at this gestational age. With a suspicion of fetal anomaly, a second scan should be performed at 20 to 22 weeks. In addition to the general anatomic survey, there should also be a focused cardiac, facial, and limb scan at this time.
Biophysical Testing
NST is the most commonly used testing method, performed weekly or semiweekly from 26 to 28 weeks of gestation onward. Some authors have suggested that this testing method alone may not be optimal because the incidence of false-positive tests is high, ranging from 8% to 15%55,56 and is increased in the premature fetus (<30 weeks). The high false-positive rate can be decreased significantly by elongating testing time.57 Furthermore, the European approach of interpreting NST into four categories of reactive, suspicious, nonreactive, and terminal/pathological will allow greater flexibility in the assessment of these patients.58 Most groups that use the NST rely on the BPP score for additional information when needed. Others use the BPP as the primary assessment tool for the fetus.
Contraction stress test (CST) remains a valuable test in the evaluation of the diabetic fetus. However, with the recognition of the BPP, it has become less popular.
Fetal BPP score is used as a backup test, particularly in very preterm gestation. BPP is a dynamic ultrasound-based assessment of a composite of acute (fetal breathing, movement, tone, heart rate reactivity) and chronic (AFV) indices of fetal health.59-61 An association was shown between fetal BPP and fetal acidemia in the high-risk population (r = 0.52; P < .001).
AFV: Although historically polyhydramnios has been associated with diabetes, this is in part due to the increased rate of anomalies in pre-existing diabetes or as a result of poor control that is sufficient to cause osmolar reaction and increased urination in the fetus. In GDM, polyhydramnios is not a common finding and if it occurs will most likely be detected in an undiagnosed type 2 diabetic woman.
Asphyxia-related oligohydramnios occurs as a result of reflex redistribution of cardiac output yielding relative renal hypoperfusion. Currently, there is no data to suggest that this reflex and its renal consequence are altered in any way in the fetus of the diabetic mother. As in nondiabetic mothers who have additional complications (e.g., SGA, hypertension), oligohydramnios may be a predictor of chronic asphyxia. In nondiabetic mothers, with isolated oligohydramnios, one can expect a nonasphyxiated fetus. However, diabetes alone is a complication, and therefore, the combination of diabetes and oligohydramnios should be considered abnormal.
Fetal Doppler Velocimetry
A 27-year-old primigravid, insulin-dependent diabetic woman, white class B, was found to have a high-resistance index on routine Doppler screening at 23 weeks. Her glycosylated hemoglobin was elevated throughout pregnancy (mean 13%, range 9.4%-17.2%). At 29 weeks gestation, studies showed no end diastolic flow in the umbilical artery. Cordocentesis revealed oxygen tension of 3.4 kPa and pH 7.35. At 32 weeks gestation, because of fetal heart rate deceleration on the NST, patient was delivered by cesarean section. A female infant weighing 1660 g with cord blood pH of 7.20 was delivered.
This represents a case of who comes first: the biophysical or the Doppler velocimetry abnormalities? What is the impact of glycemia in these cases?62
A maternal factor that may play a role in the control of fetal growth is uteroplacental blood flow. If nutrients and oxygen cannot be delivered in adequate amounts to the fetus, fetal growth may be restricted.63 With the aid of the Doppler technique, we64,65 demonstrated a relationship between maternal diabetes, glycemic profile, and alterations in fetal blood flow to the placenta as measured by umbilical vein flow rates. When controlled for gestational age and estimated fetal weight, fetal-placental blood flow was 20% to 25% greater in diabetic women. In circumstances of either longterm maternal hypo- or hyperglycemia, fetal-placental blood flow was reduced and placental resistance increased when compared with euglycemic control. These changes in flow correlated only with the overall maternal glycemic profile and did not appear to be affected by acute changes in maternal glucose levels, consistent with a mechanism of chronic structural changes rather than acute vasoreactive changes in the placenta.
There is controversy over the role of Doppler waveform analysis in pregnancies complicated by diabetes. Studies in pregnant ewes demonstrated that chronic fetal hyperglycemia is associated with a 30% increase in fetal oxygen consumption66 and acute maternal hypoglycemia produces redistribution of fetal blood flow to vital organs.67 Moreover, in pregnant ewes rendered diabetic by streptozocin, fetal brain and renal perfusion increased significantly without any change in umbilical-placental blood flow.68 These observations suggest that in the presence of maternal diabetes, placental perfusion does not change to meet the increased oxygen demands of the fetus, and Doppler waveforms of the umbilical arteries remain unchanged in the face of fetal hypoxia. Salvesen et al.12 confirmed these findings in human pregnancies complicated by diabetes. Doppler studies of umbilical and fetal vessels were essentially normal except in the few cases complicated by preeclampsia or fetal growth restriction, whereas umbilical venous pH values were significantly lower than normal.
The association of abnormal Doppler indices with vascu- lopathy, hypertension, and fetal growth restriction in diabetic pregnancies has been demonstrated by several investigators.69-72 Others73,74 observed that in normotensive pregnant women with insulin-dependent diabetes, 34% had abnormal Doppler studies with increased risk of perinatal complications. They also studied GDM patients and found that 13% had abnormal Doppler indices without fetal growth restriction or preeclampsia. Bracero et al.75 reported that abnormal Doppler studies obtained within one week of delivery are more reliable predictors of adverse outcome compared to the NST or BPP. Thus, there is lack of agreement on whether abnormal indices of Doppler flow velocimetry are associated with diabetes, per se, or only with diabetes complicated by vascular disease. Most authors, however, agree that the sensitivity of Doppler studies in determining fetal compromise in pregnancies complicated by diabetes is low, ranging from 32% to 61%. Williams et al. in a randomized study that compared NST with umbilical Doppler velocimetry found an overall similar outcome. The women in the Doppler velocimetry group had twice the rate of induction and a lower cesarean section rate for nonreassuring fetal heart rate tracing. The data suggest but does not prove that Doppler surveillance will detect the fetus at risk earlier than NST.76
Whether the quality of glycemic control affects Doppler flow indices and perinatal outcome is also a matter of controversy. Although Bracero et al.77 first reported a significant correlation between umbilical artery S/D ratios and mean maternal blood glucose concentrations, other investigators have not found evidence of such a correlation.78 Also, in hypoglycemic clamp studies, where maternal blood glucose concentrations of pregnant women with type 1 diabetes were lowered to 40 to 45 mg/dL, very slight or inconsistent changes in umbilical artery Doppler indices were observed.45,46 In summary, it appears that Doppler studies of the fetoplacental vasculature have a clinical value for pregnancies complicated by diabetes and vasculopathy (D, RF, hypertensive disorder, etc.) In nonvascular GDM and pre-existing diabetes, Doppler studies perform a limited role.
WHEN TO START TESTING
Lack of clarity and controversy surround the issue of when to initiate fetal surveillance testing. A simple response would be that every fetus has the right to life and, therefore, testing should commence once he/she is a viable fetus. On the other hand, issues such as risk/benefit and cost/benefit ratios cannot be ignored.
Along the Borders of Viability
Factors influencing survival are measured differently. Some include or ignore intrapartum death, gestational age used for definition of stillbirth ranging from 20 to 30 weeks gestation, congenital malformations, gestational age definition using nearest week or completed weeks, and period of survival that can include from discharge, 28 days of life, up to 1 to 2 years. As a rule of thumb, the survival as reported by the National Institute of Child Health (NICHD) is approximately 24% at 23 weeks; 59% at 24 weeks; and 75% at 25 weeks. Similar survival rates are obtained using weight categories with 100 g increments from 500 g. It should be noted that these survival rates are associated with relatively high morbidity for the child.
Who decides for the newborn, and on what basis, when the fetus has the right to be tested to identify potential life-threatening risk? Is it the parents, the physician or both?
Disputes between physicians and patients over medical care have tended toward resolution in both the courts and ethics committees with each of these bodies ultimately deciding that the informed, competent patient must be the final decision maker. Parents, too, have the authority to make medical decision for their children, but these decisions can be challenged if physicians do not believe they are medically reasonable. One bioethical issue, however, is as intractable today as it was 30 years ago, when it began to be publicly discussed: the extent of parental authority to refuse life-sustaining medical treatment for an extremely premature infant. Who decides for the newborn, and on what basis, when there is conflict between the parents and the physician? There is virtually no change in either the substantive criteria to apply to the decision or the procedures to follow, and decision-making is even more complex with extremely preterm infants.79
WHEN TO BEGIN TESTING THE GDM PATIENT?
Current beliefs echoed in many review articles and clinical opinions not based on facts are that fetuses of gestational diabetic mothers are not at risk for fetal death. However, all the new data suggest the opposite. Current studies suggest over threefold higher mortality in women with GDM compared to non-GDM80 and national US data demonstrates three- to sevenfold higher rates of mortality as fetal weight increases.81
Kjos et al.82 evaluated whether antepartum fetal surveillance testing can predict fetal distress in labor. Of 1400 women, 13% of women with GDM were admitted for delivery as a result of nonreassuring testing. There were two cases of intrauterine fetal demise at 36 and 38 weeks, 1 week after reassuring testing in women who had missed their previous interval testing session. There were no stillbirths within four days of reassuring testing. They did not use antenatal testing prior to 40 weeks in women with uncomplicated GDM treated with diet alone and performed NST twice weekly from 34 weeks onward in women with complicated GDM and in all women treated with insulin. Like all nonrandomized studies, this study and others cannot provide the information of what would be the rate of stillbirths in the 13% of patients who were admitted for elective delivery. Girz et al.83 reported 3 stillbirths within 72 hours of reassuring testing in 389 GDM pregnancies. Seven percent of women were delivered as a result of nonreassuring testing. Their clinical protocol for testing diabetic patients included weekly testing from 28 to 34 weeks and then biweekly until delivery. Johnson et al.84 reported no stillbirths among 188 GDM pregnancies and a 2.7% delivery rate for nonreassuring testing. They are opponents of the BPP for antenatal fetal surveillance including GDM pregnancies. They recommend a BPP once a week from 32 weeks onward in women with diet-controlled GDM and twice weekly from 32 weeks for women treated with insulin.
Landon and Gabbe85 recommended no antenatal testing before 40 weeks for patients with uncomplicated GDM treated with diet alone. For women with complicated GDM (chronic hypertension, history of previous stillbirth, preeclampsia, maternal complications), regardless of treatment modality (diet or insulin), they recommend monitoring FMs from 28 weeks and twice weekly NST from 32 weeks onward. These recommendations are based in part on a series of 261 women with GDM and normal fasting who were tested at 40 weeks.86 In another study of 97 women treated with insulin, FMs were recorded daily and antepartum surveillance began at 40 weeks. However, complicated GDM testing was initiated on a weekly basis at 34 weeks.87 Coustan described the fetal testing protocol at his institution. For diet-treated patients, testing is initiated at 40 weeks and includes twice weekly NST and amniotic fluid assessments. For insulin and complicated GDM, testing ensues at 36 weeks or before, depending on clinical evaluation.88
The Fourth International Workshop on GDM89 in 1997 recommended that decisions regarding the commencement and frequency of fetal surveillance be influenced by the severity of maternal hyperglycemia and the presence of other adverse clinical factors. Patients should be taught to monitor FMs from 24 weeks gestation (threshold for viability). In addition, NST should be considered from 32 weeks in cases where hyperglycemia warrants insulin therapy and at or near term in those requiring only dietary management. The American College of Obstetrics and Gynecology90 concluded: “There is insufficient evidence to determine the optimal antepartum testing regimen for women with relatively normal glucose level on dietary therapy.” Fuentes and Chez91 reviewed 7 studies with a total of 491 patients studying antenatal fetal surveillance. There were seven stillbirths in the studies, two of these associated with congenital malformations not compatible with life and three stillbirths in GDM mothers requiring insulin. They concluded that, overall, the sample sizes were too small to affirm or deny the value of antepartum fetal testing in well-controlled insulin-managed diabetic women.
The general principles behind these practices are based on the assumption that women with uncomplicated GDM who are controlled on diet alone are at very low risk for adverse fetal outcome; therefore, they do not require antenatal testing prior to 40 weeks gestation. Those who are treated with insulin incur a greater risk and, therefore, warrant antenatal testing starting at some point in the third trimester. There are, however, very few published data with few subjects to support this position.50,92-95
From a realistic perspective, only a small number of patients will be categorized as uncomplicated GDM with normal fasting plasma glucose managed with diet therapy. It has been demonstrated that even mild hyperglycemia (fasting < 95 mg/dL) is associated with adverse pregnancy outcome. In light of the fact that the majority of GDM patients is obese and older than non-GDM patients and carries the added burden of preeclampsia and chronic hypertension leaves few patients who will not need fetal testing from diagnosis. It is the ethical responsibility of the physician to treat and provide the best medical care to his/her patients in a timely manner. It is the author’s opinion that in the presence of gestational and pre-existing diabetes, fetal testing should be initiated at viability, starting with FM count and NST on a weekly basis in addition to fetal growth monitoring and other tests as indicated. To start testing at 40 weeks gestation will expose some fetuses to higher risk of stillbirth. At the end, every fetus has the right to be delivered well born and not stillborn.
We found in a randomized study of insulin and glyburide therapies, comparable perinatal outcomes.95 In another study, with intensified therapy that achieved targeted levels of glycemic control in the majority of patients, the stillbirth rate was 4-5/1000, comparable to the general population.50 We evaluated perinatal mortality in 4757 GDM patients to 10,804 nondiabetic controls. The fetal surveillance protocol consisted of daily FM count and weekly NST as the primary mode with BPP and Doppler studies as the secondary mode for patients compromised by vascular disease. The stillbirth rate in the GDM group was 4.8/1000 in comparison to 4.2/1000 in the nondiabetic group. The neonatal death was 5.8/1000 for GDM and 5.3/1000 in the non-GDM women. Sixty-five percent of the GDM stillbirths were poorly controlled and 60% with growth diversity (large for gestational age/SGA). Fifty-two percent of the GDM stillbirths and 38% of the neonatal deaths were derived from the diet-treated group; 44% of stillbirths and 56% of neonatal deaths originated from the insulin group.96
If approximately 50% or more of the deaths occur in diet-treated GDM patients, it is mandatory that fetal testing be initiated at viability (approximately 28 weeks in reality) regardless of treatment modality.
In which pregnancy period do the majority of stillbirths occur? The answer to this question would again bring us closer to making a decision on when to start testing. Thirty-eight percent of the stillbirths and 57% of the neonatal deaths occurred after 37 weeks gestation. Moreover, 17% of the stillbirths and 14% of the neonatal deaths occurred between 24 and 30 weeks gestation (19-1, neonatal and stillbirth rates in GDM). These data again support the concept of timely fetal testing for both diet and pharmacologically-treated GDM women.
WHEN TO INITIATE FETAL TESTING IN PRE-EXISTING DIABETES
Less controversial and routinely accepted is the importance of antepartum fetal testing in pre-existing diabetes. Despite aggressive testing and development of newer technology in the past few decades, perinatal mortality has not markedly decreased.5,7 The advent of self-monitoring blood glucose has facilitated the maintenance of glucose control. Overall, intervention for testing of abnormal fetuses is now performed in approximately 5% to 10% of pregnancies complicated by pre-existing diabetes.85
Drury et al. reported in a study of 129 insulin-dependent women that fetal surveillance was undertaken for only 19 women who also had additional pregnancy complications. Only one woman delivered because of the results of abnormal fetal heart testing.96 However, the small sample size precludes making a determination whether only a subset of pre-existing diabetic women with pregnancy complications need to be tested or whether all pre-existing diabetic women should be enrolled in testing programs. In a study by Landon et al. of 114 type 1 diabetic women with overall mean blood glucose of 110 mg/dL during the first and second trimesters, 9% (10/114) of the study group required intervention for abnormal fetal testing.56 Eight of these 10 women had either nephropathy or hypertensive disease. Nephropathy hypertension was associated with intervention for abnormal fetal testing in 9 of 20 women with these risk factors in comparison to 1 in 94 without these complications. Olofsson et al.97 studied fetal testing from 1977 to 1984 using a weekly NST as the primary method. They concluded that the predictive value of normal NST is 99% to 100% regarding 5- and 10-minute Apgar scores and 95% regarding ominous intrapartum FHR patterns. Teramo et al.58 studied 145 pregnant women with insulin-dependent diabetes. Nonstress fetal heart rate was used as the test to detect fetal distress. NST was performed every other day starting at week 32 of gestation and daily after week 34 until delivery. One hundred and eighteen (81.4%) had normal, 9 (6.2%) suspicious, and 18 (12.4%) pathologic FHR readings. Nine of the 25 women (35%) with poor metabolic control had a suspicious FHR recording, which was significantly more frequent than in women with good metabolic control (18 of 120, 15%). The mean value of HbA1C during the last trimester with pathologic FHR readings was 7.63%, which was significantly higher than in diabetic women with normal FHR (6.91%).
Lagrew et al.98 sought to evaluate when testing should be started in all pregnancies that were managed in their centers from 1981 to 1991. The primary mode of surveillance was weekly contraction stress test with an interval mid-week NST. Patients with multiple equivocal CSTs or contraindication to stress testing were followed with twice weekly NST. Of six hundred and fourteen pregnancies complicated by insulin-dependent diabetes mellitus, 71% were class A/B; 14% class C; 10% D; and 5% FM. Forty-nine percent of the positive CSTs occurred prior to 34 weeks gestation with an intervention rate of 21%. Three stillbirths and 6 neonatal deaths occurred during the 10-year study period (perinatal mortality 14.65/1000). They concluded that pre-existing diabetic patients, especially class R or F, with additional pregnancy complications may require testing to be initiated at 26 weeks gestation.
We99 recently evaluated our experience of perinatal mortality in pre-existing diabetes in a cohort of 1104 pregnancies (358 type 1; 746 type 2 diabetic women). The testing protocol was based on daily FM count and weekly NST as the primary mode. BPP was used as the secondary mode with the addition of Doppler studies for patients compromised by vascular disease. The overall stillbirth for type 1 and type 2 diabetes was 12/1000 and 13/1000, respectively, in comparison to 4.2/1000 in the nondiabetic population (sample size of over 10,000 women). The neonatal death for type 1 and type 2 diabetes was 8/1000 and 5/1000, respectively, in comparison to 5.3% in the general population. Over 60% of the stillbirths in type 1 occurred prior to 34 weeks, whereas approximately 70% in the type 2 occurred after week 37. In contrast, 90% of the neonatal death occurred after week 37. Finally, 73% of the stillbirths and 72% of the neonatal deaths occurred in LGA infants. Of interest, only 5% of stillbirths and 6% of neonatal deaths were growth-restricted fetuses (Figures 19-1 and 19-2).
The March 2005 American College of Obstetricians and Gynecologists Practical Bulletin, entitled Pre-gestational diabetes mellitus recommended: “...Antepartum fetal monitoring including fetal movements, counting, the non-stress test, the BPP and the contraction stress test when performed at appropriate intervals. . initiation of testing is appropriate for most patients at 32-34 weeks’ gestation.However, testing at earlier gestational ages may be warranted in some pregnancies complicated by additional high risk conditions.twice weekly testing has been widely adapted.”100
Our data and that of others98 demonstrated that starting testing at 32 to 42 weeks will expose many diabetic fetuses to the risk of fetal death without major efforts to prevent it due to lack of testing. However, it leaves a segment of patients between 24 and 32 weeks gestation exposed to the risk of stillbirth without any attempt to prevent it. Again, it emphasizes the moral issue of the fetus versus the physician’s opinion and cost considerations. Finally, weekly or twice-weekly testing remains the subject of opinions rather than data from even descriptive studies. Studies supporting twice-weekly testing are over 30 years old and the only additional data are sporadic case reports. It is the author’s opinion, based on our program results, that testing should start at 26 to 28 weeks gestation (viability) and in the majority of cases weekly testing will be sufficient.
SUMMARY
The primary approach in fetal testing in diabetes in pregnancy can be the use of NST and FMs, and in the majority of cases, this combined testing approach will suffice to screen and identify the fetus at risk. Several barriers (levels) exist from normal testing to preterminal and/or fetal demise (Figure 19-3). As the second line of defense, testing should include the BPP, AFV, Doppler studies (especially for vasculopathy and growth restriction cases), and level of glycemic control. In addition, the diagnosis-related group such as hypertension should always be addressed in the decision-making process for elective delivery in the presence of either abnormal or normal testing results. Our experience using this approach once weekly from the 26th to 28th week of gestation resulted in perinatal outcome comparable to that in the general population including high-risk patients (Figure 19-4).
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