Doppler Sonography in Pregnancies Complicated with Pregestational Diabetes Mellitus

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Introduction

During the past few decades, tremendous advances have been made in the medical and obstetrical management of pregnancies complicated with pregestational diabetes resulting in considerable improve- ments in maternal and perinatal outcomes [1]. Strin- gent periconceptional glycemic control and advances in fetal surveillance have significantly contributed to this improvement. The successful management of a pregestational diabetic mother requires timely and appropriate antepartum fetal surveillance which per- mits the pregnancy to progress while identifying the fetus who may be compromised and may benefit from delivery. Doppler velocimetry enables the investigation of fetal circulatory decompensation, and thus provides a noninvasive monitoring tool for assessing fetal well-being. There is considerable evidence af- firming the efficacy of umbilical arterial Doppler sonography in predicting and improving adverse perinatal outcome in pregnancies with fetal growth restriction (FGR) and preeclampsia; however, the utility of Doppler fetal surveillance in managing uncomplicated pregnancies with pregestational diabetes remains controversial.

This chapter presents a review of the role of Dop- pler sonography in assessing the fetus of a pregestational diabetic mother and recommends a management plan based on the current evidence.

Maternal Glycemic State and Fetal Hemodynamics

Fetal circulatory response to altered maternal glycemic state appears to be complex. This section briefly addresses this issue pertaining to both hyper- and hypoglycemia.

In an experimental model involving late gestation ewes, induction of acute maternal hyperglycemia produced a 27%±29% reduction in the placental share of the cardiac output which was redistributed to fetal carcass, heart, renal, adrenal, and splanchnic circulations [2]. Concordant with the changes in perfusion,

the fetuses also developed systemic hypoxemia and mixed acidemia during induced maternal hyperglycemia without any alterations in fetal cardiac, brain, and renal oxygenation. The response to hyperglycemic challenge, however, was different in the fetuses of ewes rendered diabetic by streptozocin administration [3]. The umbilical±placental blood flow did not change significantly in these fetuses but significantly declined in the controls, whereas fetal brain and renal perfusion was significantly higher in the former at all times than in the controls. The fetuses of the diabetic mothers were also more hypoxemic than the controls.

Fetal hypoxemia induced by maternal hyperglycemia could be explained by the earlier observation that chronic fetal hyperglycemia is associated with acceler- ated fetal oxidative metabolism. In the latter study, chronic fetal hyperglycemia produced by fetal glucose infusion via chronic in utero catheterization led to an increase in calculated fetal O2 consumption by ap- proximately 30% (p<0.01) [4]. The intensity of fetal hyperglycemia, and not the degree of fetal hyperinsulinemia, was the prime determinant of the magnitude of fetal O2 consumption which was associated with a significant increase in fetal O2 extraction with no alterations in either fetal O2 delivery or fetal blood O2

affinity.

The relationship between fetal hypoxemia and acidemia, and fetal and uterine hemodynamics, was investigated in a cross-sectional study involving women with well-controlled diabetes mellitus [5]. Of the 65 patients who had Doppler investigations performed, 41 had cordocentesis performed. The changes in the umbilical arterial Doppler indices correlated well with the changes in fetal pH (correlation coefficient ±0.402; p<0.01) and in pO2 (correlation coefficient ±0.544; p<0.001); however, this correlation was limited to the cases with FGR or preeclampsia as the Doppler findings were abnormal only in the presence of these complications. This finding is consistent with the known association between umbilical arterial abnormality and fetal growth restriction and preeclampsia. As the mothers' glycemic state was well controlled, this study did not address the issue of human fetal hemodynamic response to in utero hyperglycemia.

Doppler Sonography in Pregnancies Complicated with Pregestational Diabetes Mellitus

Dev Maulik, Genevieve Sicuranza, Andrzej Lysikiewicz, Reinaldo Figueroa

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The effect of maternal hypoglycemia on fetal cardi- ovascular system has been investigated in an animal model and also in humans. Maternal hypoglycemia induced by infusion of insulin in a ewe model led to increased fetal plasma catecholamine and free fatty acid levels (p<0.01) [6]; however, no significant effects were noted on the fetal heart rate, blood pres- sure, or arterial blood gases. Moreover, fetal insulin and glucagon levels were also unaffected. The studies in pregnant diabetic mothers were experimental in design and involved the use of the insulin clamp method for inducing hypoglycemia. Moderate maternal hypoglycemia induced by the insulin clamp technique in ten insulin-dependent diabetic women in the third trimester was associated with no consistent changes in the umbilical arterial Doppler waveform.

No significant alterations were observed in fetal breathing movements or the heart rate, although maternal epinephrine and growth hormone levels were significantly (p<0.001) increased [7]. In a similar study, the effect of hypoglycemia induced by hyperin- sulinemic hypoglycemic clamp on the fetal heart rate and the umbilical artery flow velocity waveforms was investigated in a prospective experimental study in ten women with insulin-dependent diabetes mellitus in the third trimester of pregnancy. Maternal hypoglycemia led to increases in the frequency and ampli- tude of fetal heart rate accelerations and maternal catecholamine levels but only a slight decline in the pulsatility index of the umbilical artery [8].

In summary, the above experimental and clinical studies enhance our understanding of maternal diabetes-induced modifications in fetal circulatory homeostasis. Fetal response to hyperglycemic challenge is modulated by the chronic glycemic state and the intensity of the glycemic challenge. In the presence of maternal diabetes, the fetus increases its oxidative metabolism becoming more hypoxemic. Perfu- sion of the brain and kidneys increases without any significant changes in the fetoplacental perfusion and the Doppler velocimetry of the umbilical arteries remains unchanged unless FGR is also present. Cordo- centesis data confirm that significant hypoxemia and acidemia in maternal diabetes mellitus may not be associated with Doppler-recognizable changes in fetal flow impedance unless the pregnancy is complicated with FGR or preeclampsia. Human and animal studies indicate that the fetal response to moderate maternal hypoglycemia is unremarkable and inconsistent.

Umbilical Artery Doppler

Sonography in Diabetic Pregnancies

This section reviews the role of Doppler ultrasound investigation of the umbilical artery in relation to ad-

verse perinatal outcome and also in relation to maternal glycemic state.

Umbilical Artery Doppler and Perinatal Outcome

The efficacy of umbilical arterial Doppler indices for predicting adverse perinatal outcomes in high-risk pregnancies has been affirmed by numerous studies.

Abnormally elevated umbilical arterial Doppler indices have been associated with low Apgar score, fetal distress (late and severe variable decelerations), absent variability, low fetal scalp and umbilical cord arterial pH, presence of thick meconium, and admis- sion to the neonatal intensive care unit [9]. As pre- sented in Chap. 25, an absent or reversed end-diastolic velocity in the umbilical arterial Doppler waveform is particularly ominous and is associated with mark- edly adverse perinatal outcome including a high perinatal mortality rate.

It remains somewhat controversial whether such diagnostic efficacy of Doppler sonography also en- compasses pregnancies with diabetes. The studies in this area differ in several respects including the sam- ple size, the Doppler parameter used and its thresh- old value, the measures of perinatal outcome, and prevalence of complications such as vasculopathy.

Although there is no complete unanimity in the con- clusions regarding efficacy, critical appraisal of these studies reveal that the controversy is mostly apparent.

The relevant studies regarding adverse perinatal outcome are summarized in Table 21.1 and are selec- tively discussed below.

Bracero and associates [10] observed a significant correlation between elevated umbilical arterial S/D and adverse perinatal outcome including increased stillbirths and neonatal morbidity such as hypoglycemia and hyperbilirubinemia in a mixed population of class A and insulin-dependent diabetic mothers. In a more recent report, the same investigator noted that umbilical arterial SD ratio was superior to biophysical profile or nonstress test in predicting preterm labor (<37 weeks), FGR, hypoglycemia, hyperbilirubinemia, respiratory distress and cesarean for fetal distress (rel- ative risk 2.6, 1.7, and 1.7, respectively; p<0.001).

Landon and colleagues [11] performed multiple umbilical arterial S/D measurements in 35 insulin-dependent diabetic women and observed significantly elevated mean second- and third-trimester S/D values in women with vasculopathy compared with women without the complication (4.34Ô0.7 and 3.2Ô0.65 vs 3.72Ô0.42 and 2.55Ô0.32, respectively; p<0.03). The elevated ratio preceded development of preeclampsia and fetal growth restriction.

Johnstone and associates [12] prospectively investigated the efficacy of the umbilical arterial resistance

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index in 128 pregnancies with uncomplicated diabetes mellitus. Abnormally elevated umbilical arterial RI significantly predicted nonassuring antepartum fetal heart rate tracing and/or a low biophysical profile score requiring immediate caesarean delivery; however, the RI was not predictive in four of seven pregnancies with fetal compromise which led the authors to caution against undue dependence on umbilical arterial RI in uncomplicated diabetic pregnancies.

In a patient population of 56 diabetic mothers including 14 with vasculopathy, Reece and associates [13] observed higher mean umbilical arterial indices in those with vasculopathy than those without vasculopathy or diabetes. Elevated Doppler indices were significantly associated with FGR and neonatal meta- bolic complications. This relationship between abnormal umbilical arterial Doppler indices, and the presence of maternal vasculopathic complication and var- ious adverse perinatal outcomes has been corroborated by other investigators [14±17].

Umbilical Arterial Doppler Sonography and Maternal Glycemic Control

In contrast to adverse outcome, the relationship between abnormal umbilical arterial Doppler indices

and the quality of glycemic control remains highly controversial. Bracero and associates [10] first noted a significant positive correlation between umbilical arterial S/D and mean serum glucose values (r=0.52, p<0.001). This finding however was refuted by Lan- don and associates [11] who found no significant correlation between mean third-trimester umbilical arterial S/D, and glycosylated hemoglobin (r=0.25) or mean blood glucose levels (r=0.15). This lack of correlation was corroborated by other investigators.

These studies are summarized in Table 21.2.

In summary, most studies suggest significant diagnostic efficacy in diabetic pregnancies complicated by the presence of FGR or hypertension. It is noteworthy that these studies were heterogeneous regarding the outcome measures and the population size, and that the Doppler method demonstrated varying degrees of diagnostic efficacy. Moreover, the presence of normal Doppler may not always rule out fetal compromise.

The ability of the umbilical artery Doppler indices to reflect maternal glycemic control remains controversial.

Doppler Sonography of Other Fetal and the Uterine Circulations in Pregestational Diabetic Pregnancies

Fetal Middle Cerebral Artery Doppler

There is insufficient information regarding the clinical value of Doppler investigation of the fetal cerebral circulation. In the neonate, Van Bel and associates found unaffected cerebral hemodynamics in the macrosomic infants of insulin-dependent diabetic mothers during the first 4 days of life even in the presence of ventricular septal hypertrophy with re- duced cardiac output and stroke volume [18]. Salve- sen and co-workers found no significant changes in the fetal circulation in a longitudinal Doppler study of 48 relatively well-controlled diabetic pregnancies except when complicated by preeclampsia or FGR [5].

The study included Doppler velocimetry of the middle cerebral artery. In a separate report, the authors Table 21.1. Diagnostic efficacy of umbilical arterial Doppler in diabetic pregnancy. PPV positive predictive value, NPV negative predictive value, LR+ positive likelihood ratio, LR± negative likelihood ratio, FGR fetal growth restriction, FD fetal distress, C/S cesarean section. (From [36])

Reference Outcome Prevalence Sensitivity Specificity PPV NPV LR+ LR± Accuracy

[10] Stillbirth 0.04 1 0.83 0.22 1 7.6 0 0.85

[11] FGR, FD 0.09 1 0.89 0.51 1 9.7 0 0.90

[12] FD 0.05 0.42 0.95 0.33 0.96 8.6 0.6 0.92

[15] C/S for FD 0.30 0.93 0.93 0.75 0.75 6.0 0.7 0.75

[16] Composite 0.23 0.32 0.92 0.57 0.81 4.2 0.7 0.78

[17] C/S for FD 0.27 0.61 0.75 0.48 0.84 2.5 0.5 0.71

Table 21.2. Umbilical arterial Doppler and maternal glycemic control. S/D systolic to diastolic ratio, RI resistance index, D the change, r correlation coefficient, NS not statisti- cally significant. (From [36])

Reference Doppler

index HbA1c D HbA1c Mean

blood glucose

[10] S/D r=0.52,

p<0.001

[11] S/D r=0.25, NS r=0.15,

[12] RI r=0.02±0.17, NS

[14] S/D NSr=0.28, NS 0.19

[13] S/D NS NS

[15] PI NS

[5] D PI 0.011, NS

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found normal Doppler results in the uterine and fetal circulations including the middle cerebral artery of most patients (five of six) with diabetic nephropathy despite the cordocentesis evidence of fetal acidemia within 24 h before delivery [19]. Ishimatsu and colleagues observed that the Doppler waveforms of the middle cerebral artery in 43 pregnant women with diabetes mellitus between 24 and 38 weeks of gestation were unaffected by maternal glycemic control [20].

Fetal Cardiac Doppler

Rizzo and colleagues studied fetal cardiac function in 37 mothers with type-I diabetes [21, 22]. The ratio between the peak velocities during early passive ventricular filling and active atrial filling (E/A ratio) were measured at the level of mitral and tricuspid valves. The investigators demonstrated that the E/A ratios were significantly lower in fetuses of diabetic mothers than in control fetuses, and were significantly and independently affected by the interventricular wall thickness, heart rate, and hematocrit values.

No significant alterations were observed in aortic and pulmonary peak velocities or in time-to-peak velocity values. The investigators also noted interventricular septal hypertrophy despite adequate glycemic control.

This was corroborated by Miyake who observed significantly smaller E/A ratios of the left and right ven- tricles in later gestation in the fetuses of diabetic mothers than those in the controls [23].

Rizzo and associates also investigated the venous blood flow patterns in insulin-dependent diabetic mothers in early gestation, and observed higher values of percent reverse flow in inferior vena cava and a significantly higher frequency of umbilical venous pulsations at 12 weeks which lasted until 16 weeks [24]. These abnormalities were more pronounced in pregnancies with poorer glycemic control. In fetuses of well-controlled insulin-dependent diabetic mothers, Gandhi and co-workers demonstrated that the ratio of the right ventricular shortening fraction/left ventricular shortening fraction was significantly higher from that in the control group indicating increased right ventricular hypercontractility in late diabetic pregnancy [25].

The cardiac dysfunction apparently continues in the neonatal period as shown by Kozak-Barany and colleagues who investigated the left ventricular systolic and diastolic functions in term neonates of mothers with well-controlled pregestational and gestational diabetes between 2 and 5 days after birth [26]. Prolonged deceleration time of early left ventricular diastolic filling was observed. The authors specu- lated that this probably reflected an impaired left ventricular relaxation related to maternal hyperglycemia

leading to subsequent fetal hyperinsulinemia and cardiac hypertrophy.

Uterine Artery Doppler

The efficacy of uterine artery Doppler for managing pregnancies with pregestational diabetes remains unproven despite initial enthusiasm.

Bracero and associates noted abnormal uterine artery velocity waveforms in 15.4% of 52 diabetic pregnancies compared with 2% in a nondiabetic population (p<0.001) [27]. Those with abnormal uterine Doppler had a higher occurrence of suboptimal glycemic control, chronic hypertension, polyhydramnios, vasculopathy, preeclampsia, cesarean delivery for fetal distress, and neonates with respiratory distress syn- drome. In 37 pregnant patients with pregestational and gestational diabetes, uterine Doppler demonstrated a sensitivity of 44.5%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 84.3% in predicting the later development of vascular complications [28].

Bracero and associates studied the association between uterine artery Doppler velocimetry discordance and perinatal outcome in 265 women with singleton pregnancies complicated by diabetes who underwent Doppler examinations within 1 week before delivery [29]. Adverse outcome was defined as stillbirth, intra- uterine growth restriction, delivery before 37 weeks' gestation, or cesarean delivery for fetal risk. Consid- erable overlap in discordance was present between the good and adverse outcome groups. The discordance between right and left uterine artery systolic±

diastolic ratios was significantly higher in pregnancies with adverse outcome (p=0.018). The uterine artery S/D ratio differences of 0.60 or greater was predictive of cesarean delivery for fetal risk. In diabetic women with chronic hypertension the discordance was not predictive of adverse outcome.

Grunewald and associates noted the absence of the normal third trimester decline in uteroplacental pulsatility indices in 24 well-controlled insulin-dependent pregestational diabetics [30]. The pulsatility index was not influenced by glycemic control. Barth and co-workers investigated the uterine arcuate artery Doppler and decidual microvascular pathology in 47 gravidas with type-I diabetes mellitus [31]. Signifi- cant correlation was noted between the abnormal Doppler indices from the uterine arcuate arteries and decidual microvascular pathology including fibrinoid necrosis, atherosis, and thrombosis (p<0.05).

In contrast to the above findings, other studies failed to confirm any predictive utility of the uterine Doppler velocimetry in pregnancies complicated with diabetes. Kofinas and associates observed that in gravidas with gestational (n=31) and insulin-depen-

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dent (n=34) diabetes mellitus, the umbilical and uterine artery flow velocity waveforms could not dif- ferentiate between good and poor glycemic control, although it discriminated the patients with preeclampsia from those without preeclampsia [32]. The investigators concluded that the clinical utility of Doppler waveform analysis in diabetic pregnancies might be limited to only those with preeclampsia.

In a cross-sectional study of 65 well-controlled diabetic pregnancies, Salvesen and co-investigators found that the Doppler indices of the placental and fetal circulations were essentially normal, except when complicated by preeclampsia or FGR [5]. In a study involving 43 pregnancies with insulin-dependent diabetes mellitus, Zimmermann and colleagues reported that long- and short-term glycemic control were unrelated to vascular resistance in the uterine artery, although the latter was higher in the presence of vasculopathy; however, more than half of the diabetics without vasculopathic complications showed a persistent notch in the uterine artery Doppler waveforms. Furthermore, uterine artery Doppler velocimetry did not demonstrate efficacy in predicting diabetes-related adverse fetal outcome [33].

In summary, the Doppler sonographic investigations of fetal central and cerebral circulations, and the maternal uterine circulation have yielded information of varying degrees of importance on maternal and fetal hemodynamic changes in pregnancies complicated with pregestational diabetes; however, there is no evidence that they are clinically useful in managing these pregnancies.

Clinical Effectiveness and Guidelines

As discussed in Chap. 30, the clinical effectiveness of umbilical Doppler velocimetry has been demonstrated in high-risk pregnancies by randomized clinical trials. But no such level of evidence exists for other biophysical tests of fetal well-being, which still constitute a critical component of the antepartum management of these pregnancies, and most often in- clude the nonstress test (NST) and the biophysical profile (BPP). These tests are usually initiated at 32 weeks and performed twice a week. Daily fetal movement count is also used as an adjunct screening test. There are no randomized trials dealing exclu- sively with the clinical effectiveness of Doppler fetal surveillance in pregnancies complicated with pregestational diabetes mellitus; however, in a randomized trial recently reported by Williams and colleagues, umbilical artery Doppler was compared with NST as a test for fetal well-being in a population of 1,360 high-risk gravidas 11% of whom had diabetes mellitus [34]. The Doppler group had a significantly lower

cesarean delivery rate for fetal distress than the NST group (4.6% vs 8.7%, respectively; p<0.006). The greatest effect was observed in pregnancies with hypertension and suspected FGR suggesting diabetic pregnancies with these complications may benefit from the use of Doppler velocimetry of the umbilical artery.

In utilizing the Doppler results, the clinical practice guidelines derived from the available evidence are also applicable to managing selected pregnant patients with pregestational diabetes. These guidelines are summarized here. It is emphasized that the over- all obstetrical management in pregestational diabetes in pregnancy depends on multiple factors which in- clude the severity of diabetes, adequacy of glycemic control, presence of vasculopathic complications, gestational age, assurance of fetal well-being, and past obstetrical history.

In diabetic pregnancies with FGR or preeclampsia, umbilical artery Doppler sonography should be added to the current standards of practice for fetal surveillance involving the NST and the BPP. If the Doppler index remains within the normal limits or is not pro- gressively rising, weekly Doppler tests should con- tinue. A high or increasing S/D ratio warrants more intense fetal surveillance consisting of umbilical Dop- pler ultrasound twice a week or more along with NST and BPP. If absent end-diastolic flow velocity (AEDV) develops, the likelihood of poor perinatal outcome is high and urgent clinical response is indicated. At or near term, the development of AEDV should prompt immediate consideration for delivery. Cesarean delivery may be preferable in the presence of reversed end-diastolic velocity or other ominous fetal monitoring findings (nonreactive NST, poor FHR baseline variability, persistent late decelerations, oligohydram- nios, and BPP score <4). In preterm pregnancies, further assurance of fetal well-being is sought by daily surveillance with umbilical Doppler, NST, and BPP.

Determination of fetal lung maturity may also assist in timing the delivery in this circumstance. In preterm pregnancies, considerations should also be given to steroid administration along with the modification of glycemic management as needed. Delivery is indicated when a single or a combination of the fetal tests indicate imminent fetal danger irrespective of lung maturity or when fetal risk from a hostile intrauter- ine environment is judged to be greater than that from pulmonary immaturity in a given neonatal ser- vice.

Current concepts and controversies on the general management of diabetic pregnancies and also on fetal surveillance may also be found elsewhere [35±37].

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Conclusion

Antepartum fetal surveillance constitutes an essential component of the standards of care in managing pregnancies complicated with pregestational diabetes mellitus. Fetal hyperglycemia is associated with increased oxidative metabolism, hypoxemia, and increased brain and renal perfusion without any significant changes in fetoplacental perfusion. Moreover, the relationship between abnormal umbilical arterial Doppler indices and the quality of glycemic control remains unproven; however, observational studies suggest significant diagnostic efficacy of the umbilical arterial Doppler method in diabetic pregnancies complicated with FGR or hypertension. Although there are no randomized trials specifically addressing this issue, existing evidence suggests that Doppler velocimetry of the umbilical artery may be beneficial for antepartum fetal surveillance in diabetic pregnancies in the presence of these complications. Such utiliza- tion should be integrated with the existing standards of practice.

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