Elevated fetal middle cerebral artery peak systolic velocity in diabetes type 1 patient: a case report

Introduction

Fetal anemia is a condition caused by multiple etiologies [1]. Red cell alloimmunization is the most common cause of fetal anemia, followed by parvovirus B19 infection. Other causes include inherited conditions such as alpha-thalassemia, genetic conditions producing aplastic anemia (such as Fanconi and Diamond Blackfan anemia), or genetic metabolic disorders (particularly lysosomal storage diseases such as Gaucher and Niemann-Pick diseases). Other acquired fetal conditions associated with fetal anemia are fetomaternal hemorrhage or a complication of monochorionic twin pregnancies referred to as twin anemia-polycythemia sequence. Doppler measurement of fetal middle cerebral artery peaks systolic velocity (MCA-PSV) is used to screen fetuses at risk of developing fetal anemia and in need of intrauterine transfusion. This non-invasive test has proved to be accurate to estimate the likelihood of moderate to severe fetal anemia and it is used in the management of this pathology [2, 3].

Few cases of increased MCA-PSV in the absence of fetal anemia have been described. We present the case of a fetus of 31 weeks with persistently elevated fetal MCA-PSV in absence of fetal anemia.

Case presentation

A 30-year-old gravida two para one woman of Moroccan descent with a singleton unplanned pregnancy was referred to our institution at 21 weeks of gestation after a sonographic finding of left fetal renal agenesis and single umbilical artery in a female fetus.

The patient had poorly controlled type 1 diabetes, and she had no surgical history or alcohol or smoking habit. There was no family history of birth defects or genetic disorders. She had no parental relationship with her couple and only insulin was administered to her during pregnancy. In her previous pregnancy she had an induced labor because of a premature rupture of membranes at 39 weeks. A 3540 g female child was born by instrumental delivery. Her Apgar score was 9–10–10. Twenty-five hours post-delivery the baby was shifted to neonatal intensive care unit (NICU) due to thrombocytopenia, and platelet concentrates were administered twice. In view of persistent thrombocytopenia due to suspected neonatal autoimmune thrombocytopenia (despite maternal normal platelet count) gammaglobulin was administered. In the extension study, thrombosis was detected at the level of the inferior vena cava. Hepatic and adrenal calcifications without involvement of the renal veins were found. Thrombosis was attributed to maternal diabetes. Echocardiography at one month of life showed persistent foramen ovale, hypertrophic interventricular septum (IVS) of 6.9 mm with the persistent thrombosis in the inferior vena cava. She was treated with one year of heparin.

In this pregnancy, she was a late booker with her first control at 21 weeks of pregnancy. Her initial HbA1c was 9.1%, and she had weekly appointment at the endocrinologist unit. Sonographic examination revealed a single intrauterine pregnancy dated with the biparietal diameter with an estimated gestational age of 21 weeks. The study revealed a left fetal renal agenesis and single umbilical artery in a female fetus, adequate amniotic fluid, and no other abnormalities. Magnetic resonance imaging was performed, which confirmed the diagnosis. Fetal echocardiography scan was normal at 22 weeks. In view of fetal malformation and no first-trimester screening performed because of the late booking, amniocentesis test was offered but the patient declined. The patient was scheduled for follow-up by ultrasound every 4 weeks. At 31 weeks of gestation, color Doppler measurement demonstrated an abnormally raised fetal MCA-PVS of 86 cm/s (Figure 1), more than 1.5 times the multiples of the median (MoM) value for the particular gestational age (Median 40.5 cm/s, 1.50 MoM 60.7 cm/s) by international and local standards. A diagnosis of severe fetal anemia was suggested. In addition, a discrepancy of ventricular size with normal IVS and fetal heart function were noted. Soft tissues of the fetal forehead (Figure 2) as well as the abdomen (Figure 3) were thick. However, there was no abnormal pleural, pericardial or peritoneal free fluid, and the amniotic fluid appeared normal. The estimated fetal weight was on the 100th percentile. The most common causes for fetal anemia were ruled out: prenatal screening for congenital infection was normal, the patient was Rhesus Positive, the indirect Coombs and Kleihauer tests were negative and the cardiotocography test (CTG) was reassuring. We did not perform a cordocentesis test in view that usual causes of fetal anemia had been excluded. Ultrasound follow-up showed a persistent increased MCA-PSV in a large for gestation age (LGA) fetus. At 34 weeks' follow-up scan, an IVS was thickened of 8 mm (Figure 4) and the diagnosis of biventricular hypertrophic cardiomyopathy (HC) was suggested. Due to the prenatal diagnosis of persistent elevated MCA-PSV in LGA fetus with possible biventricular HC in a poorly controlled type 1 diabetic patient and induction of labor was performed at 34.3 weeks, after fetal lung maturation with corticosteroids.

Figure 1:

Color Doppler ultrasound showing an abnormally raised fetal MCA-PVS at 31 weeks.

Figure 2:

Left: Grey scale ultrasound showing the profile and thickening of the soft tissues of the fetal forehead at 31 weeks is seen. Right: 3D picture of the face.

Figure 3:

Grey scale ultrasound showing the thickening of soft tissues of abdominal wall (arrows) at 31 weeks.

Figure 4:

Grey scale ultrasound showing axial section of thorax at 34 weeks.

Thickening of interventricular septum of 8.3 mm is seen.

A female 3, 610 g child was born. Her Apgar score was 6–8–9. The neonate was admitted in NICU for further management. At physical examination, a mesocardial IV/VI systolic murmur with palpable snoring was noted. Pulses were present and symmetrical and the skin had normal color. Vital signs were in the normal range with pulse oximeter of 99% without oxygen. The fetal blood sugar level was 38 mg/dL at 2 h of life. The neonate had a hemoglobin value of 134 g/L and platelet value of 264 x10*9/L on delivery. She received 145 cc of intravenous glucose at 12.5% increasing to 25% because of uncontrolled hypoglycemia. On day 5, hemoglobin was 131 g/L and platelet count was 159 × 10*9/L. The child's blood group was A Rhesus Negative and direct Coombs test was negative.

Echocardiography scan at birth demonstrated biventricular hypertrophy with septal measurement of 7 mm and normal contractility. The aortic flow had a maximum peak velocity of 1.7 m/s with subaortic gradient of 33 mmHg and the pulmonary flow had a maximum peak velocity of 2.2 m/s and 16–18 mmHg of gradient. These findings suggested HC with mild pulmonary infundibular stenosis and moderate subaortic stenosis. She initiated treatment with oral propranolol 1 mg/mL 0.5 mg every 8 h increasing at 2.5 mg every 8 h.

Follow up ultrasound on day 5 demonstrated a normal MCA-PVS, and the prenatal diagnosis of left renal agenesis was confirmed by abdominal scan. Chest X-ray showed a normal heart size. Repeat echocardiography was performed on day 11, showing a persistent HC with improvement of the infundibular gradients. The baby was discharged at 11 days after birth with a weight of 3, 785 g. Physical examination revealed a II/IV systolic murmur. She was booked a follow-up visit at one month of life.

Discussion

We present the case of a child of a diabetic mother who, during antenatal period, presented MCA-PSV higher than 1.5 MoM, without any cause of anemia. HC, a complication associated with diabetic pregnancies, could explain increased MCA velocity due to an increase of the ejection of blood from the heart to the aorta that is transmitted to the MCA.

Several studies have proved that measuring MCA-PVS is the mainstay for the detection of fetal anemia [1], [2], [3], [4]. As originally described by Mari et al. [2], MCA-PSV above 1.5 MoM indicates moderate or severe fetal anemia, with a sensitivity of 100% and false-positive rate (FPR) of 12% [2, 4]. The use of this tool in the assessment of red-cell alloimmunized pregnancies has led to a reduction of about 70% in the number of invasive tests, which can cause fetal complications such as fetal death [4]. Many studies have demonstrated that Doppler ultrasound measurements of the MCA-PSV predict fetal hemoglobin and hematocrit concentration [2, 4, 5]. Low red cell mass is associated with decreased blood viscosity and increased cardiac output to maintain adequate oxygenation, leading to an increase in PSV of fetal arterial blood flow [6].

To the best of our knowledge, increased MCA-PSV measurements in nonanemic fetuses have been reported only in two conditions, which are alpha thalassemia [7, 8] and fetal HC [9]. In the first one, an elevated MCA-PVS with a normal fetal hematocrit and relative fetal microcytosis seen on cordocentesis was reported to be secondary to alpha-thalassemia trait. Alpha-thalassemia trait is caused by a deletion of two of the four α globin genes, which results in deficient α chain production and associated microcytic anemia. The authors suggested that the elevated MCA-PSV could be due to reduced mean corpuscular volume [7]. Kachewar et al. [9] documented a case of elevated fetal MCA–PVS possibly attributed to cardiomyopathy that could increase left ventricular contractility, pumping more blood into the aorta, which would produce as increase in the fetal MCA–PSV [7].

It is known that infants of diabetic mothers are at an increased risk of intrauterine death, congenital malformations (mainly cardiac, urinary and vertebral), hypoglycemia, polycythemia, thrombocytopenia, dystocic delivery, fetal-neonatal HC, among others [10], [11], [12]. Diabetes mellitus is a metabolic disorder that affects the fetal heart during early and late gestation. During embryogenesis, it can alter the expression of genes needed for the correct development of the structures of the heart, causing structural heart defects. Additionally, fetal hyperinsulinemia due to poor maternal glycemic control increases the expression of fetal insulin cardiac receptors in late gestation. This leads to hyperplasia and hypertrophy of the fetal myocardium, most commonly in the IVS due to its abundance of insulin receptors, resulting in HC [11]. In the management of diabetes during pregnancy, it is important to optimize the glucose level in a diabetic pregnant woman to reduce fetal and neonatal complications [12].

Fetal echocardiography is required in pregestational diabetic pregnancies to evaluate the structure and the function of the fetal heart [13], in view that heart congenital malformations are more frequent and HC can be present. HC is defined as enlarged heart in association with ventricular wall hypertrophy of one or both ventricles. An obstruction of the inflow or outflow tract can be found. Ventricular hypertrophy and cardiac compromise increase with advancing gestation and can lead to cardiac failure, hydrops and stillbirth. It affects 12.1% of infants of diabetic mothers and can be diagnosed around 30% by prenatal echocardiography [14]. At birth, HC hinders the newborn's adaptation to extrauterine life, by decreasing ventricular compliance and altering the diastolic filling function and systolic ejection function, thus increasing the risk of perinatal death. In most cases, cardiac hypertrophy could be transient, with spontaneous resolution within the early months after birth. In some cases, beta-blockers like propranolol, which decreases heart rate and left ventricular contractility, are needed [12]. Surgical management is indicated when septal hypertrophy and outflow tract obstruction cause significant symptoms despite medical therapy. It is known that maternal hyperglycemia and high levels of HbA1c during the third trimester are associated with thick neonatal IVS as well as ventricular wall and macrosomia [11], [12], [13], [14], [15]. It is also believed that the severity of HC can be reduced by appropriate diabetic management.

In our case, the patient had poorly controlled diabetes with abnormal HbA1c from the beginning of pregnancy. She was a late booker with the first control at 21 weeks. The fetus had common complications of a diabetic mother. The baby had a congenital renal malformation with agenesis of the left kidney and single umbilical artery. Furthermore, because of her high levels of HbA1c during all pregnancy the baby was LGA with a birthweight of 3, 610 g at 34.3 weeks of gestation and HC was suspected with a IVS of 8 mm. Our concerns were that at 31 weeks we found an abnormally MCA–PVS without any cause of fetal anemia. For that reason, cordocentesis was not performed and the case was managed with follow-up ultrasound scans and CTG. The patient was followed weekly until 34 weeks when IVS of 8 mm thickness was observed and HC was suspected. Therefore, increased PVS-MCA was attributed to HC. As previously reported by Kachewar et al., the reason of increased PVS-MCA in our fetus without any cause of fetal anemia and with pregestational diabetes was HC. We recommended to finalize the pregnancy due to the presence of several risk factors for fetal demise, a LGA fetus of type 1 diabetic patient mother with very poorly glycemic control and the suspicious of HC with persistent of MCA-PSV.

Conclusions

Although rare, not all cases of fetuses with raised PVS-ACM are associated with fetal anemia. In our case, the abnormally elevated PVS-ACM could be associated with cardiac abnormalities such as HC. Its early diagnosis and management are important for the prenatal and postnatal care.