Review Received: October 21, 2014 Accepted after revision: January 16, 2015 Published online: March 10, 2015

Fetal Diagn Ther DOI: 10.1159/000375372

Prenatal Diagnosis of Renal Vein Thrombosis: A Case Report and Literature Review Amirhossein Moaddab Alireza A. Shamshirsaz Rodrigo Ruano Bahram Salmanian Wesley Lee Michael A. Belfort Jimmy Espinoza  Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children’s Fetal Center, Texas Children’s Hospital Pavilion for Women, Houston, Tex., USA

Abstract Background: Renal vein thrombosis (RVT) is a well-characterized condition among neonates; however, this complication is rarely diagnosed prenatally. Methods: In this report, we describe a fetus with unilateral RVT and summarize the literature regarding prenatal diagnostic criteria and postnatal prognosis. We searched the English, French and Spanish literature (MEDLINE, PubMed and EMBASE) for cases with prenatal diagnosis of RVT. Results: Including our case, a total of 23 fetuses with fetal RVT were reviewed in the present study. All cases were diagnosed in the third trimester, and the survival rate among these cases was 63%. Enlargement of the kidney was the most commonly associated initial ultrasound finding. The only ultrasound finding significantly associated with mortality was the presence of bilateral RVT. Discussion: The etiology of fetal RVT is still unclear. Considering the large number of cases with RVT that manifest in the first days of life, prenatal diagnosis of this condition has relevance. © 2015 S. Karger AG, Basel

© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt

Background

Renal vein thrombosis (RVT) is the most common form of venous thrombosis in neonates, with an incidence of 2.2 per 100,000 live births [1, 2]. Most cases of neonatal RVT are diagnosed shortly after delivery [3]; thus, it is possible that the disease process in some of these neonates starts in the prenatal period and manifests postnatally as congenital hypertension or renal vein calcification [4, 5]. The etiology of fetal RVT remains unknown. However, several risk factors are associated with this uncommon fetal condition, including maternal diabetes mellitus (type 1, type 2 or gestational), perinatal asphyxia, dehydration, polycythemia, cyanotic heart disease, antenatal corticosteroid therapy and coagulation abnormalities [6, 7]. RVT can be unilateral or bilateral, and, even in severe cases, the thrombus can extend into the inferior vena cava (IVC) [8]. van der Vange and Bruinse [9] reported one of the earliest descriptions of fetal RVT in 1986, and a few additional cases have been described more recently [2, 6, 8]. Some authors suggested an increased incidence of this condition [1]; however, this may be a reflection of ascerJimmy Espinoza, MD Baylor College of Medicine, Texas Children’s Hospital Pavilion for Women 6621 Fannin St, F1040-08 Houston, TX 77030 (USA) E-Mail Jimmy.Espinoza @ bcm.edu

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Key Words Renal vein thrombosis · Prenatal diagnosis · Fetus · Prognosis

tainment bias based on improved ultrasonographic techniques and resolution. In this article, we discuss a case of fetal RVT and review the ultrasonographic findings suggestive of fetal RVT and the clinical outcomes that have been described in the medical literature.

LEFT RIGHT

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Methods Two reviewers searched the English, French and Spanish literature (MEDLINE, PubMed and EMBASE) for prenatal diagnoses of RVT. ‘Antenatal RVT’, ‘perinatal RVT’, ‘prenatal RVT’ and ‘in utero RVT’ were determined as search terms, which identified 62 articles through titles and abstracts. Five articles were added to the search list from the reference sections of the original articles. We excluded 46 papers in which the RVT was diagnosed postnatally. Thus, 21 articles describing 22 cases of prenatally diagnosed RVT were included in the present study [2, 3, 6, 8–26]. Of these pregnancies, 19 were singleton and 3 were twin pregnancies. In the twin cases, only 1 twin was affected by fetal RVT and the other twin was normal [2, 6, 20]. The demographic, clinical and sonographic characteristics of fetal RVT cases that survived were compared to those associated with perinatal death.

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RIGHT

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Results

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Fetal Diagn Ther DOI: 10.1159/000375372

1 D 5.14cm 2 D 2.90cm 3 D 3.89cm 4 D 2.14cm

b

Fig. 1. Axial (a) and sagittal views (b) of both fetal kidneys. Note that the right kidney is enlarged and there is a loss of corticomedullary differentiation when compared to the left kidney.

of the normal kidney appearance just 1 week earlier, these sonographic features were much more suggestive of fetal RVT than of other etiologies commonly attributed to echogenic fetal kidneys (e.g. obstructive uropathy, renal dysplasia, glycogen storage disease, idiopathic infantile arterial calcification, infantile polycystic kidney disease or chronic hypoxic conditions) [27, 28]. There was no sonographic evidence of fetal hydrops or ascites. Because of the risk of preterm delivery, antenatal corticosteroids were given to improve fetal lung development. Two days later, the patient had preterm premature rupture of membranes and went into labor. A 3,585-gram male infant was born at 33 weeks and 6 days by vaginal delivery, with APGAR scores of 5 and 7 at 1 and 5 min, respectively, with an arterial cord pH of 7.26. At delivery, the baby was Moaddab/Shamshirsaz/Ruano/ Salmanian/Lee/Belfort/Espinoza

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Case Report A 16-year-old primigravida at 32 weeks of gestation with bipolar disorder and type 1 diabetes mellitus was referred to the Texas Children’s Fetal Center (Houston, Tex., USA) because of abdominal pain. Earlier in the same pregnancy she had been admitted because of poor glucose control (blood glucose: 500 mg/dl; urine ketones: negative). At that time, she denied leakage of fluid, vaginal bleeding, dysuria, fever or chills. She was given an insulin pump to provide better glucose control, and, at 32 weeks of gestation, her blood glucose was 124 mg/dl. The estimated fetal weight was >95th percentile, and there was moderate polyhydramnios (amniotic fluid index: 32 cm). At least two small ventricular septal defects (one muscular and one membranous), moderate tricuspid regurgitation and moderately thickened myocardium were identified. Both kidneys had normal echogenicity and size. A follow-up scan at 33 weeks and 4 days of gestation revealed an enlarged right kidney (51 × 29 × 28 mm; volume: 21.7 ml) with loss of corticomedullary differentiation (fig. 1). The left kidney had a normal size and shape (38 × 21 × 22 mm, volume: 9.2 ml). Color and spectral Doppler ultrasonography demonstrated limited arterial and venous blood flow to the right kidney (fig. 2). In light

Power Doppler imaging demonstrates limited vascular supply to the right kidney.

hypotonic with poor respiratory effort, grunting and hypoglycemia. He was transferred to the neonatal intensive care unit for additional management. On postnatal renal ultrasound scan, the right and left kidneys measured 55 and 44 mm in maximum length, respectively. No hydronephrosis or hydroureter was seen. The urinary bladder appeared normal. An echogenic thrombus was noted to occlude the lumen of the right main renal vein and extended into the lumen of the right lateral aspect of the juxtarenal segment of the IVC. The main left renal vein was patent. Renal arterial pulse Doppler waveforms were consistent with a high resistance flow pattern. Echocardiography confirmed the prenatal diagnosis of ventricular septal defects. Initial hematologic, biochemical and coagulation studies were within normal limits except for hyperkalemia (K = 6.7 mg/dl, Na = 141 mg/dl, blood urea nitrogen = 13 mg/dl, creatinine = 0.93 mg/dl, RBC = 6.41 × 106/dl, WBC = 9.13 × 103/dl, Plt = 130 × 103/dl, Hct = 57.5%, PT = 15 s, PTT = 34.5 s, INR = 1.2). The baby’s urinary output in the first 24 h after birth was 2.5 ml/kg/h (normal range: 1–3). The neonate was started on Lovenox (enoxaparin, 1.7 mg/kg/day). A repeat ultrasound scan at 15 days of life showed normal appearing kidneys. Both right and left kidneys measured 48 mm in length, and multiple echogenic foci had developed in the right kidney. The Fetal Renal Vein Thrombosis

Literature Review A total of 23 fetuses with fetal RVT were reviewed in the present study. All cases had been diagnosed in the third trimester (mean: 31.4 ± 3.4 weeks; range: 25–36). While 6 cases (26%) had bilateral RVT, the right kidney was involved in 7 (30%) and the left kidney in 10 patients (44%). The most common clinical findings included decreased fetal movement and premature labor; however, some cases were diagnosed incidentally. Information about survival was not provided in 1 case. The survival rate was 63% (n = 14/22). Pregnancy was medically terminated in 1 case (n = 1/22, 5%). Two cases (10%) did not survive the neonatal period, while 5 died during follow-up (22%). The median follow-up interval was 6 months (range: 1 week to 4 years). Of the 14 fetuses that survived, the affected kidney was nonfunctional in only 1 case at the 2-year follow-up visit. Demographics and perinatal characteristics of all patients with fetal RVT according to perinatal mortality are summarized in table 1. Diabetes mellitus (n = 5, 22%), primary hypertension (n = 1, 4%), pregnancy-induced hypertension (n = 1, 4%), preeclampsia (n = 2, 8%) and maternal thrombophilia (n = 3, 12%) were associated maternal factors. Cases with maternal thrombophilia included deficiencies of protein C, protein S and antithrombin III. One case had a paternal 4G PA1 gene mutation. Factor V Leiden and methylene tetrahydrofolate reductase (MTHFR) gene mutations were reported in 1 infant [6, 20]. The association of diabetes mellitus and RVT deserves further research. In all cases, the prenatal diagnosis was made by ultrasonography, and 4 cases underwent postnatal angiography or venography to confirm the diagnosis [6, 10, 21, Fetal Diagn Ther DOI: 10.1159/000375372

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Color version available online

Fig. 2. Coronal view of the fetal right (RK) and left kidneys (LK).

sonographic appearance of the thrombus in the right renal vein was unchanged. Neonatal thrombophilia workup was negative. Factor V Leiden, prothrombin gene mutation, fibrinogen, antithrombin, protein C, protein S, homocysteine, anticardiolipin Ig G, anti-beta 2 glycoprotein, lipoprotein A and factor VIII were normal. The parents’ thrombophilia workups were also normal. After 34 days of hospitalization, the infant was discharged home in a stable condition. Prophylactic enoxaparin was given for 6 weeks. A repeat Duplex study at 2 months revealed a slightly larger left kidney. Doppler interrogation of the right kidney demonstrated normal arterial waveforms, and there was venous flow in the peripheral portion of the right renal vein more centrally. The renal vein did not appear to communicate with the IVC but rather with a collateral vessel. Blood urea nitrogen, creatinine levels and platelet counts were also within normal limits.

Table 1. Demographics, prenatal characteristics and outcomes in cases of fetal RVT

Gestational age at diagnosis, weeks Gestational age at delivery/TOP, weeks Birth weight, g Decreased fetal movement Oligohydramnios Polyhydramnios Renal vein calcification Intrauterine growth restriction Abnormal Doppler study Abnormal renal echogenicity Hydrops fetalis Enlarged kidney Bilateral RVT IVC thrombosis Cardiac anomalies Maternal diabetes mellitus Familial history of thrombophilia

Alive (n = 14)

Dead (n = 8)

p value

32.4 ± 3 34.4 ± 3 2,515 ± 1,005 5/14 (36) 1/14 (7) 3/14 (21) 2/14 (14) 2/14 (14) 4/14 (29) 7/14 (50) 5/14 (36) 11/14 (79) 1/14 (7) 9/14 (64) 3/14 (21) 4/14 (36) 3/14 (21)

29.6 ± 3.4 31.4 ± 3.1 2,498 ± 1,164 3/8 (38) 0/8 5/8 (63) 1/8 (13) 0/8 3/8 (38) 3/8 (38) 5/8 (63) 3/8 (38) 5/8 (63) 3/8 (38) 1/8 (13) 1/8 (13) 2/8 (25)

0.669 0.488 0.974 1.000 1.000 0.081 1.000 0.515 1.000 0.675 0.378 0.081 0.011 0.378 1.000 0.613 0.976

24]. Prenatal diagnosis was suspected by findings consistent with renal enlargement, renal size discrepancy, hyperechoic streaks, abnormal renal vein Doppler study and loss of corticomedullary differentiation. The only ultrasound finding significantly associated with mortality was the presence of bilateral RVT (p < 0.011). There was a higher frequency of hydrops and polyhydramnios in cases with perinatal death; however, the frequency of these sonographic findings was not significantly different compared to survivors. Five cases, including our case, received thrombolytic/ anticoagulation treatment after birth [6, 19, 21, 24]. Bleeding of the adrenal cortex occurred in 1 neonate who received a combination of tissue plasminogen activator and unfractionated heparin [6]. All of these cases survived; however, in 1 case, a nonfunctional kidney was found during follow-up evaluations [19]. The other cases did not receive any specific antithrombotic/anticoagulation therapy and underwent observational and supportive treatment such as hydration.

Discussion

It has been proposed that because of the well-balanced coagulation and anticoagulation systems in fetuses, thrombotic events are rare [8]. However, the double cap4

Fetal Diagn Ther DOI: 10.1159/000375372

illary circulation of the kidneys makes them vulnerable to thrombosis in the presence of predisposing conditions such as hemoconcentration and hypercoagulability [2, 22]. Both of them can be present in women with diabetes mellitus, particularly among women with poor diabetes control [7]. A thorough assessment of pregnant women to identify predisposing conditions and a complete thrombophilia workup for both parents and newborns might be appropriate in cases of fetal and neonatal RVT. However, in most cases it is unlikely that either maternal or fetal risk factors will be found [29]. The prenatal ultrasound findings suggestive of RVT are similar to what has been described during the neonatal period, including renal enlargement, hyperechoic streaks and loss of corticomedullary differentiation [18]. Fluid collections in fetal compartments and overt hydrops have also been observed in some cases [2]. Among the sonographic features, renal enlargement is the most frequent finding in the cases reported in the literature (table 1). Furthermore, it appears that there is a positive relationship between the degree of renal enlargement and worse future renal function in cases of RVT [1]. Color and spectral Doppler evaluation of the renal artery and vein can increase the index of suspicion in the prenatal diagnosis of RVT [30]. It has been speculated that IVC involvement is a more specific sign of fetal RVT Moaddab/Shamshirsaz/Ruano/ Salmanian/Lee/Belfort/Espinoza

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Values are presented as means ± SD or n (%). TOP = Termination of pregnancy.

[14]. However, this most likely represents a late stage of the disease. Bilateral fetal RVT is associated with an increased risk of fetal death. Thus, delivery could be considered if there is a high index of suspicion of bilateral RVT. Most cases of neonatal RVT manifest in the first days of life [31]. Thus, it is possible that the disease process may have started before birth in some of these cases. We suggest that fetal RVT should be a part of the differential diagnosis when the ultrasonographic features described above are seen on a prenatal ultrasound. This may alert the neonatal team to the problem and initiate earlier treatment than may otherwise occur. The left-sided predominance in cases of fetal RVT is similar to the pattern described by Kuhle et al. [31] in neonates with RVT. It has been proposed that anatomic differences may account for a higher frequency of leftsided RVT. These include (1) a longer left renal vein than right renal vein, and (2) the mechanical effect of the abdominal aorta compressing the left renal vein. The optimal treatment of RVT is unclear. There are no reports of prenatal intervention, and all therapeutic options have focused on supportive care in the neonatal period and on postnatal thrombolytic/anticoagulant drugs. Tissue plasminogen activator, unfractionated heparin, low-molecular-weight heparin and warfarin have all been used during the neonatal period in the reported cases of

fetal RVT [6, 19, 21, 24]. We could not find any report of maternal anticoagulation in the management of fetal RVT, and given the fact that heparin does not cross the placenta, the role of maternal anticoagulation may only have significance if the mother has an identified thrombophilia requiring anticoagulation. Fetal RVT is associated with long-term adverse outcomes including an increased risk of renal failure [19, 22]. Even in cases with normalization of the renal size and no signs of reduced perfusion, long-term follow-up revealed compromised renal function [32]. Moreover, loss of a kidney in fetal life is associated with an increased risk of later renal and cardiovascular disease such as tubular and glomerular damage and hypertension [33]. Given the low frequency of fetal RVT, creating a multicenter registry of fetal RVT cases may provide important insights into the natural history and long-term prognosis of fetal RVT. This database may improve our understanding of this rare fetal condition, improve the quality of our parental counseling and provide the basis for research into possible prenatal interventions.

Disclosure Statement The authors declare that they have no conflicts of interest.

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Prenatal Diagnosis of Renal Vein Thrombosis: A Case Report and Literature Review.

Renal vein thrombosis (RVT) is a well-characterized condition among neonates; however, this complication is rarely diagnosed prenatally...
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