Fetal hepatic calcifications: Prenatal diagnosis and outcome

Fetal hepatic calcifications: Prenatal diagnosis and outcome Michal J. Simchen, MD,a,b Ants Toi, MD,c Mark Bona,a Fawaz Alkazaleh, MD,b Greg Ryan, MB,b and David Chitayat, MDa Toronto, Ontario, Canada OBJECTIVE: The purpose of this study was to provide information on the causes and postnatal outcomes of fetal liver calcifications that were detected by ultrasound imaging. STUDY DESIGN: Cases with fetal liver calcifications that were encountered between 1992 and 2001 were evaluated. A detailed fetal ultrasound imaging for associated abnormalities, maternal STORCH (syphilis, cytomegalovirus, herpesvirus 1 and 2, rubella, and Toxoplasma) analysis, parvovirus serologic condition, and parental cystic fibrosis mutations analysis were performed; amniocentesis was offered in all cases. All infants who were born alive were examined and followed up. RESULTS: Sixty-one pregnant women with fetal liver calcifications were identified. Forty of 61 patients had additional fetal abnormalities; 21 of 61 cases of fetal liver calcifications were isolated; 11/61 patients (18%) had abnormal karyotypes (trisomy 13, 4 patients; trisomy 21, 2 patients; trisomy 18, 1 patient; monosomy X (45,X), 1 patient; 4p–, 22q+, and 8p+, 1 patient). Ten of 11 patients with abnormal karyotypes had other abnormalities that were found on ultrasound imaging. Two patients had intrauterine infection, one patient had cytomegalovirus, and one patient had parvovirus B19 infection. Eighteen of 40 patients underwent pregnancy termination, one fetus died in utero, one newborn infant died, and two infants had neurologic sequelae. Of 21 patients with isolated liver calcifications, one fetus had parvovirus B19 infection and one infant had trisomy 21. The remainder of the infants each had a good outcome. CONCLUSION: Fetal liver calcifications are relatively common. Isolated cases have a good prognosis after aneuploidy and infection have been ruled out. However, additional major abnormalities present a risk for chromosomal abnormalities, mainly trisomy 13. (Am J Obstet Gynecol 2002;187:1617-22.) Key words: Liver calcification, prenatal diagnosis, fetal ultrasound, chromosome abnormality, intrauterine infection Fetal liver calcifications (FLCs) are hyperechogenic areas that are detected by ultrasound imaging in the fetal liver. This is a relatively common prenatal ultrasound finding, with an estimated incidence of 1:1000 to 1:1750.1-23 Various causes have been reported for FLC, including fetal infection (mainly cytomegalovirus infection),3-5 vascular events that affect the liver,6-8 and hepatic tumors.9 FLCs have been described as isolated findings or in association with other anomalies, and cases of chromosomal abnormalities have also been reported. Although relatively common, the causes, outcome, and long-term prognosis have not been well delineated. We studied the cause and outcome of 61 cases that were diagnosed with FLC at our center over the last 10 From the Prenatal Diagnosis and Medical Genetics Programa and the Departments of Obstetrics and Gynecologyb and Medical Imaging,c Mt Sinai Hospital, University of Toronto. Received for publication January 9, 2002; accepted June 6, 2002. Reprint requests: D. Chitayat, MD, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Ontario Power Generation Building, 700 University Ave, Room 3292, Toronto, Ontario, Canada M5G 1Z5. E-mail: dchitayat@mtsinai.on.ca © 2002, Mosby, Inc. All rights reserved. 0002-9378/2002 $35.00 + 0 6/1/127899 doi:10.1067/mob.2002.127899 years. Associated ultrasound findings, chromosomal abnormalities, and long-term follow-up are reported. Because our center is a tertiary referral center, we cannot draw conclusions regarding the prevalence of FLCs or associated findings in the general population. Material and methods We followed prospectively all cases with FLCs that were detected prenatally between the years 1992 and 2001 at the Prenatal Diagnosis Program, University of Toronto, Toronto, Ontario, Canada. FLCs were defined as areas of abnormal brightness with an echogenicity similar to that of the surrounding bone with shadowing of sufficient size. The presence of hyperechogenic areas either within the liver parenchyma or on the liver surface and any additional abnormalities that were detected by ultrasound scans were recorded prospectively by the sonologist who performed the examination. Ultrasound examinations were performed with a 5- to 7-MHz curvilinear abdominal probe (ATL HDI 3000 or 5000, Bothell, Wash). A rigorous protocol was applied prospectively for the investigation of each case with FLCs, which included a detailed targeted ultrasonographic evaluation for associated abnormalities, maternal blood test for STORCH infections (syphilis, cytomegalovirus, herpesvirus 1 and 2, rubella, 1617 1618 Simchen et al December 2002 Am J Obstet Gynecol Fig 1. Ultrasound diagnosis of surface liver calcifications. Fig 3. Cs: distribution of cases according to the type of calcification. Fig 2. Ultrasound diagnosis of parenchymal liver calcifications. and Toxoplasma), parvovirus B19, and parental DNA analysis for the most common cystic fibrosis (CF) mutations. In cases of suspected fetal infection, further investigation included amniotic fluid viral culture and polymerase chain reaction when the mother elected to undergo amniocentesis. Amniocentesis for fetal chromosome analysis was offered to all women. Pregnancy outcome was recorded. In cases in which termination of pregnancy was chosen or when fetal or neonatal demise occurred, autopsy results were obtained. All live-born infants had a detailed neonatal examination with periodic follow-up visits. Women who were unable to attend follow-up visits were contacted by telephone. A single observer (D. C.) performed all postnatal examinations. In most cases, neonatal abdominal ultrasound scanning was performed to evaluate and follow ultrasonographic findings. Results Sixty-one fetuses that were seen at the Prenatal Diagnosis Program were found to have liver calcifications. The mean gestational age at diagnosis was 19 weeks 5 days (range, 15-40 weeks). Of the 61 patients, 21 patients (35%) had isolated liver calcifications, and 40 patients (65%) had additional ultrasonographic findings (Table I). Among the 40 patients with additional ultrasound findings, the most frequent major abnormalities included central nervous system anomalies (13 patients), cardiac anomalies (12 patients), cystic hygroma (12 patients), skeletal abnormalities (11 patients), and hydrops fetalis (9 patients). The most common minor abnormalities detected were echogenic intracardiac foci (11 patients) and echogenic gut (10 patients). Intrauterine growth restriction was also associated commonly with FLCs (12 patients). Of the 61 cases, 9 infants had surface calcifications (Fig 1), and 52 infants had parenchymal calcifications (Fig 2). Twenty-five patients had a single liver hyperechogenicity; 36 patients had multiple lesions. The distribution of cases according to whether the findings were surface or parenchymal liver calcifications and whether calcifications were single or multiple is presented in Fig 3. There was no correlation between the location or number of lesions and the association with infection, aneuploidy, or additional abnormalities. Thirty-four women elected to undergo amniocentesis. Ten patients had abnormal fetal karyotypes and one patient had an abnormal karyotype that was diagnosed postnatally; therefore, 11 of the women (18%) had abnormal fetal karyotypes (Table II). Four fetuses had trisomy 13, two fetuses had trisomy 21, one fetus had trisomy 18, and one fetus had monosomy x (45,X). Three patients each Simchen et al 1619 Volume 187, Number 6 Am J Obstet Gynecol Table I. Distribution of cases with a prenatal ultrasound diagnosis of liver calcification Total cases (n = 61) Isolated With additional ultrasound findings Abnormal chromosomes Infection CF No. (%) 21 (35) 40 (65) 11 (18) 2 (3.3) 0 had one other chromosome abnormalities that included 4p–, 22q+, or 8p+. Ten of 11 cases with abnormal karyotypes had other fetal abnormalities that were found at ultrasound scan (Fig 4). Two patients had evidence of intrauterine infection. One patient had intrauterine cytomegalovirus infection. This fetus had associated abnormalities including severe intrauterine growth restriction, oligohydramnios, cerebral ventriculomegaly, hydrops fetalis, and echogenic gut. The other patient had evidence of intrauterine parvovirus B19 infection, and multiple liver calcifications were evident with no additional findings. The liver calcifications remained unchanged on follow-up ultrasound scans, and no cerebral calcifications, hydrops fetalis, or additional findings developed over time. None of the patients screened positive for CF. Pregnancy outcome. Twenty-three of the 61 patients in our study group (38%) had an adverse pregnancy outcome, which was defined as a decision to terminate the pregnancy, intrauterine death, neonatal death, or a liveborn infant with adverse long-term outcome. Eighteen patients elected to terminate the pregnancy. In all these cases, additional ultrasound abnormalities or chromosome abnormalities were present. There was one case of intrauterine death after bowel perforation and meconium peritonitis. Ultrasound findings in this case included peripheral liver calcifications, dilated bowel loops, diffuse peritoneal calcifications, and ascites at 31 weeks’ gestation. One infant died of cardiac failure in the early neonatal period, possibly caused by myocarditis. This fetus was diagnosed with multiple liver calcifications at 33 weeks of gestation and was delivered at 34 weeks of gestation. Additional ultrasound findings were nonimmune fetal hydrops, echogenic gut, and evidence of poor cardiac contractility. No evidence of intrauterine infection was found prenatally. Postnatal follow-up of the liveborn infants ranged from several days to 7 years of age. Nine cases were lost to follow-up: four cases in the group with isolated liver calcifications and five cases in the group with additional findings. One pregnancy is ongoing. Two infants had long-term neurologic sequelae: one infant has flaccid lower limb paralysis of an unknown cause, and the other infant has seizure disorder. As previously mentioned, one infant was diagnosed postnatally with tri- Fig 4. Cs: distribution of cases according to the presence or absence of associated abnormalities. somy 21. In this case, a single parenchymal liver calcification was the only remarkable finding on prenatal ultrasound; STORCH screening was negative for intrauterine infection, and amniocentesis was declined. The prenatal ultrasound findings in five cases with an unfavorable outcome (death or long-term sequelae), excluding pregnancies in which the decision was made to terminate the pregnancy, are presented in Table III. In the subgroup of women with isolated liver calcifications, most infants showed normal growth and development on postnatal follow-up examination. One pregnancy (with parvovirus B19) is ongoing, and the mother and fetus are doing well apparently. One infant was diagnosed with trisomy 21 after delivery. Comment To the best of our knowledge, ours is the largest series of fetuses with liver calcifications that have been reported so far. All cases were followed prospectively, and most cases were followed postnatally. Possible causes for fetal ultrasound hyperechogenicities in the area of the liver include infection, ischemic insults, portal and hepatic vein thromboemboli, tumors, and sludge and lithiasis in the gallbladder. Carroll and Maxwell10 distinguished between peritoneal, parenchymal, and vascular calcifications. They stated that peritoneal calcifications that consisted of surface liver calcifications resulted from meconium peritonitis because of ruptured bowel. This association has been commented on by other investigators also.6,11,12 Some of the 1620 Simchen et al December 2002 Am J Obstet Gynecol Table II. Associated ultrasound findings in cases of liver calcification with abnormal karyotypes Case Karyotype Gestational age at diagnosis 1 2 47,XY+13 47,XX+13 21 wk 6 d 19 wk 1 d 3 47,XX+13 17 wk Single Multiple surface calcification coarse liver texture Multiple 4 47,XY+13 16 wk Multiple 5 47,XX+21 16 wk 6 d Single 6 7 47,XX+21 47,XX+18 17 wk 15 wk 2 d Single Single 8 45,X 18 wk Single 9 46,XX add(8p) 16 wk Multiple 10 47,XY add(22q) 20 wk Multiple 11 46,XY del(4p) Multiple 19 wk Liver Ultrasound findings Additional Outcome Dandy-Walker variant, dysplastic kidney Termination of pregnancy Dandy-Walker variant, large nuchal fold, Termination of pregnancy cleft lip and palate, intracardiac papillary calcification Dandy-Walker malformation, cystic Termination of pregnancy hygroma, ascites, intracardiac papillary calcification, echogenic kidneys, echogenic cystic placenta , chorioamnion separation Two-vessel cord, intracardiac papillary calcification, peritoneal calcifications Termination of pregnancy Bilateral cerebral ventriculomegaly, bilateral choroid plexus cysts, large nuchal fold, intracardiac papillary calcification Termination of pregnancy None Live born, postnatal diagnosis Atrioventricular septal defect, “ strawberry-shaped” skull, echogenic gut Termination of pregnancy Hypoplastic left ventricle, cystic Termination of pregnancy hygroma, hydrops, Two-vessel cord, intrauterine growth restriction, anhydramnios Dandy-Walker malformation, bilateral Termination of pregnancy ventriculomegaly, septated cystic hygroma, ventricular septal defect, intracardiac papillary calcification, echogenic myocardium, echogenic gut, clenched hands, talipes Large nuchal fold, micrognathia, Termination of pregnancy unilateral renal hypoplasia, low-set ears, intracardiac papillary calcification Cystic hygroma, scoliosis, abnormal Termination of pregnancy vertebrae, large nuchal fold, intrauterine growth restriction, Two-vessel cord cases, although not all, were complicated by fetal CF.6,10,13 For this reason, we included parental and, if indicated, fetal CF screening in all cases with FLCs. Parenchymal calcifications have been associated previously with intrauterine infection (mainly cytomegalovirus and varicella).3-5,14 We used maternal STORCH analysis and parvovirus B19 screening to delineate this possibility. Vascular causes are mainly the result of thrombosis and ischemia.6-8 However, fetal ultrasound scans cannot distinguish between calcified portal vein thrombi, calcified hepatic vein thrombi, and parenchymal calcifications. Our report shows no difference between parenchymal and surface liver calcifications regarding the cause and outcome. We therefore divided our group with FLCs into the isolated group (when no other abnormalities were detected) and the group in which additional abnormalities were present. Hawass et al15 found liver calcifications in 33 of 1500 spontaneously aborted fetuses. These calcifications were identified by radiography, and their location was delineated by contrast studies, anatomic dissection, and histopathologic studies. Of the 33 cases, 18 cases were calcified portal veins, 12 cases were calcified portal vein thrombi, 2 cases were parenchymal calcifications, and 1 case was a mixed case. There was a high rate (85%) of as- sociated abnormalities, and no difference was found between the type of anomalies and the existence of calcified hepatic and portal vein thrombi. On searching the literature, we found several studies that reported outcomes of fetuses with FLCs. Avni et al16 reported on six cases, of which four cases had scattered surface and two cases had parenchymal calcifications. Three of the cases were isolated and had good outcome; three cases were associated with other abnormalities. Of these, two pregnancies were terminated (trisomy 18, 1; miscarriage, 1). Bronshtein and Blazer1 described 14 fetuses with liver calcifications. Nine fetuses had isolated liver calcifications, and all of the fetuses had good outcome. Five fetuses had associated abnormalities, of which two fetuses had trisomy 18. Stein et al17 reported on 33 cases. Investigation information regarding CF and chromosome analysis was not provided. In this group, four fetuses had surface calcifications, and 29 fetuses parenchymal calcifications. No correlation was reported between the type of calcification and associated abnormalities or outcome. Of the 25 isolated cases, 24 fetuses had good outcome, and one fetus had cytomegalovirus. Eight fetuses had associated abnormalities, and two of the fetuses had good outcome. However, the abnormalities in the two fetuses were mild (hydronephrosis and border- Simchen et al 1621 Volume 187, Number 6 Am J Obstet Gynecol Table III. Associated ultrasound findings in cases with an unfavorable pregnancy outcome (excluding terminations of pregnancy) Case Gestational age at diagnosis 1 31 wk 2 33 wk 3 22 wk 4 16 wk 4 d 5 17 wk Ultrasound findings Outcome Multiple liver calcification, diffuse calcified peritoneum, ascites, dilated bowel loops, talipes Multiple liver calcification, hydrops, Doppler venous pulsations, poor cardiac contractility, echogenic gut Multiple liver calcifications, ventriculomegaly, ascites, myocardial calcification, pericardial effusion Multiple liver calcifications, intrauterine growth restriction, bilateral ventriculomegaly, microcephaly, bilateral talipes, dense leg soft tissue Single mid liver calcification, left upper quadrant calcification line nuchal folds). Achiron et al18 reported on five fetuses, three of which had parenchymal calcifications, and two had mixed parenchymal/surface calcifications. Four fetuses had isolated calcifications and a good outcome; one fetus had associated abnormalities, and the pregnancy was terminated. None of the fetuses had chromosomal abnormalities. Koopman and Wladimiroff2 reported on seven cases. Five fetuses were isolated and had a good outcome, and two fetuses had associated abnormalities. One fetus had trisomy 18, and the pregnancy was terminated; one fetus died in utero. The rate of associated abnormalities in these reports ranged between 20% and 50%, although fetuses with isolated liver calcifications always had a good outcome. Chromosomal abnormalities are a risk in any pregnancy, and over the last 20 years considerable effort has been put into trying to identify prenatally those fetuses with an increased risk for chromosome abnormalities. Several authors have found FLCs in fetuses with trisomy 181,2,16; a calcified intrahepatic foci in a fetus with trisomy 9 was reported.19 Moreover, neonates and stillborn infants with trisomy 21, 18, 14, 13, D, and monosomy x have been reported also.6,7,20 In the present series, an abnormal karyotype created complications for 18% of patients with prenatally detected liver calcifications; the most common abnormality was trisomy 13. This association has been hinted at previously in neonates,7 but to our knowledge this is the first published report of such an association prenatally. Fetuses with trisomy 13 tend to have evidence of diffuse calcium deposits; therefore, this association is biologically plausible and should be kept in mind when counseling patients with fetal liver hyperechogenicities. A special note should be made of the fetus with trisomy 21 who had no additional abnormalities on ultrasound scanning. Previous reports have stressed the association between additional abnormalities found on ultrasound scanning and chromosome abnormalities, which implies that liver calcifications found in isolation carry a negligible risk of Intrauterine fetal death Early neonatal death after delivery because of heart failure, possibly because of viral myocarditis Seizures, bilateral multiple foci of chorioretinal atrophy Microcephaly, flaccid paralysis of lower limbs, poor growth Postnatal diagnosis of trisomy 21 karyotype abnormalities. In our opinion, the possible association between liver calcifications and chromosome abnormalities should be kept in mind even in cases with isolated liver calcifications, although the risk is obviously smaller if no other abnormalities are identified. Two cases of intrauterine fetal infections occurred in association with FLCs. One of these cases had isolated liver calcifications and no additional findings, and the fetus was eventually diagnosed with an intrauterine parvovirus B19 infection. Fetal parvovirus B19 infection poses a risk of nonimmune fetal hydrops and fetal death.21,22 Additional complications may include hemolysis, anemia, hepatosplenomegaly, and meconium peritonitis.12,13,22,23 A recent report demonstrated liver involvement in a fetus with intrauterine infection with parvovirus B19.22 To our knowledge, there are no published reports that link liver calcifications and parvovirus B19 infection without additional characteristic findings. Therefore, our findings underscore the importance of ruling out intrauterine infection in patients with isolated FLCs. None of our study patients had positive test results for CF mutations. Only a few previous reports concerning CF as a cause for intra-abdominal fetal calcifications have been published,6 although other investigators have found no association.11 To the best of our knowledge, there are no reports in the literature that link CF to prenatally detected liver calcifications. Therefore, this test should be provided mainly to populations with high carrier rates of CF. The population represented in this report is a referral population to a tertiary care center. As such, various abnormalities may be over-represented when compared to the general population potential. The present series emphasizes associations that may be overlooked in smaller series. Finally, fetal hepatic calcifications are relatively common and can be isolated or associated with additional ultrasound findings. Isolated cases have a good prognosis 1622 Simchen et al once chromosome abnormalities and intrauterine infection have been ruled out. However, additional major abnormalities present a risk for chromosomal abnormalities, mainly trisomy 13. It is our recommendation that a detailed, high-quality fetal ultrasound scan be performed as the first step in the evaluation of a pregnant women with FLCs. Counseling should include an offer of amniocentesis for chromosome analysis especially, but not exclusively, in cases in which additional findings are apparent. Additional investigations should include maternal STORCH and parvovirus B19 studies. Further investigations may be indicated by the specific ultrasound findings in each case. December 2002 Am J Obstet Gynecol 10. 11. 12. 13. 14. 15. REFERENCES 1. Bronshtein M, Blazer S. Prenatal diagnosis of liver calcifications. Obstet Gynecol 1995;86:739-43. 2. Koopman E, Wladimiroff JW. Fetal intrahepatic hyperechogenic foci: prenatal ultrasound diagnosis and outcome. Prenat Diagn 1998;18:339-42. 3. Drose JA, Dennis MA, Thickman D. Infection in utero: US findings in 19 cases. 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