Fetal cholelithiasis (Fetal gallstones)

Fetal cholelithiasis or gallstones are echogenic foci noted within the lumen of the fetal gallbladder on ultrasound.¹ 

Fetal gallstones are a rare finding.  The incidence is reported to be 0.07%-1.15%.^2-9 The frequency of diagnosis has increased in the past 20 years due to improved ultrasound technology and the increasing use of third trimester ultrasound in clinical practice.^10-11

The etiology and pathogenesis of fetal cholelithiasis is unknown. Fetal gallstones do not appear to be strongly associated with other fetal anomalies. Case reports suggest that greater than 75% of cases occur as a benign isolated finding.^{1, 8, 10, 11-14}  For the remaining cases, there may be maternal or fetal factors which predispose to the formation of fetal gallstones.¹¹ The associated maternal factors which predispose to gallstones include: placental abruption, increased estrogen levels, narcotic use, prolonged fasting, diabetes of any type, enteral nutrition, pharmacologic treatment (ceftriaxone, furosemide, prostaglandin E2), intoxication with denatured oil treated with steroid, sepsis, maternal history of cholelithiasis.^{5, 10, 11} The proposed fetal factors include: Rhesus or ABO blood group incompatibility, congenital anomalies (cardiovascular, gastrointestinal, urinary), twin pregnancy with fetal demise of one twin, genetic anomalies (trisomy 21), chromosomal aberrations (translocation 10, 11), growth restriction, oligohydramnios, hepatitis and prenatal leukemoid reaction.^{5, 10, 11}

There is thought to be an increased risk of pigment stones in any maternal or fetal factor which potentially increases the indirect bilirubin crossing the placenta into fetal circulation. For example, in placental abruption, hemoglobin from a placental hematoma breaks down and increases maternal indirect bilirubin. A similar pathway may be involved in maternal or fetal hemolytic diseases, fetal-maternal blood group incompatibility or single fetal demise in a twin pregnancy.^{1, 11, 15}
A proposed pathway for the formation of cholesterol stones is that high maternal and placental estrogens may increase cholesterol secretion and suppress bile acid synthesis. Estrogen levels generally increase from 14 to 40 weeks gestation, particularly in multiple gestation pregnancies.  This may help explain the cases found in twin pregnancies, as well why fetal gallstones are a third trimester phenomenon.^{1, 8, 11, 16}

Other proposed modes of pathogenesis include maternal narcotic use potentially slowing gastrointestinal activity and increasing gallbladder emptying time, which may increase the propensity for stone formation^{4, 17} or a genetic predisposition to gallstone formation.^{1, 18 -19}
It has been debated whether or not there is a higher risk in male fetuses.  Some studies have suggested male predominance with the rationale that the increased metabolic rate and developmental differences seen in males could explain the increased lithogenicity.^{3, 5, 12, 14, 20}  However, more recent reviews of all published reported cases show no significant difference in the incidence in males versus females.^{1, 2, 8, 11, 13}

There is no pathological analysis available for gallstones found in the prenatal period.

Fetal cholelithiasis is typically diagnosed incidentally by routine third trimester ultrasound between 29 to 42 weeks gestation, with most being diagnosed at about 34-36 weeks gestation.^{1, 7, 8, 10, 12, 18} The fetal gallbladder is perpetually distended without regular contractions.  It appears as an oblong, pear-like anechoic structure beneath the right liver lobe, to the right of the intrahepatic portion of the umbilical vein⁸, and is commonly visible after 18-20 weeks of gestation. The formation of identifiable stones and/or sludge within the gallbladder appear to be a specific phenomenon of the third trimester.^{2, 10, 14, 16} The echogenic foci may appear as single or multiple foci, which may or may not have distal acoustic shadowing.  Occasionally, the gallbladder is filled with a diffuse echogenicity without recognizable discrete foci. This diffuse echogenicity isthought to be biliary sludge.^{1, 8}

Diagnosis can further be confirmed using 3-dimensional (3-D) ultrasound approach to characterize the fetal gallbladder and its contents¹⁰, however, this is neither routine nor necessary. Once other differential diagnoses are reasonably ruled out, further maternal or fetal testing is not needed, unless otherwise recommended for other indications. 

When the diagnosis of fetal gallstones is suspected, it is important to exclude the following diagnoses: intrahepatic calcification, calcified liver mass, meconium peritonitis, subphrenic sequestration of the lung, hepatoma, and haemangioendothelioma of the gallbladder.

Fetal cholelithiasis is generally asymptomatic and self-limiting. ^{1, 8, 12 -14, 17} The stones are thought to resolve due to dissolution or passage through the biliary tract (1).  As the neonate begins oral feeding, cholecystokinin plasma levels increase promoting gallbladder contraction and passage of the stones and/or sludge.⁸  Stones with distal shadowing are least likely to resolve and are more likely to be calcified or true gallstones. Foci without distal shadowing may represent cholesterol crystals, sludge, or some other substance.^{1, 21}
Asymptomatic patients should be managed expectantly.^{10, 22} Of the reported cases with post-natal follow up, over 70% resolve spontaneously within the first three months of life and almost all resolved within the first year of life.^{1, 8, 12-14, 17} Rarely, fetal gallstones can persist for years, even in children without hemolytic anemia or clinical problems associated with biliary tract disease or childhood cholelithiasis.  However, the majority of these patients have been asymptomatic.¹
Symptomatic neonates can be successfully medically managed with ursodeoxycholic acid^{7, 10, 18} and when indicated, surgical treatment at the discretion of the pediatrician.²²

The management of the pregnancy is not altered by a diagnosis of fetal gallstones.  Neonatal follow-up in the newborn and pediatric periods is indicated. Evaluation of the neonate is indicated if there is non-bilious vomiting, mild jaundice or icteric sclera as medical or surgical treatment may be necessary.^{7, 10, 18, 22}
 
 

1. Brown DL, Teele RL, Doubilet PM, DiSalvo DN, Benson CB, Van Alstyne GA. Echogenic material in the fetal gallbladder: sonographic and clinical observations. Radiology 1992; 182: 73-76.
2. Agnifili A, Verazo R, Carducci G, et al. Fetal cholethiasis: a prospective study of incidence, predisposing factors, and ultrasonographic and clinical features. Clin Pediatr (Phila) 1999; 38: 371-73. 
3. Cancho Candela R, Diaz Gonzalez J, Perandones Fernandez C, Vinuela Rueda B, Relea Sarabia A, Andres de Llano JM. Echogenic material in fetal gall bladder: prenatal diagnosis and postnatal follow-up. An Pediatr (Barc). 2004; 61:326-9.
4. Devonald KJ, Ellwood DA, Colditz PB. The variable appearances of fetal gallstones. J Ultrasound Med 1992; 11: 579-85.
5. Kiserud T, Gjelland K, Bogno H, Waardal M, Reigstad H, Rosendahl K. Echogenic material in the fetal gallbladder and fetal disease. Ultrasound Obstet Gynecol 1997; 10: 103-6.
6. Muller, R., Dohmann, S., & Kordts, U. Fetal gallbladder and gallstones. Ultraschall in der Medizin 2000; 21(3), 142-144.
7. Munjuluri N, Elgharaby N, Acolet D, Kadir RA. Fetal gallstones. Fetal Diagn Ther 2005; 20:241-243.
8. Sepulveda W, Wong AE. Echogenic material in thefetal gallbladder: prevalence, sonographic spectrum, and perinatal outcome in an unselected third-trimester population.  The Journal of Maternal-Fetal & Neonatal Medicine 2018,DOI: 10.1080/14767058.2018.1517310
9. Wendtland-Born A, Wiewrodt B, Bender SW, Weitzel D. Prevalence of gallstones in the neonatal period. Ultraschall Med 1997; 18:80-83.
10. Trifuno S, Rosati P, Ferrara P, Gatto A, Scambia G. Fetal cholethiasis: A diagnostic update and a literature review. Clinical Medicine Insights: Case Reports 2013; 6: 153-158. 
11. Hurni Y, Vigo F, von Wattenwyl BL, Ochsenbein N, Canonica C. Fetal Cholelithiasis: Antenatal Diagnosis and Neonatal Follow-up in a Case of Twin Pregnancy – A Case Report and Review of the Literature. Ultrasound Int Open 2017; 3: E8-E12.
12. Sheiner E, Abramowitcz JS, Hershkovitz R. Fetal gallstones detected by routine third trimester ultrasound. Int J Gynecol Obstet 2006; 92: 255-56.
13. Suma V, Marini A, Bucci N, Toffoluti T, Talenti E. Fetal gallstones: Sonographic and clinical observations.  Ultrasound Obstet Gynecol 1998; 12: 439041.
14. Stringer MD, Lim P, Cave M, Martinez D, Lilford RJ. Fetal Gallstones. J Pediatr Surg 1996; 31: 1589 -91
15. Fanaroff AA,  Martin RJ, Miler MJ. Identification and management of ihgh-risk problems in the neonate. In: Creasy RK, Resnik R. editors. Maternal-Fetal Medicine, Principles and Practice. 2nd ed. Philadelphia, PA: Saunders: 1989: 1176-9.
16. Beretsky I, Lankin DH. Diagnosis of fetal cholelithiasis using real-time high resolution imaging employing digital detection. J. Ultrasound Med 1983; 21: 567-569.
17. Suchet IB, Labatte MF, Dyck CS, Salgado LA. Fetal cholelithiasis: a case report and review of the literature. J Clin Ultrasound 1993; 21: 198-202.
18. Iroh Tam P, Angelides A. Perinatal detection of gallstones in siblings. Am J Perinatol 2010; 27: 771-774.
19. Holloway S, Edwards H. Antenatal diagnosis of fetal cholelithiasis. Ultrasound 2010; 18: 152-154.
20. Sheiner E, Levy A, Katz M, Hershkovitz R, Leron E, Mazor M. Gender does matter in perinatal medicine.  Fetal Diagn Ther 2004; 19: 366-9.
21. Schiermer WJ, Grisoni ER, Gauder MWL.  The spectrum of cholethiasis in the first year of life. J Pediatr Surg 1989; 24: 1064-7.
22. Gertner M, Farmer D. Laparoscopic cholecystectomy in a 16 day old infant with chronic cholelithiasis. J Pediatr Surg 2004; 39: 17-9.

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