Congenital Hepatitis C Virus and Fetal Ascites: History
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Perinatal Hepatitis C Virus (HCV) transmission occurs in 4–7% of the cases with detectable viremia at delivery. HCV testing in pregnancy is recommended. The fetal infection was previously described as asymptomatic although there are two cases, including this one, to report the presence of isolated fetal ascites in HCV infected fetuses.

  • fetal infections
  • fetal ascites
  • congenital hepatitis

1. Congenital Hepatitis C Virus

Hepatitis C virus (HCV) infection is a global health issue, affecting 2–3% of the worldwide population. The declared highest infection rate is in Northern Africa, almost 3%, and the lowest is in Northern Europe, under 1%. The CDC (Centers for Disease Control and Prevention) recommends HCV testing for all pregnant women. Unfortunately, there is no antiviral treatment approved during pregnancy yet. However, HCV screening allows for appropriate assessment of liver disease status and improves the follow-up for infants at risk of vertical transmission [1,2].
Acute HCV infection develops in the first six months after the virus exposure and is usually asymptomatic. When symptoms occur, they are not specific and involve jaundice, anorexia, nausea, and abdominal pain [3,4]. Although 15–45% of the patients usually clear the virus in the first six months, those who do not will develop chronic infection. After 20 years of infection, the patients with chronic disease have a high risk for cirrhosis and hepatocellular carcinoma [5,6].
HCV is a bloodborne infection. The main risk factors for HCV transmission are blood products transfusions, transplantation of solid organs, injecting drug use, unsafe therapeutic injections, occupational exposure to blood, and unprotected sexual intercourse with an infected partner [1,7,8,9,10]. Data on the effect of virus concentration are inconsistent, but the transmission mostly appears to consistently increase in levels of HCV-RNA above 106 IU per mL [11,12,13,14]. Vertical transmission or mother-to-child transmission of HCV may occur intrauterine, at delivery, or in the first 28 days after birth. The mechanisms of mother-to-child transmission (MTCT) are not well understood, but it is stated that HCV monoinfected pregnant women have a 2–8% risk of viral transmission to their infant [15].
As expected, mothers’ intravenous drug use has an increased vertical transmission rate compared to women who have not been involved in such practices [16,17]. In addition, associated infections play an important role in HCV transmission. HIV co-infection increases the transmission rate two-fold [11,18,19]. Other authors declare even higher rates [15,20,21]. However, recent studies are showing an additional risk of HCV transmission in the setting of maternal HIV co-infection – this risk is reduced if maternal HIV is well controlled with antiretroviral therapy (ART) [22,23,24]. Peripheral blood mononuclear cell infection with HCV is associated with a higher risk of vertical transmission, possibly as a vector for HCV [25,26].
The relation between the mode of delivery and HCV perinatal transmission is controversial. Some authors have suggested that with vaginal delivery, vertical HCV transmission increases due to an increased risk of exposure to virus-contaminated maternal blood. Therefore, cesarean section was proposed as a safer option [27]. Four large studies were carried out to evaluate the HCV transmission risk with elective cesarean versus vaginal or emergency cesarean section [13,28,29,30]. Two studies reported a higher transmission risk with vaginal delivery or emergency caesarian section than in the cases with planned caesarian delivery, which was statistically significant in only one of them [29,30]. Other studies, including the European Pediatric Hepatitis C Virus Network study, reported that delivery mode does not appear to influence transmission rate [15,28,31,32,33].
As a general concept, maternal age, mode of delivery, parity, HCV genotype, and breastfeeding (if nipples are not cracked or bleeding) do not appear to be risk factors for HCV vertical transmission [7,20,21,34].
Clinics and perinatal treatment. HCV infection transmitted vertically is usually asymptomatic in infancy and is associated with elevated ALT (alanine aminotransferase) levels in the first years of life. At the moment, there are few long-term follow-up studies on the natural history of HCV infection in children and adolescents and no long-term studies to evaluate if the vertically transmitted HCV progresses into hepatic failure or hepatocellular carcinoma [13,35,36,37,38,39]. Elevated ALT levels (in 1/3 of the children) and hepatomegaly (in 10%) were the most common changes reported [13]. Most of the studied children did not obtain a spontaneous clearance in those cases (92%), and some of them (1.8%) even progressed to decompensated cirrhosis [35].
The HCV screening strategy aims to identify and treat all persons HCV-positive before conception [10].
There are no treatment options recommended during pregnancy. IFN (interferon) alpha is considered category C class risk during pregnancy [15,40]. Ribavirin is considered category X, and treatment is forbidden during pregnancy or in couples (also for male partners) who intend to obtain a pregnancy for at least 6 months before conception [18].
A newly developed treatment, direct-acting antivirals (DAAs), has replaced IFN regimens. The advances in HCV treatment do not apply during pregnancy [15]. A small phase 1 study evaluating the pharmacokinetics of ledipasvir-sofosbuvir in pregnancy reported 100% SVR12 (sustained virological response 12 weeks after completion of treatment) and no safety concerns [41]. Recently, the FDA approved DAA regimens for children after 3 years old, for any HCV genotype [38].
Children born from HCV-positive mothers are at risk of contracting HCV intrauterine, intrapartum, or after delivery. Therefore, they should be tested for HCV infection. In addition, ¼ to ½ of infected infants obtain a spontaneous clearance of the infection in the first 4 years [36,38,42,43,44,45,46].
The diagnosis of HCV infection in children born from HCV mothers has become important due to new studies and guidelines that allow HCV treatment for children as young as three years old [38]. Anti-HCV antibodies pass the placental barrier from the mother’s blood to the fetal bloodstream and may persist in the infant’s blood until 18 months. HCV-RNA can be determined by PCR (polymerase chain reaction). This test is more expensive but allows an earlier diagnosis of HCV infection in infants. Still, this type of very early diagnosis cannot be proved useful because treatment options are available only after the age of 3 [38,47].

2. Fetal Ascites

Fetal ascites is usually diagnosed by ultrasound examination. It is always considered an abnormal finding, and the etiology must be investigated. Fetal ascites may appear isolated or associated with organic malformations, hydrops, infections, genetic syndromes, and other conditions [48,49].
Fetal hydrops is usually associated with pericardial effusion, pleural effusion, and skin edema. When these signs are missing, an isolated fetal ascites is assumed. It is essential to differentiate the two because the prognosis and management are significantly different [50]. When associated with hydrops and respiratory tract malformation, the fetal prognosis is mainly unfavorable, with a high risk of fetal or neonatal death [48].
Perinatal prognosis of fetal ascites is better when isolated. A study of 79 cases of nonimmune fetal ascites showed a 57% mortality. This study involved 25 (31.6%) isolated fetal ascites. The survival rate was reported to be higher for the fetuses with isolated fetal ascites (49.2%), compared with a 33% survival rate for the cases with hydrops fetalis [51]. Secondary to stretching, the newborn may present diastasis of rectus abdominalis muscles and redundant abdominal skin [52].
When investigating the etiology of fetal ascites, a systematic protocol must be followed [49,53]. The workup should include the mother Rhesus, infection screening, fetal karyotyping, and detailed ultrasound examination to establish if other congenital abnormalities are associated [53]. When paracentesis is performed, the evaluation of serum-ascites albumin gradient (SAAG) may be used to discriminate between transudate and exudate and differentiate the possible causes of fetal ascites. If SAAG is greater than 1.1 g/L, the ascites may be caused by portal hypertension; otherwise, it may have a non-portal hypertension etiology [54].
The assessment of fetal ascites may Ide various biological screening such as maternal isoimmune antibodies, feto-maternal hemorrhage, fetal anemia, fetal hemoglobinemia, glucose-6-phosphate deficiency, thalassemia, and infections (syphilis, toxoplasmosis, cytomegalovirus, parvovirus, and coxsackievirus). In addition, ultrasound evaluation for fetal malformations and genetic tests (chromosomal analysis and fetal karyotype) are also necessary. Other causes of fetal ascites may be chylous ascites, meconium peritonitis, and urinary peritonitis. According to a recent metanalysis involving 315 cases of isolated fetal ascites, the etiology was genitourinary (24%), gastrointestinal (20%), viral or bacterial infections (9%), cardiac (9%), genetic disorders (8%), chylous ascites (6%), metabolic storage disorders (3%), other structural disorders (4%), other causes (4%), and idiopathic (13%) [55].
Chromosomal abnormalities can be associated with fetal ascites; therefore, prenatal genetic testing is essential. Chorionic villus sampling and amniocentesis are used for the genetic assessment, but they can also help diagnose fetal infections and inherited metabolic disease [50,52].
Few cases are reporting the association between isolated fetal ascites and viral infections. Hepatitis A is not usually involved in congenital infections. We found 2 cases reporting hepatitis A virus associated with fetal ascites and meconium peritonitis. Both were surgically treated after delivery [56,57,58]. One case of HCV infection associated with isolated fetal ascites in the second trimester of pregnancy was reported. A paracentesis was performed, and a favorable outcome was reported [59]. In addition, one case of Hepatitis E virus infection associated with fetal ascites was reported. In this case, the ascites resolved spontaneously during pregnancy, and the fetus had a good outcome [58].
Hyperechoic fetal bowel is a soft ultrasound genetic marker that may be associated with fetal aneuploidies, especially Trisomy 21 [60,61], but also with small bowel obstruction, oligohydramnios [62], Hirschsprung disease, bowel atresia, intrauterine growth restriction [63], intraamniotic hemorrhage [64], cystic fibrosis [65,66], maternal infection with CMV, Toxoplasmosis, Parvovirus B19 [64], or HCV [59]. In many cases, it may resolve itself, with normal bowel function, in most newborns [60,67,68,69]. The pathogenic mechanism of hyperechogenic bowel may be explained by hypoperistalsis, decreased fluid content of the meconium [60,70], or chronic intrauterine bowel ischemia [60,71,72]. Another cause of the hyperechoic aspect of the bowel is meconium peritonitis, which is a sterile inflammatory reaction of the peritoneum caused by in utero bowel perforation with intraperitoneal extravasation of the meconium [50,73,74,75]. It is a rare cause of peritonitis, often fatal [76], that may be caused by ischemia in the mesentery, volvulus, intestinal atresia, meconium plugs, internal hernia, Hirschsprung’s disease, colon atresia, torsion of a fallopian tube, and cystic fibrosis. In addition to the echogenic aspect of the bowel, meconium peritonitis may be suspected during the ultrasound examination in the presence of polyhydramnios (100%), bowel dilatation (53%), ascites (33%), and pseudocyst (13%) [77].

This entry is adapted from the peer-reviewed paper 10.3390/pathogens11111335

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