Q J Med 2000; 93: 597-601
© 2000 Association of Physicians
Pregnancy and pregnancy outcome in hepatitis C type 1b
From the Departments of Medicine, Pathology, and Statistics, Cork University Hospital, and University College Cork, Cork, Ireland
Received 8 May 2000 and in revised form 4 July 2000
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A large cohort of rhesus-negative women in Ireland were inadvertently infected with hepatitis C virus following exposure to contaminated anti-D immunoglobulin in 1977–8. This major iatrogenic episode was discovered in 1994. We studied 36 women who had been infected after their first pregnancy, and compared them to an age- and parity-matched control group of rhesus-positive women. The presence of hepatitis C antibody was confirmed in all 36 by enzyme-linked immunosorbent assay and by recombinant immunoblot assay, while 26 (72%) of the cohort were HCV-RNA-positive (type 1b) on PCR testing. In the 20 years post-infection, all members of the study group had at least one pregnancy, and mean parity was 3.5. They had a total of 100 pregnancies and 85 of these went to term. There were four premature births, one being a twin pregnancy, and 11 spontaneous miscarriages. One miscarriage occurred in the pregnancy following HCV infection. There were two neonatal deaths due to severe congenital abnormalities in the PCR-positive women. Of the children born to HCV-RNA positive mothers, only one (2.3%) tested positive for the virus. Significant portal fibrosis on liver biopsy was confined to HCV-RNA-positive mothers apart from one single exception in the antibody-positive HCV-RNA-negative group. Comparison with the control group showed no increase in spontaneous miscarriage rate, and no significant difference in obstetric complications; birth weights were similar for the two groups.
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Introduction |
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At least 704 rhesus-negative Irish women were exposed to hepatitis C virus (HCV) type 1b following receipt of contaminated anti-D immunoglobulin in 1977–8 from a single source.1,2 Subsequent to the discovery of this iatrogenic exposure in 1994, concern was expressed that subsequent pregnancies might have been adversely affected. This retrospective study investigated such concerns. First cloned in 1989, the HCV genome is a positive single-stranded RNA molecule, and exhibits certain genetic features of the flaviviridae family. Individual isolates consist of closely related yet heterogenous populations of viral genomes. As a consequence of this genetic diversity, HCV has the ability to escape the hosts' immune surveillance, thus leading to a high rate of chronic infection. Common modes of HCV transmission include blood transfusion and intravenous drug abuse.3 Transmission of HCV from mother to foetus is well documented, appears to be closely related to maternal viral levels at the time of delivery4 and seems to be related to the maternal HCV genotype.5 Vertical transmission of HCV is more common where the mother is co-infected with HIV, probably as a result of increased immunosuppression, leading to high-titre HCV viraemia.6 While acute illness is usually mild, a high proportion of those infected will progress to chronic liver disease.7 Acute maternal infections which lead to general illness with high temperature can stimulate uterine activity, and cause loss of pregnancy. A large number of bacterial and viral agents have been implicated as possible causes of spontaneous miscarriage.8 In hepatitis B virus (HBV) infection, intrapartum transmission may occur if the mother either has acute hepatitis in late pregnancy or is a chronic carrier of HBVe antigen.9,10 Non-A, non-B hepatitis has been associated with fulminant hepatic failure in pregnant women.11
There is an increased incidence of hepatitis E virus (HEV) transmitted via the faecal-oral route in pregnant women. Khuroo reported an incidence of HEV of 17.3% in pregnant women compared to 2.1% in non-pregnant women. The incidence of fulminant hepatic failure in pregnant women was higher than non-pregnant women. Nonfulminant hepatitis in pregnant women did not increase their risk of loss of pregnancy.12 HEV is commonly transmitted from infected mothers to their babies, with significantly increased perinatal morbidity and mortality rates.13 However, hepatitis A virus (HAV) infection caused no increase in morbidity or mortality in more than 5000 pregnant women in a food-borne outbreak in Shanghai.14
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Methods |
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We retrospectively studied the birth histories of 36 rhesus-negative women who were infected with HCV after their first pregnancy by contaminated anti-D immunoglobulin.
The control group comprised 36 age- and parity-matched rhesus-positive women, primipara in 1977. No control had significant acute or chronic illness at that time. HBV, syphilis, and diabetes were specifically excluded by laboratory investigations. Diagnosis was based on detection of HCV antibodies by third-generation enzyme-linked immunosorbent Assay (ELISA3, Abbott Laboratories) with confirmation by third-generation recombinant immunoblot assay (RIBA3, Ortho Diagnostic Systems, Chiron). For this assay, recombinant HCV-encoded antigens (C33-NS5) and synthetic HCV-encoded peptides (C22 and C100) were tested and interpreted as either positive (two or more positive antigens), intermediate (one positive antigen), or negative.
Reverse-transcription polymerase chain reaction (RT-PCR) was used to detect HCV RNA virus (Amplicor Tm Roche Monitor). HCV genotype was performed by restriction-fragment-length polymorphism analysis of sequence in the 5' non-coding region.15
Standard liver function tests were performed in all cases. These included serum alanine amino transferase (ALT), aspartate amino transferase (AST), and alkaline phosphatase (ALP) by auto-analyser. Urea, creatinine, serum calcium, and magnesium levels were measured. Full blood count, serum B12, folate, and ferritin were also measured, as was a coagulation screen.
All patients were screened for smooth muscle (SMA), antinuclear (ANA) and anti-mitochondrial (AMA) antibodies. Alpha-1 antitrypsin, alpha fetoprotein, and ceruloplasmin were determined.
Ultrasound examination of the liver and spleen was carried out by Real-time Ultramark 9 ultrasound system.
Histological features of liver biopsies were assessed and scored using the grading and staging system of Ishaks’ modification of the Knodell histopathology index.16 Grading assessed the severity of necro-inflammatory disease activity, based on a cumulative 18-point scale, consisting of a score of 0–6 for confluent necrosis, 0–4 piecemeal necrosis, 0–4 periportal inflammation, and 0–4 lobular inflammation. Stage of fibrosis was assessed using slides stained with Massons’ trichrome (0=no fibrosis, 1=periportal or portal fibrosis, 2=portal–portal bridging, 3=portal–central bridging, 4=probable or definite cirrhosis). Statistical analysis involved the use of standard descriptive and inferential techniques. The statistical software package used was SPSS for Windows.
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Results |
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All 36 study patients were confirmed to be antibody-positive for HCV using ELISA3 and RIBA3, while 26 women (72%) were PCR-positive for HCV genotype 1b. The mean age was 29 years (SD 5.7; range 17–41 years) at the time of infection in 1997/8 (Table 1
).
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Based on the initial examination in 1994, full blood count including haemoglobin, platelet count, white cell count, serum ferritin, B12 and folate level were in the normal range.
Abnormal liver tests were present in 20 (55%) of the study group. In 17 patients, serum ALT concentrations were elevated, at 0.63–2.87 ukat/l (normal 0.12–0.06 ukat/l) while AST levels were increased in three patients at 0.73–2.21 ukat/l (normal 0.0–0.70 ukat/l). Thus both AST and ALT were raised in four patients.
Histological grading and staging of liver biopsy showed six (17%) patients with minimal inflammation (score of 1–2), 12 (33%) patients had chronic mild hepatitis (score of 3–5 with predominantly lymphocyte infiltration), and three (8%) patients had moderate to severe inflammation (score of 7–9) as shown in Figure 1. Mild fibrosis was found in eight (22%) patients, portal to portal fibrosis in five (14%) cases, and portal to central in two (5.6%) instances, including one patient with evidence of early cirrhosis (only one of these patients, with mild fibrosis, was in the HCV-RNA-negative, antibody-positive group).
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The obstetric history of the study group post HCV-infection was compared with that of the control group in terms of the number of pregnancies, miscarriage rate, and mode of delivery in Table 2
. In the case of the study group, one of the premature deliveries involved a twin birth at 32 weeks.
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The average birthweight was similar for both groups, being 3469 g (SD 605) for the study group and 3406 g (SD 496) for the control cohort. This finding remained when the data were corrected for variation in gestational age.
During the period 1994–1996, all mothers in the study group were offered an HCV testing service for children born post-infection. There were 69 such children of HCV-RNA-positive mothers, and 21 children of antibody-positive but HCV-RNA-negative mothers (all had survived, with exception of one road traffic accident victim). Forty-four of 69 offspring in the former group presented for testing, and one (2.3%) was found to be HCV-RNA-positive. None of 17 offspring from the latter group who presented for testing were virus-positive.
There were two neonatal deaths in the infected group. Both of these pregnancies went to term. The first baby died after a few hours. This infant was born by emergency caesarean section because of fetal distress, breech presentation, and non-progression of labour. Post-mortem report showed achondroplasia, pulmonary hypoplasia, situs inversus of both thoracic and abdominal organs, abnormalities of fingers and toes, and protrusion of the frontal bones containing the frontal lobes of the brain.
The second neonate, who died after 15 days due to cardiac failure, had a patent ductus arteriosus with coarctation of the aorta. The baby was delivered vaginally, and had an APGAR score of nine.
Two further abnormalities in the infected group involved Down's syndrome (maternal age 40 years) and cleft palate. In the control group, there were five minor congenital abnormalities, including two instances of undescended testis, two talipes-equinovarus, and a sacral dimple.
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Discussion |
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The introduction of anti-D immunoglobulin has proved extremely effective in the management of rhesus haemolytic disease, with deaths attributed to rhesus immunization falling dramatically from 46 per 100 000 births before 1969 to 1.6 per 100 000 in 1990.17 While intravenous immunoglobulin was thought to be a relatively safe product,18 there have been two reported epidemics of hepatitis C as a result of its use. Two distinct cohorts of Irish women became infected following exposure to contaminated anti-D immunoglobulin in 1977/8 and 1991/3, respectively.1 Intravenous anti-D immunoglobulin was implicated in the large scale transmission of hepatitis C in the former East Germany in 1978.19
Production of anti-D immunoglobulin in Ireland was commenced by the Blood Transfusion Service Board (BTSB) in 1970. Freeze-dried intravenous anti-D immunoglobulin was prepared from plasma containing a high concentration of anti-D antibody procured in Ireland by the Hoppe method.20 The Hoppe method was refined in 1972, with the main objective of increasing the volume of anti-D produced. The 1972 method replaced the process of ethanol precipitation with an ultrafiltration step, and also involved a quarantine period of 6 months before using plasma for the preparation of anti-D. Hoppe believed that by pooling and fractionating only those plasmas which had been stored at least 6 months at -40°C provided a further safeguard against transmitting hepatitis. He believed that storing the plasma until the donor had been examined and repeatedly tested would provide further protection. However, modification of the Hoppe method21 in 1972 was not implemented by the Irish BTSB.
We have studied women who were primipara and received contaminated anti-D immunoglobulin post delivery in 1977/8. This represents a unique group of patients for whom the source and time of infection are clearly defined. While mindful of the relatively small size of the study group, we have found no evidence of either an increased risk of miscarriage or an adverse effect on subsequent pregnancies. Indeed in the general population, the incidence of spontaneous miscarriage has been estimated at 15–20% of all pregnancies,22 as compared with just 12.4% in the study group. Our study indicates that obstetric intervention and mode of delivery (including normal vaginal delivery, forceps/vacuum delivery and caesarean section) is not significantly influenced by the presence of HCV infection. Our study also shows that HCV infection does not increase the risk of obstetric complications and obstetric interventions.
The favourable outcome of pregnancy and the low transmission rate of HCV may be explained partially by the endogenous production of interferon (IFN). Evidence of this production is indicated by findings from a number of studies. For example, the human placenta has been demonstrated to be a site of IFN manufacture.23 Interferon activity has also been detected in human amniotic fluid,24,25 in placental blood26 and in perfused placenta.27 Immunohistochemical studies have demonstrated IFNs in feto-placental units.28
Vertical transmission of HCV occurred in one pregnancy in the study group. While we noted two major congenital abnormalities in the affected group, the number of cases is too small to test any hypothesis as to the possible role of HCV infection.
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Notes |
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Address correspondence to Dr M.J. Whelton, Department of Medicine, Cork University Hospital, Wilton, Cork, Ireland
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