The influence of HBV or HCV infections on the pregnancy course

Weight of neonates delivered by healthy women was higher as compared with children born by women infected with HBV or HCV (3,517 vs. 3,347 and 3,366). The Apgar score of neonates delivered by women with HBV and HCV infections was lower as compared with the children born by healthy women (9.4 vs. 9.3 vs. 9.7; p < 0.05). Premature births occurred more often in HBV and HCV-infected women than in the control group (14.6% and 24.5% vs. 6.96%; p < 0.05). Miscarriages were signifi cantly more common among the pregnant with HCV infections as compared with the pregnant who were healthy (9.4% vs. 1.8%; p < 0.05). In comparison with the healthy individuals, this group of patients experienced pruritus (10.5% vs. 4.2%; p < 0.05), oedemas (9.4% vs. 2.4%; p < 0.05), and hypertension (9.4% vs. 1.5%; p < 0.05) more often.


Introduction
The incidence of HBV (Hepatitis B Virus) infections with the pregnant in Europe ranges from 1% to 7% [1]. Pregnant women are usually aware of the HBV infections; less often they learn about the infection upon examination performed during initial stages of the pregnancy. Neonates delivered by women infected with HBV become infected in less than 1% of cases in Europe [2]. The likelihood of a neonate becoming infected in a perinatal or postnatal way does not exceed 10% thanks to widely applied active and passive prophylaxis of children delivered by HBV-infected women (a vaccine and a HBIG (Hepatitis B immunoglobulin) speci ic serum administered within 12 hours after the delivery) [3,4]. It is possible for a child to become infected via an intrauterine way. Also, a child may become infected by an HBV-infected woman who has high HBV viraemia (> 200,000 IU/ml) or high HBsAg (surface antigen of the hepatitis B virus) concentration (> 4-4.5 log10 IU/ml) [3]. The risk of such an infection regards most often the pregnant with HBV viraemia above 6 Log10 IU/mL and HBeAg (+) (Hepatitis B envelope antygen) presence. The likelihood of an infection with the virus increases proportionally to the viraemia increase [4,5]. The devised guidelines present the ways of dealing with women infected with HBV that want to become pregnant. Table 1 Guidelines regarding the ways of dealing with pregnant women infected with HBV [3,6]. Antiviral drugs used in the pregnant infected with HBV decrease the risk of infecting the foetus, however, none of the currently used NAs (nucleoside/nucleotide analogues) are listed as category A according to FDA (Food and Drug Administration), and thus, their use in pregnant women should be careful. European (EASL-European Association for the Study of the Liver) and American (AASLD-American Association for the Study of Liver Diseases) guidelines allow for administering TDF between the 24 th and 32 nd week of pregnancy in special cases. The drug is used in order to decrease the risk of infecting the foetus.
The probability of a newborn being infected by an HCVinfected mother ranges from 1.7% to 4.3%. It is the highest among the women that are infected with HCV/HIV (19.4%), and also, among individuals that take intravenous intoxicants (and who are not HIV-infected; 8.6%) [7]. The risk of infecting a neonate and a negative in luence on the clinical pregnancy course of patients infected with HCV were the basis for EASL and AASLD guidelines for antiviral treatment for all women at procreative age "in the irst place" (especially the ones who wanted to become pregnant) [8]. Limited studies on DAA ef icacy and adverse reactions among the HCV-infected pregnant women indicate a decreased likelihood of infecting a neonate among the pregnant that take such antiviral drugs. Although these drugs have not been approved to be used in the pregnant yet, about 60% of women infected with HCV and pregnant declare that they are eager to use them in order to avoid infecting the child [9].
Despite speci ied procedures that concern dealing with the pregnant infected with HBV and HCV, observations regarding the in luence of these viruses on the course of pregnancy are ambiguous.

Aim of the work
The aim of the work was to perform a clinical assessment of the pregnancy course among women infected with HBV or HCV. The following was determined: type of delivery, neonates' condition in the ifth minute after the delivery, weight at birth, and sex. All patients had their biological parameters of liver function monitored. The pregnant infected with HBV had viraemia monitored during the course of pregnancy and after the delivery. HCV-infected women had the virus genotype and initial viraemia assessed.

Material and methods
The study included 157 pregnant women infected with HBV aged from 21 to 42 (mean age: 29 y/o), and 53 pregnant women infected with HCV aged from 19 to 46 (mean age: 28 y/o). Three hundred and thirty healthy pregnant women aged from 18 to 40 (mean age: 28 y/o), who lived in the same region as the infected women, constituted a control group.
None of the women infected with HBV and HCV as well as from the control group was HIV-infected and none of them took intoxicants.
Quali ication criteria for HBV-infected women included no HBeAg and exclusion of cirrhosis. None of the pregnant infected with HBV had been quali ied to the treatment earlier nor had been treated with antiviral drugs. The following was monitored among the HBV-infected women: viraemia, ALT activity, serum ALP within the irst six weeks of pregnancy, between the 28 th and 32 nd week of pregnancy and six months after the delivery. In the group of the pregnant infected with HCV, viraemia and virus genotype were determined in the 5 th week of pregnancy, whereas ALP and ALT activity was determined in the irst 6 weeks of pregnancy, between 28 th and 32 nd week of pregnancy, and six months after the delivery.
Neonates had their clinical condition assessed in the ifth month of life by means of Apgar score.
All patients had serum HBsAg, HBeAg, anti-HBe, and anti-HCV antibodies assessed once by means of microparticle enzyme immunoassay (MEIA), and using Abbott tests (Germany).
HBV-DNA quantity was determined by RT-PCR using sets of COBAS AmpliPre/COBAS TagMan HBV Test, version 2.0 produced by ROCHE. The sensitivity amounted to 9 IU/mL, whereas linearity was 20 IU/mL.
Among women with positive anti-HCV, quantitative assessment and genotype were determined by RT-PCR method and using sets of COBAS HCV Test, version 2.0 produced by ROCHE (Germany).
The pregnant provided their informed consent to participate in the study according to the protocol accepted by the Bioethical Committee of Medical University in Bialystok (R-I-002/134/2019).
Statistical analysis of data was conducted by using STATISTICA.PL produced by StatSoft for Windows 10 operating system. The study used Mann-Whitney U test, Spearman's rho, student's t-test, and chi-squared test (χ2). The level of signi icance was set at p < 0.05. There is no indication to start the therapy for women without advanced fi brosis.
Women with advanced fi brosis or cirrhosis -TDF therapy is recommended.
The pregnant with high DNA HBV concentration (> 200,000 IU / mL) or HBsAg [> 4 log 10 IU / ml) should receive TDF in 24 th -28 th week of the pregnancy. It is recommended to discontinue the drug 12 weeks after the delivery.
Pregnant women that are treated with NA should continue the TDF therapy; in case of ETV or another NA treatment, the drug should be changed to TDF.
Breastfeeding is not contraindicated for women infected with HBV that are not and are treated with TDF. https://doi.org/10.29328/journal.cjog.1001058

Results
Mean pregnancy duration in HBV-and HCV-infected as well as among the healthy patients was similar and amounted to 38-39 weeks. The frequency of spontaneous labour was comparable and amounted to 52% for HBV patients, 42% for HCV patients, and 58% in the control group.
Weight of children delivered by healthy women was higher as compared with children delivered by HBV-or HCV-infected females (3,517 vs. 3,347 vs. 3,366). In case of HBV-infected women, the weight was signi icantly lower as compared with the healthy women ( Figure 1).
Having assessed the Apgar score at the ifth minute of life, neonates of HBV-and HCV-infected women showed lower scores as compared with children born to healthy females (9.4 vs. 9.3 vs. 9.7; p < 0.05), (Figure 2).
Premature births occurred signi icantly more often in the HBV-and HCV-infected as compared with the control group (6.96% vs. 14.6% and 24.5%; p < 0.05). In the group of HCVpatients miscarriages were signi icantly more common as compared with the healthy women (9.4% vs. 1.8%; p < 0.05). Among the HBV-patients miscarriages were more frequent than in the control group, however, it was not statistically signi icant. Table 2 Characteristics of pregnant women, pregnancy and basic data on newborns.
Among the HBV-patients, an increase in viraemia between the 6 th and 28 th -32 nd week of pregnancy was con irmed in 46% of patients, a decrease in 15% of patients, and in 39% of cases there were no changes. In 90% of women without detectable viraemia, in the 6 th week of pregnancy, its increase was not con irmed between the 28 th and 32 nd week of pregnancy. (Figure 3).
Among the HBV-patients, an increase in viraemia was observed between the 6 th and 28 th -32 nd week of pregnancy. The highest increase was con irmed among the pregnant with initial viraemia of HBV DNA ≤ 4 Log10 IU/mL in the 6 th week of pregnancy.
An in luence of HCV RNA viraemia on possible clinical symptoms in the pregnant females was not observed.
In HBV-and HCV-patients, a mean ALT and ALP activity during the pregnancy did not change and remained within normal limits.
There were no cases of infecting a neonate both with regard to HBV and HCV.

Discussion
Patients with chronic HBV infections in Europe and the US are usually characterized by the lack of HBeAg. The situation is different in Asia, and it may exert a signi icant in luence on the course of this infection among the pregnant.
HBV and HCV infections have an effect on an increased activity of proin lammatory cytokines: IL-2, IL-6, IL-10, macrophage migration inhibitory factor (MIF), and TNF-α. In pregnant women they may cause an increase in the percentage of miscarriages, premature births, and a worse clinical condition of delivered neonates that is determined by the Apgar score [10]. Cui, et al. compared 513 pregnant women that suffered from chronic HBV infections with 20,491 pregnant women without this infection, and showed a statistically more frequent occurrence of miscarriages in HBV-patients that were pregnant [5]. In the authors' studies, premature births were observed more often in HBV-and HCV-patients. However, the frequency of miscarriages was statistically higher among HCV-patients as compared with the healthy individuals. Although miscarriages were often observed in HBV-patients, there was no statistically signi icant difference as compared with the healthy females.
During pregnancy, high concentration of adrenal corticosteroids may in luence the increase in HBV viraemia [11,12]. In most pregnant women with HBV infections and absent HBeAg, viraemia is stable. However, in some patients an increase in HBV-DNA and ALT activity is observed during the late pregnancy and in the postnatal period [13]. In the authors' studies, an increase in viraemia was observed at the turn of the 2 nd and 3 rd trimester, and then, a decrease was observed during the 6 th month after the delivery. A signi icant increase with 2 Log10 was observed among the patients with HBV-DNA ≤ 4 Log10 IU/mL in the 6 th week of pregnancy. In other pregnant females, a worrying increase in viraemia was not con irmed. Occasionally, during the perinatal period a signi icant HBV reactivation, and a serious liver damage with encephalopathy and hepatic coma may occur [14]. Among such patients, an occurrence of disseminated intravascular coagulation (DIC), hepatorenal syndrome, brain oedema, and bile duct infections were observed. Interestingly, prophylactic administration of NA from the 2 nd /3 rd pregnancy trimester does not decrease the risk of liver failure, although it prevents a child from becoming infected [15]. Miscarriages were observed in 6 pregnant women infected with HBV. However, in none of them an HBV-DNA viraemia was con irmed to exceed 3 Log10 IU/mL. Appgar scoring in 5 minutes 9,7 9,4 9,3 1, 2 -statistically signifi cant diff erence