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Crana Hagmm^a go pegaKmi' 03.08.2021
♦
UDC 616.36-002.2-02-07:618.3-06-036.3-053.2(55) https://doi.Org/10.26641/2307-0404.2022.1.254377
M.N. Moghadam, hepatitis b vertical transfer
& Amirian, and its risk factors
M. Afshari, in pregnant women
F Parooie
K.R. Keikhaie, ^ In the eastern part of iran
I. Shahramian ,
A. Bazi,
P. Ostadrahimi,
M. Sheikh,
H. Mirzaie,
A. Aminisefat
Zabol University of Medical Sciences
Pediatric Gastroenterology and Hepatology Research Center Zabol, Iran
Забольский унгверситет медичних наук
Дослгдницький центр дитячо'1 гастроентерологИ та гепатологИ Забол, 1ран
е-mail: irajshahramian@gmail.com
Цитування: Медичш перспективы. 2022. Т. 27, № 1. С. 123-131 Cited: Medicniperspektivi. 2022;27(1):123-131
Key words: Hepatitis B infection, HBV, Vertical transmission Ключовi слова: ¡нфекцгя гепатиту B, HBV, вертикальна передача Ключевые слова: инфекция гепатита В, HBV, вертикальная передача
22/ Том XXVII/1
123
Abstract. Hepatitis B vertical transfer and its risk factors in pregnant women in the eastern part of Iran. Moghadam M.N., Amirian S., Afshari M., Parooie F., Keikhaie K.R., Shahramian I., Bazi A., Ostadrahimi P., Sheikh M., Mirzaie H., Aminisefat A. One of the main causes of chronic hepatitis is mother to child transfer which is also known as vertical transfer (VT). Although there are several studies regarding the VT mechanism and its risk factors, none of these studies succeeded in explaining this process, completely. We conducted this study aiming at investigating VT mechanism and risk factors in this region. The present study was a descriptive-analytic cross-sectional study on HBS Ag positive pregnant women, which was conducted from March 2018 to March 2020 in Amir-Al-Momenin Hospital in Zabol, Sistan-and-Baluchestan province, Iran. In this study all samples were tested for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, and HBV-DNA) and anti-HCV by enzyme-linked immunosorbent assay (ELISA). All statistical analyzes were performed using SPSS version 22 software. Totally 43 infants of HBS antigen positive mothers were investigated. HBe antibody and HBe antigen were found in 25 (62.5%) and 2 (5%) of mothers, respectively. There was no significant difference between the newborns with and without hepatitis B infection regarding maternal age (p=0.216), duration of the infection in mother (p=0.892), AST (0.779), AL (0.449) and ALP (0.065). Mothers with positive viral load during pregnancy delivered newborns with positive HBS antigen much more than mothers with negative HBS antigen. However, this difference was not statistically significant (p=0.642). Although positive viral load was more common in neonates delivered from positive viral load mothers, the observed difference was also remained non-significant (p=0.978). Our study provided evidences regarding that demographic, immunologic and clinical characteristics of mothers with hepatitis B infection did not play considerable role in the vertical transmission of the infection to the newborns as well as the severity of the following infection. We also suggested the possibility ofplacenta acting as a source of infection in VT. Further longitudinal studies with larger sample sizes are needed to show the exact predictors of transmission of the infection from infected mothers to their children.
Реферат. Вертикальна передача гепатиту В та його фактори ризику у вагггиих жшок у схщнш частиш 1рану. Могадам М.Н., Амiрiан С., Афшарi М., Паруi Ф., Кейхаi Х.Р., Шахрампаи I., Базi А., Остадрахiмi П., Шейх М., МiрзаT Х., Амшкефат А. Одтею з основних причин хротчного гепатиту е передача його eid Mamepi до дитини, яка також вiдомa як вертикальна передача (ВП). Хоча е кшька до^джень, що стосуються механ1зму ВП та ii фaкmоpiв ризику, жодному з цих до^джень не вдалося повнктю пояснити цей процес. Це до^дження проведено з метою вивчення механизму ВП та фaкmоpiв ризику у вaгimних жток у схiднiй чaсmинi 1рану. Це до^дження було описово-аналтичним мiжсeкmоpaльним до^дженням вaгimних жток з позитивним результатом HBS Ag, яке проводилося з березня 2018 року до березеня 2020 року в лiкapнi Ам-р-Аль-Момент у Зaболi, пpовiнцiя Останч-Белуджистан, 1ран. У цьому до^джент вс зразки були пepeвipeнi на нaявнiсmь мapкepiв вipусу гепатиту В (HBV) (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, i HBV-DNA) та anti-HCV за допомогою iмунофepмeнmного анализу (1ФА). Ус статистичш аналгзи проводили за допомогою программного забезпечення SPSS версп 22. Усього було до^джено 43 немовляти мamepiв з позитивним антигеном HBS. Антитшо до HBe та антиген HBe виявлено у 25 (62,5%) та 2 (5%) мamepiв вiдповiдно. Не було досmовipноi piзницi мiж новонародженими з тфекщею гепатиту В та без нього вiдносно вк мamepi (p=0,216), mpивaлосmi тфекцп в мamepi (p=0,892), AST (0,779), AL (0,449) та ALP (0,065). Mamepi з позитивним вipусним навантаженням пiд час вaгimносmi народжували новонароджених з позитивним антигеном HBS набагато частше, нiж мamepi з негативним антигеном HBS. Однак ця pi-зниця не була статистично значущою (р=0,642). Хоча позитивне вipуснe навантаження було бтьш поширеним у новонароджених, народжених вiд мamepiв з позитивним вipусним навантаженням, спостережувана pi-зниця також залишалася незначущою (p=0,978). Наше до^дження надало докази того, що дeмогpaфiчнi, iмунологiчнi та кл-шчш характеристики мamepiв з тфекщею гепатиту В не вiдiгpaвaли значно'1' ролi у вертикальнт пepeдaчi тфекцп новонародженим, а також mяжкосmi подальшо'1' тфекцп. Ми також припустили можлж-^ь того, що плацента виступае джерелом тфекцп при ВП. Поmpiбнe подальше лонгтудинальне до^дження з бшьшими pозмipaми вибipки, щоб показати mочнi предиктори пepeдaчi тфекцп вiд тфжованих мamepiв iхтм дimям.
Hepatitis B virus (HBV) is a serious global health issue, especially among Asian countries. Around 257 million people are infected by HBV, worldwide [1]. HBV infection can present as an acute, chronic or even fulminant hepatitis. Hepatocellular carcinoma and liver cirrhosis can occur as long-term outcomes of HBV infection, as well [2]. One of the main causes of chronic hepatitis is mother to child transfer which is also known as vertical transfer (VT) [3]. Despite providing early vaccination as well as HBV immunoglobulin in order to prevent
neonates from developing chronic infection, immu-noprophylaxis fail to inhibit HBV infection in up to 1-10% of infants [4, 5, 6, 7, 8]. Currently, there is no definite explanation for this failure, meanwhile it is assumed that it can be attributable to the high maternal viral load leading to intra-uterine infection ,or just the absence of adequate response in neonates who receive the vaccine [7, 9].The neonates infected through VT have a 90% risk of developing chronic infection which is mostly due to the immune response of the children compared with adults [10].
Intrauterine transmission (IUT) of HBV is the main route of VT (13-44%), which is defined as all sorts of transmission happening prior to the onset of labor. Some of the suggested mechanisms for IUT are placental infection, transplacental leakage, germline transmission, and transmission by peripheral blood mononuclear cells. Other means of VT include intrapartum and breastfeeding transmission [11, 12]. There are several studies investigating the risk factors of VT. It has been reported that factors like vaginal delivery [13], prolonged labor [14], and amniocentesis [15] can play a major role in VT. On the other hand, HBV viral factors such as HBV preS/S gene mutations and Serum HBV-DNA level have been indicated as reliable markers for predicting VT [16, 17, 18, 19]. Although there are several studies regarding the VT mechanism and its risk factors, none of these studies succeeded in explaining this process completely. On the other hand, as genetic factors are among the important factors affecting VT of HBV, and there was no such study evaluating VT and its risk factors in eastern Iran. We conducted this study aiming at investigating VT mechanism and risk factors in this region.
MATERIALS AND METHODS OF RESEARCH
The present study was a descriptive-analytic cross-sectional study on HBS Ag positive pregnant women, which was conducted from March 2018 to March 2020 in Amir-Al-Momenin Hospital in Zabol, Sistan-and-Baluchestan province, Iran. In this study, all pregnant women with HBV referred to the hospital for delivery during the above period were included in the study. Among them, pregnant mothers with various underlying diseases, hepatitis C, immunodeficiency, and/or family history of hereditary immunodeficiency diseases and patients with a variety of fetal abnormalities or fetal death were excluded. Finally, 43 infants born to HBS antigen positive mothers were evaluated. General characteristics, including maternal age, gravidity, and parity, as well as the date of delivery were
documented. This project was approved by the ethics committee of Zabol University of Medical Sciences, and informed consent was obtained from patients prior to their enrollment.
Laboratory Investigation
After obtaining the patients' informed consent, a 5-cc blood sample was taken from each of them. All samples were tested for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, and HBV-DNA) and anti-HCV by enzyme-linked immunosorbent assay (ELISA).
The commercial enzyme immunoassay kits used were as follows: HBsAg and anti-HBs (Hepano-sticka Biomerieux, Boxtel, The Netherlands), anti-HBc (Dia.Pro Diagnostic BioProbes, Milan, Italy), anti-HCV (Biorad, Segrate, Italy). Liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase (ALP)] were also determined in all of the patients. To investigate latent hepatitis infection, HBV-DNA was extracted from all samples using the DNA extraction kit, High Pure Viral Nucleic Acid kit (Roche Diagnostics GmbH, Mannheim, Germany). Then HBV-DNA was determined quantitatively by real-time PCR using the artus HBV RG PCR kit (QIAGEN, Hamburg, Germany) on the Rotor-Gene 3000 realtime thermal cycler (Corbett Research, Sydney, Australia). The analytical detection limit of this kit was 20 IU/ml.
DNA Amplification
For all samples, Nested PCR was performed with surface antigen primers including external (S1, S2) and Internal (S6, S7) by Taq DNA Polymerase kit. The sequence and size of the primers are given in the figure below (Figure). The second-round PCR products were transferred to 1% gel electrophoresis. Their positive sequence samples were determined, and their nucleotide sequence was determined bilaterally by ABI sequencer 3130Xi, and the mutations in this fragment were identified.
Primer Gene Seq 5' to 3' Base
S1 Surface 5-CCTGCTGGTGGCTCCAGTTC-3' 20
S2 Surface 5 -CCACAATTCKTTGACATACTTTCCA-3' 25
S6 Surface 5-GCACACGGAATTCCGAGGACTGGGGACCCTG-3' 31
S7 Surface 5'-GACACCAAGCTTGGTTAGGGTTTAAATGTATACC-3' 34
Sequence and size of hepatitis B surface gene primers
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Statistical analysis
The correlation between categorical variables was estimated using the Spearmen correlation coefficient. All statistical analyzes were performed using SPSS version 22 software. Age, Liver enzyme, and other laboratory and demographic information were expressed as mean ± standard deviation. The Chi-square test and Fisher's exact test were used to compare categorical data. The significance level was set at p<0.05. The prognostic value was expressed as odds ratios (OR) and corresponding 95% confidence interval (CI).
RESULTS AND DISCUSSION
Totally 43 infants of HBS antigen positive mothers were investigated 25 (58.1%) of whom were boys and mean (SD) age of them was 3.6 (2) months. The youngest and oldest infants were one and 10 months old, respectively. Mothers were in average 30.2±6.3 years old ranging from 14 to 44 years.
Of the studied mothers, 21 (71%) experienced normal vaginal delivery. Most of them were Iranian (74.4%) and the others were Afghan residents. Only 3 (9.7%) mothers reported a history of anti-viral treatment. Exclusive breast feeding was reported by 19 (44.4%) of mothers while 3 (9.7%) were feeding their neonates just by formula milk.
HBe antibody and HBe antigen were found in 25 (62.5%) and 2 (5%) of mothers, respectively. The prevalence of HBs antigen positive children was 16 (37.2%), while 27 (62.8%) of them were HBS negative. HBe antibody and HBe antigen were positive in 28 (70%) and 1 (2.5) of the infants respectively.
Positive and negative HBs antigen newborns did not have any significant difference regarding gender (p=0.405), type of delivery (p=0.086), mother's nationality (p=0.130), history of antiviral therapy (p=0.452) and feeding type (p=0.338) (Table 1).
Table 1
Demographic and clinical characteristics of newborns with and without positive HBs antigen
Characteristics Infant's HBS Antigen
negative 1 positive
gender female number 10 8
% 37.40 50
male number 17 8
% 62.96 50
Type of delivery NVD number 18 9
% 81.82 56.25
Cesarean number 4 7
% 18.18 43.75
nationality Iranian number 18 14
% 66.67 87.5
Afghan number 9 2
% 33.33 12.5
History of Drug use no drug number 18 9
% 94.74 81.82
drug history number 1 2
% 5.26 18.18
Type of breast feeding breast milk number 14 5
% 70 45.45
replacement feeding number 2 1
% 100 9.09
mixed feeding number 4 5
% 20 45.45
P value
0.405
0.086
0.130
0.452
0.338
As demonstrated in table 2, frequencies of positive maternal HBe antibody among newborns with and without HBS antigen were 11 (68.7%) and 14 (58.33%) respectively (p=0.505). Corresponding figures for HBe antigen were zero and 2 (8.33%) respectively (p=0.508). There was no
significant difference between the newborns with and without hepatitis B infection regarding maternal age (p=0.216), duration of the infection in mother (p=0.892), AST (0.779), AL (0.449) and ALP (0.065) (Table 3).
Table 2
Maternal immunological factors of the HBs antigen positive and negative infants
Maternal factors
Infant's HBS antigen
negative positive
number 10 5
% 41.67 31.25
number 14 11
% 58.33 68.75
number 22 16
% 91.67 100
number 2 0
% 8.33 0
P value
Hbe Antibody
Hbe Antigen
negative
positive
negative
positive
0.505
0.508
Comparing demographic and biochemical factors between children with and without hepatitis B infection showed that just mean ALP was significantly higher among HBS antigen positive newborns (p=0.017). Other factors were not differed between the two groups (Table 4). As demonstrated
in table 5, crude and adjusted odds ratios for maternal positive HBe antigen were 0.60 (p=0.708) and 0.55 (p=0.662), respectively. The corresponding figures for positive HBe antibody in mothers were 1.57 (p=0.506) and 1.34 (p=0.702), respectively.
Table 3
Maternal characteristics of HBS antigen positive and HBS antigen negative children
Maternal factors Infant's HBsAg Number Mean Std. Deviation P value
Maternal age negative 18 30.65 6.47 0.532
positive 16 29.38 6.22
Duration of the infection negative 15 8.75 7.46 0.619
positive 13 11.77 11.32
AST negative 16 14.85 7.74 0.897
positive 13 14.15 4.77
ALT negative 16 3.85 2.30 0.685
positive 13 4.38 2.53
ALP negative 16 198 92 0.067
positive 13 144.92 52.06
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Table 4
Demographic and biochemical characteristics of the newborns with and without hepatitis B infection
Infant factors Infant's HBsAg Number Mean Std. Deviation P value
age negative 7 3.89 2.52 0.724
positive 6 3.17 .41
AST negative 13 31.75 14.94 0.659
positive 12 42.92 41.43
ALT negative 13 5.56 3.93 0.444
positive 12 6.75 4.09
ALP negative 13 180 88.5 0.017
positive 11 238.73 143.97
Viral load
Positive viral load was observed in 7 (16.28%) of neonates which was vanished after three months in all infants. Although the frequency of positive viral load at birth in neonates of positive HBe antibody mothers was higher than that among those with
negative HBe antibody mothers, this difference was not significant (p=0.819). Conversely, frequency of positive viral load at birth for neonates of positive HBe antigen was lower than that among those with negative antigen mothers, this difference was also non-significant (p=0.542) (Table 6).
Table 5
Crude and adjusted associations between maternal HBe antigen/antibody and hepatitis B infection vertical transmission
Maternal factors crude odds ratio (p value) 95% CI Adjusted* odds ratio (p value) 95% CI
Hbe antigen 0.60 (0.708) 0-8 0.55 (0.662) 0-7.55
Hbe antibody 1.57 (0.506) 0.41- 5.96 1.34 (0.702) 0.30-5.92
Note: Controlling for the effect of maternal nationality and type of delivery
Mothers with positive viral load during pregnancy delivered newborns with positive HBS antigen much more often than mothers with negative HBS antigen. However, this difference was not statistically significant (p=0.642). Although positive viral load was more common in neonates delivered
from positive viral load mothers, the observed difference also remained non-significant (p=0.978). Crude and adjusted odds ratios for having positive HBS antigen or positive viral load at birth were also non-significant (Table 7).
Table 6
Neonatal viral load based on the immunological characteristics of mother
Maternal HBe antibody p value Maternal HBe antigen p value
negative positive negative positive
Viral load negative no 13 21 0.819 32 2 0.542
at birth
% 86.67 84 84.21 100
positive no 2 4 6 0
% 13.33 16 15.79 0
Total no 15 25 38 2
% 100 100 100 100
Table 7
Maternal viral load and its association with hepatitis B infection at birth
maternal viral load P value Crude OR (p value) 95% CI Adjusted* OR (p value) 95% CI
Negative no (%) Positive no (%)
Neonatal Negative 17(56.67) 2(40) 0.642 1 1
HBS (n=19)
antigen
Positive 13(43.33) 3(60) 1.85(0.489) 0.32-10.48 1.70 (0.577) 0.26- 11.10
(n=16)
Neonatal Negative 31(83.78) 5(83.33) 0.978 1 1
Viral load (n=36)
Positive 6(16.22) 1(16.67) 1.03(0.978) 0.10- 10.49 0.89 (0.922) 0.08- 9.32
(n=7)
Notes: OR - Odds ratio, CI - confidence interval, Controlling for the effect of maternal nationality and type of delivery.
Mean liver enzymes of the HBS antigen positive newborns were the same among those delivered from mothers with negative and positive viral load. That was the case for neonates of mothers with positive and negative HBe antibody, as well (Table 8).
Finally, we did not find any evidence of mutation in the S gene of the HBV which causes considerable changes in the a determinant area of HBS antigen.
We found that hepatitis B infection was vertically transferred from carrier mothers with positive HBe antigen the same as those with negative HBe antigen. Although having HBe antigen, increased the risk of developing hepatitis B infection in the newborn (18%), this association was not statistically significant.
Table 8
Severity of the newborn infection (HBS antigen positive neonates) based on the maternal factors
Maternal factors Newborn liver enzymes
AST ALT ALP
Mean (SD) Mean (SD) Mean (SD)
Viral load negative 47(44.54) 6.80 (4.47) 249 (158)
Positive 22.50(4.95) 6.50 (2.12) 194 (46.67)
P value 0.451 0.930 0.722
HBe antibody negative 48.80 (65.26) 7.60 (5.59) 203 (29)
Positive 38.71 (16) 6.14 (2.97) 259 (181)
P value 0.290 0.568 0.635
On the other hand, mothers with positive HBe antibody had transferred hepatitis B infection to their newborns the same as those with negative HBe antibody indicating that although positive maternal HBe antibody caused approximately 60% increased risk of hepatitis B vertical transmission, the observed association was also not significant in our study. Meanwhile, Boucheron et al. in their recent systematic review and meta-analysis indicated that a positive HBe Ag test can predict vertical transmission in spite of infant immunoprophylaxis with a
sensitivity of 99.5% and a specificity of 62.2%.That was not consistent with our findings which showed that vertical HBV transmission was similar in mothers with and without HBe antigen .However, they mentioned that they could not evaluate the effects of different HBV genotypes on the performance of HBe antigen [20]. Dwivedi et al reported that mother to child transmission of hepatitis B infection is directly associated with the hepatitis B virus replicative status of mother. They found that 76.4% of positive HBe antigen mothers compared
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with 23.6% of HBe negative mothers transmitted hepatitis B infection to their neonates. That was not in keeping with our findings which showed that vertical HBV transmission was similar in mothers with and without HBe antigen [21]. Therefore, in contrast to the recent evidences reporting high frequency of maternal HBe antigen as the main cause of HBV vertical transmission in the endemic regions [22], it seems that in the study area other factors should also be considered as the routes of transmission.
We also observed that hepatitis B infection vertical transmission occurred with the same rate after vaginal or cesarean delivery. However, previous researches reported the influence of delivery mode on HBV transmission with controversies [23]. Deng et al. in a more recent study indicated that cesarean section might decrease the vertical transmission of HBV in pregnant women with HBV DNA>107 copies/mL [24]. Moreover, mothers of different age or different treatment durations had no different chance of hepatitis B infection vertical transmission.
In addition, Iranian mothers showed the same rate of infection transmission compared to Afghan mothers. Although refugees and immigrants are expected to be more suspected to transmit infection due to low quality of care, it seems that low sample size of Afghan participants makes our finding prone to bias. Investigating the viral load in neonates at birth showed that mothers with positive HBe antigen compared to those with negative antigen delivered newborns with similar viral load rates. In addition, viral load was the same in neonates of mothers with positive or negative HBe antibody indicating that HBe antigen or antibody cannot predict the degree of viral load in neonates. We also observed that although having a positive viral load during pregnancy was associated with more than two folds increased risk of HBV infection at birth, the observed association was not statistically significant. It demonstrates that viral load status of pregnant mothers with hepatitis B infection, cannot be a reliable predictor of neonatal infection at birth. Meanwhile, Boucheron et al. reported that HBV
DNA levels higher than f 5 30 logi0 IU/mL increases the risk of vertical transmission [20]. It should be noted that some neonates with positive viral load were delivered from mothers with negative viral loads indicating some other probable sources of infection such as placental infection. Chen et al. in their study evaluated individual cell layers of placenta and found HBV DNA, HBsAg as well as HBcAg in these cells. Their results could be indicative of the presence of infection in placenta. They also reported this type of infection in 31% of their patients as the main cause of vertical transmission [25]. In our study, viral load was vanished during the first three months of life which was much shorter than that reported in the previous literature. These differences might be due to the fact that none of our mothers with hepatitis B infection had S mutant. Similar liver enzymes of mothers giving birth to infants with and without hepatitis B infection indicates that probably liver function during pregnancy cannot be a predictor for hepatitis B infection vertical transfer.
In the present study, we found that mothers with positive viral load or positive HBe antibody, delivered infected newborns with the same levels of liver enzymes indicating that maternal factors did not affect the severity of the hepatitis B infection in their newborns.
In conclusion, our study provided evidences regarding that demographic, immunologic and clinical characteristics of mothers with hepatitis B infection did not play considerable role in the vertical transmission of the infection to the newborns as well as the severity of the following infection. We also suggested the possibility of placenta acting as a source of infection in VT. Further longitudinal studies with larger sample sizes are needed to show the exact predictors of transmission of the infection from infected mothers to their children.
Funding. This research received no external funding.
Conflict of interests. The authors declare no conflict of interest.
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Crana Hagmmga go pega^ii' 08.09.2021
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