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Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring
Early Human Development 140 (2020) 104904
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring
T
⁎
Yoad Govrin-Yehudaind, , Tamar Wainstockb, Naim Abu-Frehac, Eyal Sheinera a
Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel Faculty of Health Sciences, The Department of Public Health, Ben-Gurion University of the Negev, Beer-Sheva, Israel c The Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel d Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Hepatitis B Hepatitis C Pediatric respiratory complications Follow up Carrier status of HBV and HCV during pregnancy Long-term morbidity
Objective: Maternal HBV or HCV carrier status is a cause for concern regarding both the course of pregnancy and the short-term perinatal outcomes. Our main aim was to evaluate whether offspring born to carrier mothers during pregnancy, also suffer from long-term pediatric respiratory morbidity (until 18 years of age). Method of study: A population-based cohort analysis was conducted at a single tertiary medical center. The study included all singleton deliveries between the years 1991–2014, comparing incidence of respiratory-related hospitalization of offspring born to mothers who were carrier of HBV or HCV during their pregnancy to those born to nonexposed mothers. Respiratory morbidities were based on a predefined set of ICD-9 codes. A Kaplan-Meier survival curve was used to compare cumulative hospitalization incidence between the groups and a Cox regression model was used to adjust for confounding variables. Results: During the study period, 242,342 deliveries met the inclusion criteria. Of them, 771 (0.31%) were to HBV or HCV mother carriers during pregnancy. A Kaplan-Meier curve demonstrated that children born to HBV or HCV carriers had higher cumulative incidence of respiratory morbidity (Log rank test p = 0.007). In the Cox regression model, while controlling for maternal age, diabetes mellitus, hypertensive disorders, caesarian section and gestational age at birth, maternal HBV or HCV carrier status was noted as an independent risk factor for long-term respiratory morbidity in the offspring (adjusted HR = 1.43, 95% CI 1.07–1.90, p = 0.015). Conclusions: Maternal HBV or HCV carrier status in pregnancy may increase offspring susceptibility to long-term respiratory morbidity.
1. Introduction Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are common and important causes of chronic liver disease and both are among the most highly infectious diseases causing significant morbidity worldwide [1]. It is widely known that aside from the enhanced affinity with the liver cells (hepatocytes), these viruses can also lead to extrahepatic manifestations [2]. Most pregnant women are notified of their HBV or HCV status at the beginning of pregnancy by their attending physician [3]. The proportion of pregnant women who are carriers of HBV tends to differ among ethnic populations and has been estimated at between 0.6 and 4.0% [4]. The prevalence of anti-HCV antibodies in pregnant and reactive
women, also varies according to their geographical location, with HCV prevalence ranging from 0.6% in Japan to 4.5% in the US [5]. Hepatitis B and C infections during pregnancy require special case care and management [3,6]. Multiple factors warrant consideration including the effects of infection on the fetus and the mother, the effects of pregnancy itself on the course of the disease and the prevention of perinatal infection [6]. A causal link has been established between maternal carrier status of hepatitis B and C viruses and the risk of delivery complications in general and specifically preterm delivery (11.5% vs 7.9%; p < 0.001) [3]. Preterm delivery is a well-established risk factor for immediate as well as long-term respiratory complications in children up to the age of 18 [7,8]. This study was aimed to evaluate whether maternal HBV and
Abbreviations: SUMC, Soroka University Medical Center; HBV, hepatitis B virus; HCV, hepatitis C virus; MC, mixed cryoglobulinemia; PAN, polyarteritis nodosa; OSA, obstructive sleep apnea ⁎ Corresponding author at: Ben-Gurion University Medical School, Soroka University Medical Center, Sapir 25, Caesarea 3096925, Israel. E-mail address: [email protected] (Y. Govrin-Yehudain). https://doi.org/10.1016/j.earlhumdev.2019.104904 Received 12 August 2019; Accepted 12 October 2019 0378-3782/ © 2019 Elsevier B.V. All rights reserved.
Early Human Development 140 (2020) 104904
Y. Govrin-Yehudain, et al.
disorders (chronic or pregnancy related). Mean gestational age in weeks was significantly lower in the exposed group and rates of low birth weight infants and preterm deliveries, were significantly higher. In addition, the exposed group had higher rates of cesarean deliveries. Mean birth weight, low birth weight (< 2500) and low Apgar score at 1 min and 5 min (< 7), as well as perinatal mortality, did not differ between the two groups. Hospitalization rates and the long-term respiratory morbidities in the offspring are presented in Table 2. The total respiratory hospitalization rate was non-significantly higher in the offspring of HBV or HCV maternal carriers as compared to the offspring of non-carriers (6.1% vs 4.8%, p = 0.11). In the Kaplan–Meier survival curve (Fig. 1), children born to mothers who were HBV or HCV carriers during pregnancy showed a significantly higher cumulative incidence of respiratory-related hospitalizations, when compared with children born to non-HBV or HCV exposed mothers (Kaplan-Meier, log-rank p = 0.007). The Cox regression model, shown in Table 3, presents the association between maternal HBV or HCV carrier status during pregnancy and the long-term risk for respiratory-related hospitalizations in the offspring (up to the age of 18 years). The model adjusted for maternal age at birth, maternal diabetes (pregestational and gestational), maternal hypertensive disorders (chronic or pregnancy related), cesarean sections and gestational age in weeks. As can be seen, maternal positive carrier status during pregnancy was a significant and independent risk factor for long-term respiratory-related hospitalization in the offspring, with an adjusted hazard ratio of 1.43 (95% CI 1.07–1.90, p = 0.015).
HCV carrier status during pregnancy had a long-term impact on respiratory complications of the offspring (until 18 years of age), regardless of prematurity. 2. Methods In this population-based retrospective cohort study, all singleton deliveries between 1991 and 2014 were included. The study has been performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments (Helsinki Declaration 1975, revision 2013), and was approved by the institutional review board (SUMC IRB Committee). The study was based on a large non-selective population data, as it was conducted at Soroka University Medical Center (SUMC), which is the largest birth center in the country and the sole tertiary medical center in the Negev (Southern Israel). We compared deliveries and offspring of mothers who were carriers of hepatitis B or hepatitis C during pregnancy (the exposed group) and mothers who were no (unexposed group). Adverse perinatal outcomes assessed included low birthweight (LBW, defined as birthweight < 2500 g.), preterm delivery (PTB, < 37 gestational weeks), low Apgar score at 1 min (< 7), low Apgar score at 5 min (< 7) and cesarean delivery. Multiple pregnancies, fetuses with congenital anomalies and perinatal mortality were excluded from the analysis. Offspring respiratory-related hospitalizations up to the age of 18 years were assessed using diagnoses that were pre-defined by a set of ICD-9 codes presented in the Supplementary Table A. Patient follow-up was terminated if either of the following occurred: offspring first hospitalization with any respiratory morbidity; reached the age of 18 years; any hospitalization resulting in death; or end of the study period. Two databases were cross-linked and merged, based on patients' ID number. The first database was the computerized perinatal database of the obstetrics and gynecology department, containing maternal and neonatal information recorded immediately following delivery by an obstetrician. The second was the computerized pediatric hospitalization database of SUMC (“Demog-ICD9”), which includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations in the SUMC pediatric departments.
5. Discussion Maternal HBV or HCV carrier status is a cause for concern regarding both the course of pregnancy and the short-term perinatal outcomes. The major finding of our study is that offspring born to mothers who were carriers of HBV or HCV during their pregnancy appear to suffer not only from immediate adverse perinatal outcomes, but also from long-term and varied pediatric respiratory morbidity. The higher tendency for respiratory morbidity and hospitalizations, Specifically, higher risk for obstructive sleep apnea (OSA) and asthma in these children, may cause a substantial burden on health care services and should not be underestimated [9,10]. There are many guidelines related to management of chronic hepatitis B or C in pregnancy, due to mainly maternal complications, short-term pregnancy complications and short-term fetal morbidity [11,12]. Our findings help to further expand on the current knowledge base about the significance of maternal disease during pregnancy and its impact on the future respiratory health of the offspring. Our cohort study results concur with several studies, suggesting an association between positive maternal carrier status during pregnancy and adverse perinatal outcome. Safir et al., demonstrated a significantly higher rate of preterm deliveries, cesarean deliveries as well as low birth weight, within the exposed group, as per our study findings, but also demonstrated significantly higher rates of low Apgar score (< 7) at 1 min, in contrast to the non-significant difference found with this variable in our study. These findings in the maternal carrier group should be taken into account when considering the effect on the long-term respiratory health of the offspring, as each of these aforementioned conditions could be regarded as an influencing factor. Maternal hypertensive disorders (chronic, gestational or pre-eclampsia with or without severe features) for example, were found to be associated with respiratory morbidity in the offspring [13]. This association is probably due to the changing of the intrauterine environment influenced by the pattern of hormonal signals and substrate transported to the fetus, seen in those diseases [14,15]. Cesarean delivery, was found as well, to be associated with asthma and bronchiolitis in the offspring [16]. With regard to preterm birth, our group found an association with long term respiratory
3. Statistical analysis Statistical analysis was performed using the SPSS package 23rd ed. (IBM/SPSS, Chicago, IL). Categorical data are shown in counts and rates and the differences were evaluated by chi square tests. For the comparison of continuous variables with normal distribution, student t-test was used. The cumulative hospitalization incidences over time among the study groups, was compared using the Kaplan–Meier survival curves and the differences between the curves was compared using the log rank test. Multivariable Cox survival analysis was used to establish an independent association between maternal carrier status to HBV or HCV in pregnancy and future incidence of respiratory-related hospitalizations in the offspring. The model adjusted for confounding and clinically significant variables. All analyses were two-sided, and a pvalue of ≤0.05 was considered statistically significant. 4. Results There were 242,342 singleton deliveries based on initial analysis, after excluding deliveries which did not meet the inclusion criteria. Of those, 771 mothers were HBV or HCV carriers during pregnancy. Maternal characteristics and delivery outcomes for both groups are presented in Table 1. Several significant differences between carriers and non-carriers were found: Mothers who were carriers of HBV or HCV during their pregnancy were older and had higher rates of hypertensive 2
Early Human Development 140 (2020) 104904
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Table 1 Maternal characteristics and delivery outcomes based on study group. Characteristics
Hepatitis B/C carriers (N = 777) % (n)
No hepatitis (N = 242,905) % (n)
OR; 95% CI
p-Value
Maternal age at index birth (years ± SD) Parity 1 2–4 5+ Diabetes mellitusa b Hypertensive disorders Cesarean section Preterm delivery (< 37 W) Mean gestational age (weeks ± SD) Birth weight (grams, mean ± SD) Low birth weight (< 2500 g) Small for gestational age Low Apgar score at 1 min (< 7) Low Apgar score at 5 min (< 7) Perinatal mortality Gender of the offspring Male Female
29.25 ± 5.77 26.9 (209) 51.9 (403) 21.2 (165) 5 (39) 7.2 (56) 23.2 (180) 9.4 (73) 38.67 ± 2.14 3195.33 ± 559.76 9.5 (74) 4.8 (37) 5.5 (43) 1.5 (12) 0.8 (6) 52.6 (409) 47.4 (368)
28.16 ± 5.82 23.6 (57296) 51.1 (124111) 25.3 (61445) 5.0 (12120) 5.0 (12191) 13.5 (32846) 6.9 (16647) 39.10 ± 1.98 3205.84 ± 510.57 6.7 (16330) 4.6 (11253) 5.3 (12947) 2.3 (5497) 0.5 (1334) 50.8 (123468) 49.2 (119437)
– –
< 0.001 0.013
a b
1.01 1.47 1.93 1.41 – – 1.46 1.03 1.04 0.67 1.41 1.07
(0.72–1.38) (1.12-1.94) (1.63–2.28) (1.1–1.8)
0.97 0.01 < 0.001 0.01 < 0.001 0.57 < 0.001 0.86 0.80 0.18 0.40 0.31
(1.14–1.85) (0.73–1.43) (0.76–1.41) (0.38–1.19) (0.63–3.15) (0.93–1.23)
Including pregestational or gestational diabetes. Including chronic hypertension, gestational hypertension and preeclampsia.
Table 2 Selected long-term respiratory morbidities in children (up to the age of 18 years) based on study group. Respiratory morbidity
Hepatitis B/C carriers (N = 771) % (n)
No hepatitis (N = 241,571) % (n)
OR; 95% CI
p-Value
Asthma Obstructive sleep apnea Other Total respiratory hospitalization
3.0 1.2 2.7 6.1
2.5 0.7 1.9 4.8
1.18 1.77 1.41 1.27
0.42 0.08 0.12 0.11
(23) (9) (21) (47)
(6094) (1600) (4710) (11701)
(0.78–1.80) (0.91–3.42) (0.91–2.17) (0.95–1.71)
Table 3 Multivariable analysis for the association between HBV or HCV carrier mothers during pregnancy and offspring long-term respiratory morbidity. Variables
Adjusted HR
95% CI Min
HBV or HCV carriers Maternal age (years) Diabetes mellitusa Hypertensive disordersb Cesarean delivery Gestational age (weeks)
1.43 0.99 1.06 0.95 1.20 0.93
1.07–1.90 0.99–0.99 0.98–1.15 0.88–1.04 1.14–1.26 0.93–0.94
p-Value Max 0.01 < 0.001 0.13 0.29 < 0.001 < 0.001
a
Including pregestational or gestational diabetes. Including chronic hypertension, gestational hypertension and preeclampsia. b
morbidity in the offspring including higher rates of hospitalizations due to pneumonia, asthma and bronchiolitis [8]. All these factors, however, were controlled for, using the Cox multivariable regression model. There are several suggested biological mechanisms for the pulmonary injury accompanying the viral liver disease. The pulmonary damage caused by these viral infections can be divided into both direct (viral factors) and indirect (immune mediated) mechanisms [1]. Our hypotheses for long-term respiratory morbidity among the offspring of carrier mothers may be related mainly to indirect mechanisms of viral induced respiratory damage. Direct-injury mechanisms were less likely to be related to the respiratory complications seen in the offspring due to the fact that these infants did not have documented hepatitis B or C infection following pregnancy, following an examination of the data files of all hospitalizations in the offspring. A major extrahepatic manifestation which can be a possible
Fig. 1. Kaplan-Meier hazard function curve demonstrating the cumulative incidence of hospitalizations involving respiratory morbidity in the offspring of exposed and non-exposed groups. (Log rank p value = 0.007).
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Early Human Development 140 (2020) 104904
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that there were no children infected with hepatitis in the group of carrier mothers, as mentioned earlier. In conclusion, maternal HBV and HCV carrier status in pregnancy may increase offspring susceptibility to respiratory morbidity and was found to be an independent risk factor for long-term respiratory morbidity in the offspring of the carrier mother. This finding could help shed further light and stimulate additional avenues of further research to assist in formulating guidance on the management of seropositive HBV and HBC pregnant women, that could reduce the susceptibility and risk of long-term respiratory morbidity in their offspring. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.earlhumdev.2019.104904.
explanation for the long-term respiratory morbidity seen in the maternal offspring, is a tendency to systemic and organ-specific autoimmune diseases. Among these autoimmune diseases, mixed cryoglobulinemia (MC) and polyarteritis nodosa (PAN) are the most common extrahepatic manifestations seen in HCV and HBV respectively [17–19]. In both MC and PAN, pathogenesis is associated with the deposition of immune complexes (including IgG) that cause vasculitis [20]. The pathophysiology of respiratory injury is associated with immune-complex- mediated deposition of cryoglobulins in vascular and interstitial tissue in the lungs, which results in impaired gas exchange and an obstructive ventilatory defect [18]. It should be noted, that the presence of antibodies to the virus of an infant born to a carrier mother, can be detected in their blood up to the age of 15–18 months [5]. IgG maternal antibodies are known to be able to cross the placenta and therefore can also affect the fetus [21]. It is possible that antibodies transmitted to the embryo have the same ability to lead to pulmonary injury as demonstrated in the mother, and may be associated with the increased susceptibility to respiratory morbidity seen in the offspring. An interesting topic to examine is whether children born to carrier mothers with MC demonstrate a higher rate of respiratory morbidity later in life, compared to children of non-MC mothers. Another theory we can propose is related to the cytokines and mediators that are secreted during viral illness [22]. Increased levels of TNF-alpha appear in the serum and in hepatocytes of chronic HBV and HCV patients [23]. High levels of TNF-alpha are known to be associated with damage to fetal development, affecting embryo implantation, endometrial development, trophoblast growth and differentiation, and play a significant role in affecting placental development [24,25]. A causal link has also been established between TNF-alpha in the fetus and the effect on the surfactant, showing a dose and time response relationship between TNF-alpha levels and decreased levels of SP-c (surfactant protein c) [26]. SP-c is considered the most specific protein associated with lung development in mammals, and therefore a decrease in SP-c, may negatively impact lung development [27]. In light of this, we believe that one of the proposed mechanisms for increased susceptibility to respiratory morbidity in later life in the offspring of seropositive carriers in pregnancy, is the associated intrauterine respiratory changes caused by elevated levels of TNF alpha and other inflammatory cytokines. We propose that the association between high levels of cytokines and immunoglobulins during pregnancy of a carrier mother and respiratory disease in the offspring, should be the subject of future investigations and could perhaps be considered in the future as a predictor for infant susceptibility to developing respiratory morbidity later in life. The main strengths of our study are that our research stems from a non-preselected cohort (based on a large number of enrolled subjects), which enables us to draw conclusions from the study that may be applicable to the real-world situation within the wider general population. In addition, the long-term follow-up on the offspring's population, together with the fact that the Soroka University Medical Center is the only tertiary medical center in the South, allows for coordinated followup with a low risk for data loss. This results in a significant advantage, enabling us to obtain high quality and reliable, verifiable research results. Limitations of our research, stem from the retrospective nature of our study, which limits our ability to establish causation, only allowing us to establish proof of association. Therefore, our choice to conduct research based on a retrospective review is a main limitation and drawback of our research. Another variable that needs to be taken into account and may be a disadvantage of our research, is the lack of data on the birth status of infants and the risk of obscuring the association between maternal carrier status and neonatal respiratory disease. To reduce the likelihood of this variable being a confounding variable, we confirmed through the data files of offspring hospitalizations
Author statement I declare that I participated in the design, execution, and analysis of the paper by Yoad Govrin Yehudain and colleagues entitled “Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring”, that I have seen and approved the final version and that it has neither been published nor submitted elsewhere. Acknowledgments Performed in pat of Yoad Govrin Yehudain MD requirements. This study was conducted as part of the requirements for MD degree from the Goldman Medical School at the Faculty of Health Sciences, BenGurion University of the Negev. Funding information This study was not funded. All authors have indicated they have no financial relationships relevant to this article to disclose. Data sharing We have full control of all primary data and agree to allow the journal to review the data if requested. Declaration of competing interest All authors have indicated they have no potential conflicts of interest to disclose. References [1] L.Y. Goh, T. Card, A.W. Fogarty, T.M. McKeever, ScienceDirect, Clin. Microbiol. Newsl. 38 (13) (2016) 109. [2] H. Hartmann, Extrahepatic manifestations of HBV and HCV infection, Praxis 86 (29–30) (1997) 1163–1166 July. [3] A. Safir, A. Levy, E. Sikuler, E. Sheiner, Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome, Liver Int. 30 (5) (2010) 765–770 May. [4] C. Zamir, R. Dagan, D. Zamir, S. Rishpon, D. Fraser, N. Rimon, E. Ben Porath, Evaluation of screening for hepatitis B surface antigen during pregnancy in a population with a high prevalence of hepatitis B surface antigen-positive/hepatitis B e antigen-negative carriers, Pediatr. Infect. Dis. J. 18 (3) (1999) 262–266 Mar. [5] N. Hadzić, Hepatitis C in pregnancy, Arch. Dis. Child. Fetal Neonatal Ed. 84 (3) (May 2001) 201. [6] M.M. Jonas, Hepatitis B and pregnancy: an underestimated issue, Liver Int. 29 (Suppl. 1) (Jan 2009) 133–139 s1. [7] R. Moshkovsky, T. Wainstock, E. Sheiner, D. Landau, A. Walfisch, Elective cesarean delivery at term and the long-term risk for endocrine and metabolic morbidity of the offspring, J. Dev. Orig. Health Dis. (2018) 1–7 December 27. [8] A. Walfisch, O. Beharier, T. Wainstock, R. Sergienko, D. Landau, E. Sheiner, Earlyterm deliveries as an independent risk factor for long-term respiratory morbidity of the offspring, Pediatr. Pulmonol. 52 (2) (2017) 198–204 Feb. [9] I. Asher, N. Pearce, Global burden of asthma among children, Int. J. Tuberc. Lung Dis. 18 (11) (Nov 2014) 1269–1278. [10] V.K. Kapur, Obstructive sleep apnea: diagnosis, epidemiology, and economics, Respir. Care 55 (9) (Sep 2010) 1155.
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Y. Govrin-Yehudain, et al.
[19] S. Ozen, The changing face of polyarteritis nodosa and necrotizing vasculitis, Nat. Rev. Rheumatol. 13 (6) (2017) 381–386 Jun. [20] C. Ferri, M. Sebastiani, D. Giuggioli, M. Cazzato, G. Longombardo, A. Antonelli, R. Puccini, C. Michelassi, A.L. Zignego, Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients, Semin. Arthritis Rheum. 33 (6) (2004) 355–374. [21] V. Laugel, J. Goetz, S. Wolff, J. Beladdale, J. Sibilia, J. Messer, Neonatal management of symptomatic transplacental cryoglobulinaemia, Acta Paediatr. 93 (4) (2004) 556–558. Apr. [22] P. Spagnolo, S. Zeuzem, L. Richeldi, R.M. du Bois, The complex interrelationships between chronic lung and liver disease: a review, J. Viral Hepat. 17 (6) (2010) 381–390 Jun. [23] E. Degasperi, A. Aghemo, P. Lampertico, M. Vigano, M. Colombo, Anti-TNF Drugs in Patients With Hepatitis B or C Virus Infection: Safety and Clinical Management, (2012), pp. 193–207. [24] K. Cronise, S.J. Kelly, Maternal urinary tract infection alters water maze performance in the offspring, Neurotoxicol. Teratol. 23 (4) (2001) 373–379. [25] S. Saito, Cytokine cross-talk between mother and the embryo/placenta, J. Reprod. Immunol. 52 (1) (2001) 15–33. [26] C.J. Bachurski, G.S. Pryhuber, S.W. Glasser, S.E. Kelly, J.A. Whitsett, Tumor necrosis factor-alpha inhibits surfactant protein C gene transcription, J. Biol. Chem. 270 (33) (1995) 19402–19407. August. [27] N. Roldan, E. Goormaghtigh, J. Pérez-Gil, B. Garcia-Alvarez, Palmitoylation as a key factor to modulate SP-c–lipid interactions in lung surfactant membrane multilayers, BBA - Biomembranes 1848 (1) (2015) 184–191 Jan.
[11] J. Li, M.S. Chang, T.T. Tran, M.H. Nguyen, Management of Chronic Hepatitis B in Pregnancy, 51 (2017), p. 9. [12] M.M. Smfm, B.L. Hughes, C.M. Page, J.A. Kuller, Hepatitis C in pregnancy: screening, treatment, and management, Am. J. Obstet. Gynecol. 217 (5) (2017) B2–B12. [13] K. Nahum Sacks, M. Friger, I. Shoham-Vardi, R. Sergienko, E. Spiegel, D. Landau, E. Sheiner, Long-term neuropsychiatric morbidity in children exposed prenatally to preeclampsia, Early Hum. Dev. 130 (2019) 96–100 Mar. [14] C.S. Wu, E.A. Nohr, B.H. Bech, M. Vestergaard, J.M. Catov, J. Olsen, Diseases in Children Born to Mothers With Preeclampsia: A Population-based Sibling Cohort Study, 874 (2011). [15] K. Nahum Sacks, M. Friger, I. Shoham-Vardi, E. Spiegel, R. Sergienko, D. Landau, E. Sheiner, Prenatal exposure to preeclampsia as an independent risk factor for long-term cardiovascular morbidity of the offspring, Pregnancy Hypertension 13 (2018) 181–186. [16] M. Black, S. Bhattacharya, S. Philip, J.E. Norman, D.J. McLernon, Planned cesarean delivery at term and adverse outcomes in childhood health, JAMA 314 (21) (Dec 1 2015) 2271–2279. [17] A. Flores-Chávez, J.A. Carrion, X. Forns, M. Ramos-Casals, Extrahepatic manifestations associated with chronic hepatitis C virus infection, Revista Espanola De Sanidad Penitenciaria 19 (3) (2017) 87–97 Dec. [18] A.M. Saleh, H. Elalfy, M.M. Arafa, N. Abousamra, A. El-Badrawy, M.A. Mohamed, E.A.M.E. Barakat, B.S. El Deek, Association between HCV induced mixed cryoglobulinemia and pulmonary affection: the role of TNF-alpha in the pathogenesis of pulmonary changes, Egypt. J. Chest Dis. Tuberc. 63 (1) (Jan 2014) 259–265.
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Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring
T
⁎
Yoad Govrin-Yehudaind, , Tamar Wainstockb, Naim Abu-Frehac, Eyal Sheinera a
Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel Faculty of Health Sciences, The Department of Public Health, Ben-Gurion University of the Negev, Beer-Sheva, Israel c The Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel d Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel b
A R T I C LE I N FO
A B S T R A C T
Keywords: Hepatitis B Hepatitis C Pediatric respiratory complications Follow up Carrier status of HBV and HCV during pregnancy Long-term morbidity
Objective: Maternal HBV or HCV carrier status is a cause for concern regarding both the course of pregnancy and the short-term perinatal outcomes. Our main aim was to evaluate whether offspring born to carrier mothers during pregnancy, also suffer from long-term pediatric respiratory morbidity (until 18 years of age). Method of study: A population-based cohort analysis was conducted at a single tertiary medical center. The study included all singleton deliveries between the years 1991–2014, comparing incidence of respiratory-related hospitalization of offspring born to mothers who were carrier of HBV or HCV during their pregnancy to those born to nonexposed mothers. Respiratory morbidities were based on a predefined set of ICD-9 codes. A Kaplan-Meier survival curve was used to compare cumulative hospitalization incidence between the groups and a Cox regression model was used to adjust for confounding variables. Results: During the study period, 242,342 deliveries met the inclusion criteria. Of them, 771 (0.31%) were to HBV or HCV mother carriers during pregnancy. A Kaplan-Meier curve demonstrated that children born to HBV or HCV carriers had higher cumulative incidence of respiratory morbidity (Log rank test p = 0.007). In the Cox regression model, while controlling for maternal age, diabetes mellitus, hypertensive disorders, caesarian section and gestational age at birth, maternal HBV or HCV carrier status was noted as an independent risk factor for long-term respiratory morbidity in the offspring (adjusted HR = 1.43, 95% CI 1.07–1.90, p = 0.015). Conclusions: Maternal HBV or HCV carrier status in pregnancy may increase offspring susceptibility to long-term respiratory morbidity.
1. Introduction Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are common and important causes of chronic liver disease and both are among the most highly infectious diseases causing significant morbidity worldwide [1]. It is widely known that aside from the enhanced affinity with the liver cells (hepatocytes), these viruses can also lead to extrahepatic manifestations [2]. Most pregnant women are notified of their HBV or HCV status at the beginning of pregnancy by their attending physician [3]. The proportion of pregnant women who are carriers of HBV tends to differ among ethnic populations and has been estimated at between 0.6 and 4.0% [4]. The prevalence of anti-HCV antibodies in pregnant and reactive
women, also varies according to their geographical location, with HCV prevalence ranging from 0.6% in Japan to 4.5% in the US [5]. Hepatitis B and C infections during pregnancy require special case care and management [3,6]. Multiple factors warrant consideration including the effects of infection on the fetus and the mother, the effects of pregnancy itself on the course of the disease and the prevention of perinatal infection [6]. A causal link has been established between maternal carrier status of hepatitis B and C viruses and the risk of delivery complications in general and specifically preterm delivery (11.5% vs 7.9%; p < 0.001) [3]. Preterm delivery is a well-established risk factor for immediate as well as long-term respiratory complications in children up to the age of 18 [7,8]. This study was aimed to evaluate whether maternal HBV and
Abbreviations: SUMC, Soroka University Medical Center; HBV, hepatitis B virus; HCV, hepatitis C virus; MC, mixed cryoglobulinemia; PAN, polyarteritis nodosa; OSA, obstructive sleep apnea ⁎ Corresponding author at: Ben-Gurion University Medical School, Soroka University Medical Center, Sapir 25, Caesarea 3096925, Israel. E-mail address: [email protected] (Y. Govrin-Yehudain). https://doi.org/10.1016/j.earlhumdev.2019.104904 Received 12 August 2019; Accepted 12 October 2019 0378-3782/ © 2019 Elsevier B.V. All rights reserved.
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disorders (chronic or pregnancy related). Mean gestational age in weeks was significantly lower in the exposed group and rates of low birth weight infants and preterm deliveries, were significantly higher. In addition, the exposed group had higher rates of cesarean deliveries. Mean birth weight, low birth weight (< 2500) and low Apgar score at 1 min and 5 min (< 7), as well as perinatal mortality, did not differ between the two groups. Hospitalization rates and the long-term respiratory morbidities in the offspring are presented in Table 2. The total respiratory hospitalization rate was non-significantly higher in the offspring of HBV or HCV maternal carriers as compared to the offspring of non-carriers (6.1% vs 4.8%, p = 0.11). In the Kaplan–Meier survival curve (Fig. 1), children born to mothers who were HBV or HCV carriers during pregnancy showed a significantly higher cumulative incidence of respiratory-related hospitalizations, when compared with children born to non-HBV or HCV exposed mothers (Kaplan-Meier, log-rank p = 0.007). The Cox regression model, shown in Table 3, presents the association between maternal HBV or HCV carrier status during pregnancy and the long-term risk for respiratory-related hospitalizations in the offspring (up to the age of 18 years). The model adjusted for maternal age at birth, maternal diabetes (pregestational and gestational), maternal hypertensive disorders (chronic or pregnancy related), cesarean sections and gestational age in weeks. As can be seen, maternal positive carrier status during pregnancy was a significant and independent risk factor for long-term respiratory-related hospitalization in the offspring, with an adjusted hazard ratio of 1.43 (95% CI 1.07–1.90, p = 0.015).
HCV carrier status during pregnancy had a long-term impact on respiratory complications of the offspring (until 18 years of age), regardless of prematurity. 2. Methods In this population-based retrospective cohort study, all singleton deliveries between 1991 and 2014 were included. The study has been performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments (Helsinki Declaration 1975, revision 2013), and was approved by the institutional review board (SUMC IRB Committee). The study was based on a large non-selective population data, as it was conducted at Soroka University Medical Center (SUMC), which is the largest birth center in the country and the sole tertiary medical center in the Negev (Southern Israel). We compared deliveries and offspring of mothers who were carriers of hepatitis B or hepatitis C during pregnancy (the exposed group) and mothers who were no (unexposed group). Adverse perinatal outcomes assessed included low birthweight (LBW, defined as birthweight < 2500 g.), preterm delivery (PTB, < 37 gestational weeks), low Apgar score at 1 min (< 7), low Apgar score at 5 min (< 7) and cesarean delivery. Multiple pregnancies, fetuses with congenital anomalies and perinatal mortality were excluded from the analysis. Offspring respiratory-related hospitalizations up to the age of 18 years were assessed using diagnoses that were pre-defined by a set of ICD-9 codes presented in the Supplementary Table A. Patient follow-up was terminated if either of the following occurred: offspring first hospitalization with any respiratory morbidity; reached the age of 18 years; any hospitalization resulting in death; or end of the study period. Two databases were cross-linked and merged, based on patients' ID number. The first database was the computerized perinatal database of the obstetrics and gynecology department, containing maternal and neonatal information recorded immediately following delivery by an obstetrician. The second was the computerized pediatric hospitalization database of SUMC (“Demog-ICD9”), which includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations in the SUMC pediatric departments.
5. Discussion Maternal HBV or HCV carrier status is a cause for concern regarding both the course of pregnancy and the short-term perinatal outcomes. The major finding of our study is that offspring born to mothers who were carriers of HBV or HCV during their pregnancy appear to suffer not only from immediate adverse perinatal outcomes, but also from long-term and varied pediatric respiratory morbidity. The higher tendency for respiratory morbidity and hospitalizations, Specifically, higher risk for obstructive sleep apnea (OSA) and asthma in these children, may cause a substantial burden on health care services and should not be underestimated [9,10]. There are many guidelines related to management of chronic hepatitis B or C in pregnancy, due to mainly maternal complications, short-term pregnancy complications and short-term fetal morbidity [11,12]. Our findings help to further expand on the current knowledge base about the significance of maternal disease during pregnancy and its impact on the future respiratory health of the offspring. Our cohort study results concur with several studies, suggesting an association between positive maternal carrier status during pregnancy and adverse perinatal outcome. Safir et al., demonstrated a significantly higher rate of preterm deliveries, cesarean deliveries as well as low birth weight, within the exposed group, as per our study findings, but also demonstrated significantly higher rates of low Apgar score (< 7) at 1 min, in contrast to the non-significant difference found with this variable in our study. These findings in the maternal carrier group should be taken into account when considering the effect on the long-term respiratory health of the offspring, as each of these aforementioned conditions could be regarded as an influencing factor. Maternal hypertensive disorders (chronic, gestational or pre-eclampsia with or without severe features) for example, were found to be associated with respiratory morbidity in the offspring [13]. This association is probably due to the changing of the intrauterine environment influenced by the pattern of hormonal signals and substrate transported to the fetus, seen in those diseases [14,15]. Cesarean delivery, was found as well, to be associated with asthma and bronchiolitis in the offspring [16]. With regard to preterm birth, our group found an association with long term respiratory
3. Statistical analysis Statistical analysis was performed using the SPSS package 23rd ed. (IBM/SPSS, Chicago, IL). Categorical data are shown in counts and rates and the differences were evaluated by chi square tests. For the comparison of continuous variables with normal distribution, student t-test was used. The cumulative hospitalization incidences over time among the study groups, was compared using the Kaplan–Meier survival curves and the differences between the curves was compared using the log rank test. Multivariable Cox survival analysis was used to establish an independent association between maternal carrier status to HBV or HCV in pregnancy and future incidence of respiratory-related hospitalizations in the offspring. The model adjusted for confounding and clinically significant variables. All analyses were two-sided, and a pvalue of ≤0.05 was considered statistically significant. 4. Results There were 242,342 singleton deliveries based on initial analysis, after excluding deliveries which did not meet the inclusion criteria. Of those, 771 mothers were HBV or HCV carriers during pregnancy. Maternal characteristics and delivery outcomes for both groups are presented in Table 1. Several significant differences between carriers and non-carriers were found: Mothers who were carriers of HBV or HCV during their pregnancy were older and had higher rates of hypertensive 2
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Table 1 Maternal characteristics and delivery outcomes based on study group. Characteristics
Hepatitis B/C carriers (N = 777) % (n)
No hepatitis (N = 242,905) % (n)
OR; 95% CI
p-Value
Maternal age at index birth (years ± SD) Parity 1 2–4 5+ Diabetes mellitusa b Hypertensive disorders Cesarean section Preterm delivery (< 37 W) Mean gestational age (weeks ± SD) Birth weight (grams, mean ± SD) Low birth weight (< 2500 g) Small for gestational age Low Apgar score at 1 min (< 7) Low Apgar score at 5 min (< 7) Perinatal mortality Gender of the offspring Male Female
29.25 ± 5.77 26.9 (209) 51.9 (403) 21.2 (165) 5 (39) 7.2 (56) 23.2 (180) 9.4 (73) 38.67 ± 2.14 3195.33 ± 559.76 9.5 (74) 4.8 (37) 5.5 (43) 1.5 (12) 0.8 (6) 52.6 (409) 47.4 (368)
28.16 ± 5.82 23.6 (57296) 51.1 (124111) 25.3 (61445) 5.0 (12120) 5.0 (12191) 13.5 (32846) 6.9 (16647) 39.10 ± 1.98 3205.84 ± 510.57 6.7 (16330) 4.6 (11253) 5.3 (12947) 2.3 (5497) 0.5 (1334) 50.8 (123468) 49.2 (119437)
– –
< 0.001 0.013
a b
1.01 1.47 1.93 1.41 – – 1.46 1.03 1.04 0.67 1.41 1.07
(0.72–1.38) (1.12-1.94) (1.63–2.28) (1.1–1.8)
0.97 0.01 < 0.001 0.01 < 0.001 0.57 < 0.001 0.86 0.80 0.18 0.40 0.31
(1.14–1.85) (0.73–1.43) (0.76–1.41) (0.38–1.19) (0.63–3.15) (0.93–1.23)
Including pregestational or gestational diabetes. Including chronic hypertension, gestational hypertension and preeclampsia.
Table 2 Selected long-term respiratory morbidities in children (up to the age of 18 years) based on study group. Respiratory morbidity
Hepatitis B/C carriers (N = 771) % (n)
No hepatitis (N = 241,571) % (n)
OR; 95% CI
p-Value
Asthma Obstructive sleep apnea Other Total respiratory hospitalization
3.0 1.2 2.7 6.1
2.5 0.7 1.9 4.8
1.18 1.77 1.41 1.27
0.42 0.08 0.12 0.11
(23) (9) (21) (47)
(6094) (1600) (4710) (11701)
(0.78–1.80) (0.91–3.42) (0.91–2.17) (0.95–1.71)
Table 3 Multivariable analysis for the association between HBV or HCV carrier mothers during pregnancy and offspring long-term respiratory morbidity. Variables
Adjusted HR
95% CI Min
HBV or HCV carriers Maternal age (years) Diabetes mellitusa Hypertensive disordersb Cesarean delivery Gestational age (weeks)
1.43 0.99 1.06 0.95 1.20 0.93
1.07–1.90 0.99–0.99 0.98–1.15 0.88–1.04 1.14–1.26 0.93–0.94
p-Value Max 0.01 < 0.001 0.13 0.29 < 0.001 < 0.001
a
Including pregestational or gestational diabetes. Including chronic hypertension, gestational hypertension and preeclampsia. b
morbidity in the offspring including higher rates of hospitalizations due to pneumonia, asthma and bronchiolitis [8]. All these factors, however, were controlled for, using the Cox multivariable regression model. There are several suggested biological mechanisms for the pulmonary injury accompanying the viral liver disease. The pulmonary damage caused by these viral infections can be divided into both direct (viral factors) and indirect (immune mediated) mechanisms [1]. Our hypotheses for long-term respiratory morbidity among the offspring of carrier mothers may be related mainly to indirect mechanisms of viral induced respiratory damage. Direct-injury mechanisms were less likely to be related to the respiratory complications seen in the offspring due to the fact that these infants did not have documented hepatitis B or C infection following pregnancy, following an examination of the data files of all hospitalizations in the offspring. A major extrahepatic manifestation which can be a possible
Fig. 1. Kaplan-Meier hazard function curve demonstrating the cumulative incidence of hospitalizations involving respiratory morbidity in the offspring of exposed and non-exposed groups. (Log rank p value = 0.007).
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that there were no children infected with hepatitis in the group of carrier mothers, as mentioned earlier. In conclusion, maternal HBV and HCV carrier status in pregnancy may increase offspring susceptibility to respiratory morbidity and was found to be an independent risk factor for long-term respiratory morbidity in the offspring of the carrier mother. This finding could help shed further light and stimulate additional avenues of further research to assist in formulating guidance on the management of seropositive HBV and HBC pregnant women, that could reduce the susceptibility and risk of long-term respiratory morbidity in their offspring. Supplementary data to this article can be found online at https:// doi.org/10.1016/j.earlhumdev.2019.104904.
explanation for the long-term respiratory morbidity seen in the maternal offspring, is a tendency to systemic and organ-specific autoimmune diseases. Among these autoimmune diseases, mixed cryoglobulinemia (MC) and polyarteritis nodosa (PAN) are the most common extrahepatic manifestations seen in HCV and HBV respectively [17–19]. In both MC and PAN, pathogenesis is associated with the deposition of immune complexes (including IgG) that cause vasculitis [20]. The pathophysiology of respiratory injury is associated with immune-complex- mediated deposition of cryoglobulins in vascular and interstitial tissue in the lungs, which results in impaired gas exchange and an obstructive ventilatory defect [18]. It should be noted, that the presence of antibodies to the virus of an infant born to a carrier mother, can be detected in their blood up to the age of 15–18 months [5]. IgG maternal antibodies are known to be able to cross the placenta and therefore can also affect the fetus [21]. It is possible that antibodies transmitted to the embryo have the same ability to lead to pulmonary injury as demonstrated in the mother, and may be associated with the increased susceptibility to respiratory morbidity seen in the offspring. An interesting topic to examine is whether children born to carrier mothers with MC demonstrate a higher rate of respiratory morbidity later in life, compared to children of non-MC mothers. Another theory we can propose is related to the cytokines and mediators that are secreted during viral illness [22]. Increased levels of TNF-alpha appear in the serum and in hepatocytes of chronic HBV and HCV patients [23]. High levels of TNF-alpha are known to be associated with damage to fetal development, affecting embryo implantation, endometrial development, trophoblast growth and differentiation, and play a significant role in affecting placental development [24,25]. A causal link has also been established between TNF-alpha in the fetus and the effect on the surfactant, showing a dose and time response relationship between TNF-alpha levels and decreased levels of SP-c (surfactant protein c) [26]. SP-c is considered the most specific protein associated with lung development in mammals, and therefore a decrease in SP-c, may negatively impact lung development [27]. In light of this, we believe that one of the proposed mechanisms for increased susceptibility to respiratory morbidity in later life in the offspring of seropositive carriers in pregnancy, is the associated intrauterine respiratory changes caused by elevated levels of TNF alpha and other inflammatory cytokines. We propose that the association between high levels of cytokines and immunoglobulins during pregnancy of a carrier mother and respiratory disease in the offspring, should be the subject of future investigations and could perhaps be considered in the future as a predictor for infant susceptibility to developing respiratory morbidity later in life. The main strengths of our study are that our research stems from a non-preselected cohort (based on a large number of enrolled subjects), which enables us to draw conclusions from the study that may be applicable to the real-world situation within the wider general population. In addition, the long-term follow-up on the offspring's population, together with the fact that the Soroka University Medical Center is the only tertiary medical center in the South, allows for coordinated followup with a low risk for data loss. This results in a significant advantage, enabling us to obtain high quality and reliable, verifiable research results. Limitations of our research, stem from the retrospective nature of our study, which limits our ability to establish causation, only allowing us to establish proof of association. Therefore, our choice to conduct research based on a retrospective review is a main limitation and drawback of our research. Another variable that needs to be taken into account and may be a disadvantage of our research, is the lack of data on the birth status of infants and the risk of obscuring the association between maternal carrier status and neonatal respiratory disease. To reduce the likelihood of this variable being a confounding variable, we confirmed through the data files of offspring hospitalizations
Author statement I declare that I participated in the design, execution, and analysis of the paper by Yoad Govrin Yehudain and colleagues entitled “Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring”, that I have seen and approved the final version and that it has neither been published nor submitted elsewhere. Acknowledgments Performed in pat of Yoad Govrin Yehudain MD requirements. This study was conducted as part of the requirements for MD degree from the Goldman Medical School at the Faculty of Health Sciences, BenGurion University of the Negev. Funding information This study was not funded. All authors have indicated they have no financial relationships relevant to this article to disclose. Data sharing We have full control of all primary data and agree to allow the journal to review the data if requested. Declaration of competing interest All authors have indicated they have no potential conflicts of interest to disclose. References [1] L.Y. Goh, T. Card, A.W. Fogarty, T.M. McKeever, ScienceDirect, Clin. Microbiol. Newsl. 38 (13) (2016) 109. [2] H. Hartmann, Extrahepatic manifestations of HBV and HCV infection, Praxis 86 (29–30) (1997) 1163–1166 July. [3] A. Safir, A. Levy, E. Sikuler, E. Sheiner, Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome, Liver Int. 30 (5) (2010) 765–770 May. [4] C. Zamir, R. Dagan, D. Zamir, S. Rishpon, D. Fraser, N. Rimon, E. Ben Porath, Evaluation of screening for hepatitis B surface antigen during pregnancy in a population with a high prevalence of hepatitis B surface antigen-positive/hepatitis B e antigen-negative carriers, Pediatr. Infect. Dis. J. 18 (3) (1999) 262–266 Mar. [5] N. Hadzić, Hepatitis C in pregnancy, Arch. Dis. Child. Fetal Neonatal Ed. 84 (3) (May 2001) 201. [6] M.M. Jonas, Hepatitis B and pregnancy: an underestimated issue, Liver Int. 29 (Suppl. 1) (Jan 2009) 133–139 s1. [7] R. Moshkovsky, T. Wainstock, E. Sheiner, D. Landau, A. Walfisch, Elective cesarean delivery at term and the long-term risk for endocrine and metabolic morbidity of the offspring, J. Dev. Orig. Health Dis. (2018) 1–7 December 27. [8] A. Walfisch, O. Beharier, T. Wainstock, R. Sergienko, D. Landau, E. Sheiner, Earlyterm deliveries as an independent risk factor for long-term respiratory morbidity of the offspring, Pediatr. Pulmonol. 52 (2) (2017) 198–204 Feb. [9] I. Asher, N. Pearce, Global burden of asthma among children, Int. J. Tuberc. Lung Dis. 18 (11) (Nov 2014) 1269–1278. [10] V.K. Kapur, Obstructive sleep apnea: diagnosis, epidemiology, and economics, Respir. Care 55 (9) (Sep 2010) 1155.
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Y. Govrin-Yehudain, et al.
[19] S. Ozen, The changing face of polyarteritis nodosa and necrotizing vasculitis, Nat. Rev. Rheumatol. 13 (6) (2017) 381–386 Jun. [20] C. Ferri, M. Sebastiani, D. Giuggioli, M. Cazzato, G. Longombardo, A. Antonelli, R. Puccini, C. Michelassi, A.L. Zignego, Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients, Semin. Arthritis Rheum. 33 (6) (2004) 355–374. [21] V. Laugel, J. Goetz, S. Wolff, J. Beladdale, J. Sibilia, J. Messer, Neonatal management of symptomatic transplacental cryoglobulinaemia, Acta Paediatr. 93 (4) (2004) 556–558. Apr. [22] P. Spagnolo, S. Zeuzem, L. Richeldi, R.M. du Bois, The complex interrelationships between chronic lung and liver disease: a review, J. Viral Hepat. 17 (6) (2010) 381–390 Jun. [23] E. Degasperi, A. Aghemo, P. Lampertico, M. Vigano, M. Colombo, Anti-TNF Drugs in Patients With Hepatitis B or C Virus Infection: Safety and Clinical Management, (2012), pp. 193–207. [24] K. Cronise, S.J. Kelly, Maternal urinary tract infection alters water maze performance in the offspring, Neurotoxicol. Teratol. 23 (4) (2001) 373–379. [25] S. Saito, Cytokine cross-talk between mother and the embryo/placenta, J. Reprod. Immunol. 52 (1) (2001) 15–33. [26] C.J. Bachurski, G.S. Pryhuber, S.W. Glasser, S.E. Kelly, J.A. Whitsett, Tumor necrosis factor-alpha inhibits surfactant protein C gene transcription, J. Biol. Chem. 270 (33) (1995) 19402–19407. August. [27] N. Roldan, E. Goormaghtigh, J. Pérez-Gil, B. Garcia-Alvarez, Palmitoylation as a key factor to modulate SP-c–lipid interactions in lung surfactant membrane multilayers, BBA - Biomembranes 1848 (1) (2015) 184–191 Jan.
[11] J. Li, M.S. Chang, T.T. Tran, M.H. Nguyen, Management of Chronic Hepatitis B in Pregnancy, 51 (2017), p. 9. [12] M.M. Smfm, B.L. Hughes, C.M. Page, J.A. Kuller, Hepatitis C in pregnancy: screening, treatment, and management, Am. J. Obstet. Gynecol. 217 (5) (2017) B2–B12. [13] K. Nahum Sacks, M. Friger, I. Shoham-Vardi, R. Sergienko, E. Spiegel, D. Landau, E. Sheiner, Long-term neuropsychiatric morbidity in children exposed prenatally to preeclampsia, Early Hum. Dev. 130 (2019) 96–100 Mar. [14] C.S. Wu, E.A. Nohr, B.H. Bech, M. Vestergaard, J.M. Catov, J. Olsen, Diseases in Children Born to Mothers With Preeclampsia: A Population-based Sibling Cohort Study, 874 (2011). [15] K. Nahum Sacks, M. Friger, I. Shoham-Vardi, E. Spiegel, R. Sergienko, D. Landau, E. Sheiner, Prenatal exposure to preeclampsia as an independent risk factor for long-term cardiovascular morbidity of the offspring, Pregnancy Hypertension 13 (2018) 181–186. [16] M. Black, S. Bhattacharya, S. Philip, J.E. Norman, D.J. McLernon, Planned cesarean delivery at term and adverse outcomes in childhood health, JAMA 314 (21) (Dec 1 2015) 2271–2279. [17] A. Flores-Chávez, J.A. Carrion, X. Forns, M. Ramos-Casals, Extrahepatic manifestations associated with chronic hepatitis C virus infection, Revista Espanola De Sanidad Penitenciaria 19 (3) (2017) 87–97 Dec. [18] A.M. Saleh, H. Elalfy, M.M. Arafa, N. Abousamra, A. El-Badrawy, M.A. Mohamed, E.A.M.E. Barakat, B.S. El Deek, Association between HCV induced mixed cryoglobulinemia and pulmonary affection: the role of TNF-alpha in the pathogenesis of pulmonary changes, Egypt. J. Chest Dis. Tuberc. 63 (1) (Jan 2014) 259–265.
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