NONG THI TUYENTHE PROPORTION OF MOTHER TO CHILD TRANSMISSION OF HBsAg CARRIER MOTHERS AND THE IMMUNE RESPONSE TO HEPATITIS B VACCINE IN INFANTS IN DINH HOA DISTRICT - THAI NGUYEN Speci
Trang 1NONG THI TUYEN
THE PROPORTION OF MOTHER
TO CHILD TRANSMISSION OF HBsAg CARRIER MOTHERS AND THE IMMUNE RESPONSE TO HEPATITIS B VACCINE IN INFANTS IN DINH HOA
DISTRICT - THAI NGUYEN
Speciality: Internal Digestion Code: 62.72.01.43
Trang 2Thai Nguyen - 2019
The dissertation was completed in:
Thai Nguyen University of Medicine &Pharmacy
Thai Nguyen University
Scientific Supervisors:
1 Assoc Prof, PhD Duong Hong Thai
2 Assoc Prof, PhD Tran Viet Tu
Opponent 1:
Opponent 2:
Opponent 3:
The dissertation will be defended at the Dissertation Committee In National Level held in Thai Nguyen University of Medicine & Phrmacy Time … date …… month……year 20……
The information from this dissertation can be found at:
- National Library ;
- Learning Resource Center - Thai Nguyen University
- Library of Thai Nguyen University of Medicine &Pharmacy
Trang 31 Nong Thi Tuyen, Phung Thi Tuyet Nga, Duong Hong Thai,Hoang Anh Tuan (2016),“ Clinical and paraclinical features ofprenant women with HbsAg (+) at Dinh Hoa district in Thai
Nguyen province”, Viet Nam Medical Journal, No special /449
(2016), pp.188-194
2 Nong Thi Tuyen, Duong Hong Thai, Tran Viet Tu (2018),
“Assessment of immune response after hepatitis B vaccine
injection in infants born to mothers with HBsAg (+)”, Viet Nam Medical Journal, No 2/472 (2018), pp 71-75.
3 Nong Thi Tuyen, Duong Hong Thai, Tran Viet Tu (2018),“Study
on prevalence of HBV in pregnant women and infants withmothers with HBsAg (+) infants in Dinh Hoa district – Thai
Nguyen province”, Viet Nam Medical Journal, No 2/472
(2018), pp.115-118
Trang 5The are 3 common routes of HBV infection: bloodtransfusion, sexual transmission and vertical transmission frommother to child Vertical transmission is mostly observed in peoplewith high HBV DNA load or HBeAg positive In countries with highprevalence of HBsAg (>8%) before the implementation of Expandedprogram on immunization (EPI), HBV infection is mostly throughvertical transmission or household transmission Perinataltransmission is also present in countries with lower HBV prevalencewhere pregnant women are not examined regularly and HBVvaccinated.
In Vietnam, domestic plasma-derived hepatitis B vaccinewas first introduced in the Expanded program on immunization forinfants under 1 years old in some provinces in 1997 By the end of
2001, approximately 370.000 infants had been vaccinated againsthepatitis B, accounted for 25% of infants under 1 years old in thecountry The first dose of hepatitis B vaccine within first 24 hoursafter birth are recommended for all infants according to WHO
However, there are still mother-to-child transmission despite
of adequate hepatitis B vaccination Immune response in infantsdepends on many factors, but hepatitis B vaccination are still themost important measure to prevent vertical transmission In Vietnam,there have been not many studies on the effectiveness of GeneHBvax and Quinvaxem vaccine in infants under 1 years old Theireffectiveness in infants born to HBsAg(+) mothers also needs tostudy more thoroughly as these two vaccine are used extensively inthe Expanded program on immunization
Trang 6Dinh Hoa is a mountainous district of Thai Nguyen province.People in this district are almost from ethnic minorities who havepoor living condition and inadequate knowledge about diseaseprevention including the prevention of HBV vertical transmission Inaddition, the current prevention of HBV vertical transmission includeonly the use of those two vaccine in EPI without any other measure.
Because of those reasons, we conduct the study "Assess the proportion of mother-to-child transmission of HBsAg carrier
mothers and the immune response to hepatitis B vaccine in infants in Dinh Hoa district - Thai Nguyen" for the following
purposes:
1 To determine the prevalence of HBsAg(+) in pregnant women
in Dinh Hoa district - Thai Nguyen during the years 2015 - 2017.
2 To determine the proportion of HBsAg(+) in infants born
to HBsAg(+) mothers in Dinh Hoa district - Thai Nguyen.
3 To assess the post-vaccination immune response after administering 2 vaccine Gene HBvax and Quinvaxem in infants born
Chapter 1 Literature review: 39 pages
Chapter 2 Subjects and method: 25 pages
Chapter 3 Results: 24 pages
Chapter 4 Discussion: 38 pages
Conclusions and recommendations:3 pages
The dissertation has 130 references, including 25 Vietnamese and 105 documents in English The dissertation includes 35 tables and 4 charts, 4 pictures.The appendix includes 4 subappendices with 12 pages
Trang 7Chapter 1: LITERATURE REVIEW
1.1 Overview of Hepatitis B virus
In 1964, Blumberg S.M was found antigen Australia inAustralia aborginical that were transmitted many time blood Afterthat, scientists proved Australia antigen that was surface HBVantigen, international signal was HBsAg (Hepatitis B surface antigen).After 11 years, in 1975, Dane discoveried little corns byelectromicroscopy that had 42nm diameter, they were called Danecorns Afterwards, scientists carried out many studies for HBV anddetermined Dane corns were completed virus corns
1.1.1 Structure of Hepatitis B virus
HBV belongs to Hepadnaviridae, are virus affinity to liverthat AND structure is composed by 3.200 couple of acid nucleotids,weight of molecule are 2 x 106 dalton
1.1.2 Genome of Hepatitis B virus
HBV genotypes caused heterogenerous in clinical signs andtherapy responses in patient with chronic hepatitis B in another areaover the world Up-to-now, there were 10 genotypes of HBV (A-J)that were determined and some another sub-genotypes Thesegenotypes were determined by separating to whole of HBV genotypefamily and distributing distincted geography
1.2 Transmission of Hepatitis B virus
Mode of transmission of HBV are as following:
1.2.1 Transmission by blood transfusion
Before 60s in XX century, because there were not tests ofHBV screening for blood donors, HBV infected proportion of bloodreceiver was over 30%, and patients that had to recurrent bloodtransmission (such as patient with Hemophilia) catched up to 60%infecting HBsAg(+) Since 1970, after blood transmission, HBVprevalence decreased clearly for using HBV screening in serum
1.2.2 Mother to child transmission
Mother to child transmission is a important epidemiccharacteristic in area of high HBV prevalence including Vietnam
Trang 8The transmission can occur in foetus period, in and after delivery Sothat, beside of expand vaccination for kids we had to care aboutvaccination for reproducing women.
1.2.3 Sexual transmission
HBsAg was found in sperm, secreting fluid form vagina, blood frommenopause HBV infiltrated the body into minimal scratching trace byintercourse HBV transmission can occur homosexual intercourse and sexualintercourse
1.2.4 Intra-familial transmission
According to Hà Thị Minh Thi et al showed that prevalence ofpeople with positive HBsAg in the family having at least a person with HBVcatched up to 47.8%
1.3 Clinical manifestations of Hepatitis B
1.3.1.Clinical presentation
Chronic Hepatitis B is hepatitis being made by situation oflong lasting infected HBV Duration of infected HBV is at least 6months and these patients have chronic inflamation and necrosis inliver Chronic Hepatitis B is divided two sorts being positive andnegative HBeAg
1.3.2 Laboratory tests
* AST/ ALT increased high continuously or intermittently in ChronicHepatitis B
* Other tests of liver function also changed if liver was injuried such
as high bilirubin, low albumine, low prothrombine
* Blood cell count: anaemia, low white blood count, decreasingplalete Ultrasound: maybe cirrhosis image Liver biopsy: maybeinjuried liver on histopathology
* There were markers of HBV
1.4 Hepatitis B, pregnancy and newborn infants:
1.4.1 Hepatitis B in pregnancy
Characteristics of acute Hepatitis B in pregnant women: roret clinical sign was jaudice, especially biliruibin icterus with itching.Pregnancy was not increasing of infected HBV
Trang 91.4.2 Pregnancy outcomes of hepatitis B
Affecting to infected acute hepatitis B in pregnant womenand foetus were abortion, prematurity, stillbirths, acute hepatitis ininfant, cirrhosis but it was not made congenital defects
1.4.3 Hepatitis B in newborn infants
Hepatitis B in newborn infants usually was serious andincluded three sorts such as urgent, acute, semi-acute disease
1.5 Hepatitis B vaccine
1.5.1 First-generation hapatitis B vaccine
The First-generation hepatitis B vaccine was produced fromplasma of people with chronic HBsAg The vaccine was found the firsttime in France and the USA and was used broadly from 1981 to 1982
1.5.2 Second-generation hapatitis B vaccine
The second-generation hapatitis B vaccine was studied at theend of 70s In 1986 this vaccine was proceduced the first time in theUSA There was a vaccine recombination ADN that displayed Sgenotype to code for surface antigen HBsAg on cellulars of yeast, orbiocellular of mammals to start-up HBsAg synthetic process
1.5.3 Third-generation hapatitis B vaccine
The third-generation hapatitis B vaccine was a vaccine oforigin of S, Pre S1 and S2 genotype of HBV, its immune responsemaking better There were two surface protein including Pre S1 andPre S2 that had important role to stimulate T-help making anti-HBs
1.6 Immune response to hepatitis B vaccine in infants under 1 years old
1.6.1 The implementation of hepatitis B vaccination in Vietnam national program on immunization
On 18th August 1997, The Prime Minister officially approved toallow developing hepatitis B vaccine in national expand vaccinationprogram Pilot deployment of hepatitis B vaccine was applied in Hà Nộicity and Hồ Chí Minh city In 2003, 100% villages in the nation carriedour hepatitis B vaccine for 1.500.113 infants under 1 years old
1.6.2 Hepatitis B vaccination schedule
Today, almost of cases, we used hepatitis B vaccinationschedule as following 0 - 1 - 6 or 0 - 1 - 2 - 12
Trang 101.6.3 Post-vaccination immune response
Children was called received immune response with hepatitis
B vaccine if test of anti HBs was ≥ 10 mUI/ml in post-vaccination.These children had anti-HBs protection, it means they can preventfrom infecting HBV in the future
1.6.4 Factors affecting immune response
There were many studies in children (including infants ofpregnant women with chronic HBV) showed that, there was a bigchanging for post-vaccination immune response after hepatitis Bvaccine for many affecting factors to make immune after thisvaccination
1.7 Effectiveness of hepatitis B vaccination coverage in expanded program on immunization
Annually, many nations over the world have to inform theirvaccination schedule and estimated its fee thông qua WHO andUNICEF According to UNICEF, up to 2016, there were 101 nations(accounted for 52% of 194 nations being members of WHO) hadpolicy of hepatitis B vaccine management for all infants
1.8 Indication and contraindication of hepatitis B vaccination in Vietnam
Up-to-now, all children and people under 18 years old havenot had injected hepatitis B vaccine will be indicated this vaccine.Hepatitis B vaccine also used for high risk infected HBV
Hepatitis B vaccine was not used for people having allergy tohepatitis B vaccine No contra-indication for pregnant women or
Trang 11positive with HBsAg qick test and were confirmed by HBsAg ELISAtest These women were explained the study and agreed to join.
+ Inclusion criteria: Pregnant women came to give birth at Dinh Hoa
General Hospital, had normal course of pregnancy, family registration
in Dinh Hoa, T.hai Nguyen and had clear address
+ Exclusion criteria: Women who were co-infected with HCV, HIV;
women who had severe toxemia of pregnancy, gestational diabetes;women who were administered antiviral drugs during pregnancy;women who refused to join the study
Among 3818 pregnant women came to the hospital duringthat time, 239 women were positive to HBsAg quick test, 129 out of
239 HBsAg(+) women were unable to take blood samples or refused
to join the study, so the number of subjects was 110
* Newborn infants
+ Inclusion criteria: Infants whose mother was infected
with HBV and had HBsAg(+); no congenital heart disease orother congenital defect was discovered after birth; had adequatedoses of EPI hepatitis B by 6 months old, no asphyxia after birth
+ Exclusion criteria: Infants who were not taken blood
sample after vaccination or their family refused to join the study
110 newborn infants were enrolled to population-basedtrial on vaccination and were assessed immune response at 6months old However, 8 infants were not taken blood samplewhen they were 6 months old because they did not have adequatedoses of vaccination, some infants migrated out of the district
So the number of infants in the trial was 102
* Time and place: from 4/2015 to 6/2017.
* Population-based trial
Trang 122.2.2 Sample size
* Sample size for objective 1: all the pregnant women givingbirth at Dinh Hoa General Hospital in the period from 4/2015 to6/2017, who had family registration in Dinh Hoa district, ThaiNguyen
* Sample size for objective 2 and 3:
α = 0,05 probability of type 1 error
From the formula: n = 97 We estimated that up to 10% of the subjectmight drop out, so the minimal sample size was 110
2.3 Conducting research steps
-Step 1: Selecting a research objects
-Step 2: Explaining and consulting the benefits of
participating in research to pregmant women
-Step 3: Setting up a research case-record
-Step 4: Taking the pregnant women’s blood in labor
-Step 5: Taking blood from the newborns’ umbilical cord -Step 6: Vaccinating the newborns with Gene HBvax -Step 7: Injecting vaccine Quinvasee to infants of 2, 3, 4 months old
-Step 8: Taking blood from 6-month-old infants
-Step 9: Analysing results and completing the thesis
2.4 Variables, indexes and methods of collection
* General information in study group
- Age of pregnant women: Being divided three groups asfollowing: < 18 years old; From 18 – 35 years old; > 35 years old
- Occupation: Being divided three groups as following:Farmer; Civil servant; other
Trang 13- Ethnic: Being divided five groups as following: Kinh;Tay; San chi; Nung; other ethnic.
Mode of delivery: Being divided three groups as following:
- Normal labour; C-section; Vaginal delivery withepisiotomy
- Young genders: Being divided two groups as following:Male and female
- Birthweight of neonata: Being divided four groups as following(unit by gram): < 2500gr; 2500 - < 3000gr; 3000-3500gr; ≥ 3500gr
Author or doctor in Department of gynecology in Dinh HoaGeneral Hospital: examination, medical record and taking note study record
* Prevalence of HBsAg in pregnant women in Dinh Hoa district, Thai Nguyen
- HBsAg Marker in plasma in pregnant mother: Beingdivided two groups as following: Positive and negative HBsAg The
1st step: Quick test in all pregnant mother who give birth in deparment ofobstetrics in Dinh Hoa general hospital The 2nd step: ELISA test in Center
of Hematology, Thai Nguyen central hospital
- Number of years since diagnosis of HBV infection: Beingdivided four groups as following: under 5 years; 5 – 10 years; over
10 years; no information Author or doctor in Department ofgynecology in Dinh Hoa General Hospital: examination, medicalrecord and taking note study record
- HBeAg Marker in plasma in pregnant mother: Beingdivided two groups as following: HBeAg(+); HBeAg(-).Quick test inall pregnant mother with positive HbsAg in deparment of obstetrics inDinh Hoa general hospital
- HBV DNA load in plasma in pregnant mother: Beingdivided four groups as following: (unit by copies/ml): < 3x102;From 3x102 to < 103; From 103 to < 104; From 104 to < 105; From
Trang 14* Post-vaccination immune response in infants born to HBsAg positive mothers
- HBsAg marker in infants under 6 months old: Beingdivided two groups as following: Positive and negative HBsAg.Umbilical cord blood test by ELISA for 6-month-old infants who wereinjected enough HBV vaccine in Center of Hematology, Thai Nguyencentral hospital
- Anti HBs marker in infants under 6 months old: Beingdivided three groups as following: Anti HBs < 10(mIU/ml); From 10
to 100(mIU/ml); Anti HBs > 100(mIU/ml) Umbilical cord blood test
by ECLIA for 6-month-old infants, in Center of Hematology, ThaiNguyen central hospital
2.5 Data collection techniques
2.5.1 Clinical examination
All pregnant mother who give birth in deparment of obstetrics,
in Dinh Hoa general hospital were examinated, taken note study andmedical record by author or doctor in here The mothers with toxaemiapregnancy, pregnant diabetes were excluded the study
As soon as being delivery, infants were exminated carefully.The infans had unusual signs such as congetinal defect, congenitalheart defect, circulator and breathing failure were excluded the study
2.5.2 Hepatitis B vaccination
- Neonatas that were selected in the study were injected one GeneHbvax vaccine by mid-wife, taking note to HBV vaccination book inDepartment of Obstetrics, in Dinh Hoa general hospital
- The infants in the study were injected 1st, 2nd, 3rd Quinvaxemvaccine in turn at 2-month-old, 3-month old and 4-month-old time atmedical station where the infants lived
2.5.3 Laboratory tests
2.5.3.1 For mothers: HBsAg test (quick test); anti HCV test
(quick test); anti HIV test (quick test); HbsAg test (ELISA);HBeAg (quick test); HBV DNA test
2.5.3.2 For infants: HbsAg test (ELISA) at neonatas by umbilical
cord blood; HbsAg test (ELISA) by vein in 6 –month-old infant;anti HBs test by ECLIA in 6–month-old infant