Hepatitis B Kronik pada Kehamilan :

Tata Laksana dan Pencegahan Transmisi

Vertikal

Pokja Infeksi Sistem Reproduksi

Perkumpulan Obstetri dan Ginekologi Indonesia (POGI)
2019
 Virus Hepatitis B
• Virus DNA
• 350-400 juta manusia di dunia
• Angka mortalitas di dunia mencapai
1 juta akibat sirosis, gagal hati dan
karsinoma hepatoselular (KHS)
• Transmisi melalui seksual,
perkutaneus dan perinatal
• Terdiri atas 3 bagian :
- Protein envelope (HBsAg)
- Protein nukleokapsid inti (HBcAg)
- Protein nukleokapsid soluble
(HBeAg) : menandakan replikasi

Dienstag JL. Hepatitis B Virus Infection. N Engl J Med. 2008;359:1486-500

 Nomenclature of the hepatitis viruses,
antigens, and antibodies 5 Hepatitis
Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

Family Picornaviridae Hepadnaviridae Flaviviridae Unclassified Unclassified 

Genus Hepatovirus  Orthohepadnavirus  Hepacivirus  Deltavirus  Hepevirus 

27 nm, 30–32 nm,
Virion icosahedral 42 nm, spherical 60 nm, spherical 35 nm, spherical icosahedral
Envelope No Yes (HBsAg) Yes Yes (HBsAg) No

Genome ssRNA dsDNA ssRNA ssRNA ssRNA

Genome size 7.5 kb 3.2 kb 9.4 kb 1.7 kb 7.6 kb

Heat- and acid- Ether-sensitive,
Stability Acid-sensitive Acid-sensitive Heat-stable
stable acid-sensitive
Transmission Fecal-oral Parenteral Parenteral Parenteral Fecal-oral

Prevalence High High Moderate Low, regional Regional

Fulminant disease Rare Rare Rare Frequent In pregnancy

Chronic disease Never Often Often Often Never

Oncogenic No Yes Yes ? No

Butel JS. Hepatitis Viruses. In: Brooks GF, Carroll KC, Butel JS, Morse SA, editors. Jawetz, Melnick, & Adelberg's Medical Microbiology. 24th ed:
The McGraw-Hill Companies, Inc.; 2007
 Epidemiologi Hepatitis B di Dunia

Shephard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B Virus Infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112-25
 Reduction of the HBsAg carriage rate in endemic
countries after introduction of vaccination

Pol S, Corouge M, Fontaine H. Hepatitis B virus infection and pregnancy. Clin Res Hepatol Gastroenterol.
2011 Oct;35(10)618-22
 Transmisi Hepatitis B

Shephard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B Virus Infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112-25
 Hepatitis in pregnancy
Hepatitis
Mechanism of Best Carrier Perinatal
Infection Diagnostic Test State Transmission Vaccine Remarks
Transmission
Antibody Passive immunization
A Fecal–oral detection No No Yes with immunoglobulin
Antibody High maternal
E Fecal–oral No Rare No mortality in developing
detection countries
Passive immunization
Parenteral/ Antigen detection
B sexual contact Yes Yes Yes with hepatitis B
immunoglobulin
Prevented Virus cannot replicate
Parenteral/ Antibody by
D Yes Yes in absence of hepatitis
sexual contact detection hepatitis B B infection
vaccine
Cesarean delivery for
Parenteral/ Antibody women with
C sexual contact detection Yes Yes No detectable serum HCV-
RNA
G Parenteral/ Antibody Yes Yes No No clinical significance
sexual contact detection of infection

Duff P. Hepatitis in pregnancy. In: Queenan JT, Spong CY, Lockwood CJ, editors. Management of High-Risk Pregnancy : An Evidence-Based
Approach. 5th ed. Massachusetts: Blackwell Publishing Ltd; 2007. p. 238-41.
 Hepatitis B Akut dan Kronik

• Hepatitis B akut bersifat self-limiting

• Hanya 5-10% yang berkembang menjadi Hepatitis B Kronik
• Hanya 1% yang berkomplikasi menjadi gagal hati akut

Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49(5):13-21

 Perjalanan Alamiah Hepatitis B Kronik

MchMahon BJ. Natural history of chronic hepatitis B-clinical implications. Medscape J Med. 2008;10(4):91
 Phases of disease in chronic hepatitis B
  Phase 1 Phase 2 Phase 3 Phase 4
Immune tolerance Immune clearance Immune control Immune escape
HBeAg positive HBeAg positive HBeAg negative HBeAg negative
Serology
HBeAb negative HBeAb negative HBeAb positive HBeAb positive
ALT (IU/mL) Persistently normal Persistently or Persistently normal
intermittently abnormal  
Persistently or
intermittently abnormal
HBV DNA Very high (usually > High but less so than in < 2000 IU/mL (but up > 2000 IU/mL
(IU/mL) 2 × 106-2 × 107) Immune tolerant phase to 20000 IU/mL) (fluctuating)
Normal or mild Moderate or severe Normal or mild Moderate to severe
Liver hepatitis necroinflammation and inflammation inflammation and fibrosis
histology
fibrosis   ± cirrhosis
Age usually young Intermittent flares or May have serum Predominance of HBV
Specific (< 20-30 yr). Phase ongoing mild elevation HBsAg levels < 1000 with precore/basal core
features absent or very of ALT. Ends with IU/mL promotor mutations
short in seroconversion to    
Mediterranean CHB HBeAb positive state  
Immunotolerant HBeAg positive immune Inactive HBsAg carrier HBeAg negative CHB
Alternative   active (AASLD)/immune state (EASL and (EASL)/ reactivation or
nomencla-   reactive HBeAg positive AASLD)/residual or relapse (APASL)
ture phase (EASL) inactive chronic HBV  
infection (APASL)

Croagh CM, Lubel JS. Natural history of chronic hepatitis B: phases in a complex relationship. World J Gastroenterol.
2014;20(30):10395-404.
 Phases of disease in chronic hepatitis B
Pattern of Geographical Percent of Predominant age Predominant
prevalence area population at infection mode of
HBsAg positive transmission
High ≥ 8% Southeast Asia, 8%-20% Perinatal and early Maternal-infant,
China, Pacific childhood percutaneous
Islands, (e.g.,
  Sub- Saharan     unsterile medical
Africa equipment used
in vac-
        cination,
traditional
medicine
practices)
Intermediate Eastern Europe, 2%-7% Early Percutaneous
the childhood/adolesce (e.g., horizontal
Mediterranean nce transmis-
2%-7% basin, Middle     sion between
East, Central and children through
open
Croagh CM, Lubel JS. Natural history of chronic hepatitis B: phases in a complex relationship. World J Gastroenterol.
2014;20(30):10395-404.
 Natural history of perinatally acquired chronic
hepatitis B virus infection.

Shih C. Chronic Hepatitis B and C: Basic Science to Clinical Applications. Singapore: World Scientific Publishing Company;
2013.
 Perjalanan Alamiah Hepatitis B Kronik

McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49(5 Suppl):S45-55.
 Natural evolution and phases of chronic hepatitis B in a person
with perinatal or early-life acquisition of the infection.

Natural evolution and phases of chronic hepatitis B in a person with perinatal or early-life acquisition of the infection. The four phases are
designated the immune tolerant phase, immune clearance phase, inactive carrier state, and reactivation phase, as determined by biochemical,
virologic, and histologic activity of the disease. In some patients, hepatitis B e antigen (HBeAg) seroconversion to antibody to HBeAg (anti-HBe) is
followed by the selection of precore and/or core promoter mutant forms of HBV and continuing hepatitis. This evolution generally occurs after
several decades of infection and accounts for the frequent occurrence of active HBeAg-negative hepatitis in middle age. At this point, some patients
may have high-normal or slightly elevated serum ALT levels despite having significant underlying fibrosis and inflammation. These patients are not
in the immune tolerant phase but instead should be considered to be in the immune clearance phase with mild disease. Ultimately, prolonged
histologic activity (necroinflammation) leads to cirrhosis in at least 20% of patients; cirrhosis, in turn, as well as ongoing necroinflammatory activity
in the liver, can result in hepatocellular carcinoma. The optimal times for antiviral therapy are during the immune clearance and reactivation phases
Perrillo R. Hepatitis B and D. In: Feldman M, Friedman LS, editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease-
Pathophysiology/Diagnosis/Management. 9th ed. Philadelphia: Suanders Elsevier; 2010
 Annual rates of liver disease progression
in hepatitis B virus carriers

Kao J-H. Role of viral factors in the natural course and therapy of chronic hepatitis B. Hepatol Int. 2007;1:415–30
 Fig. 2

Journal of Hepatology 2003 39, 3-25DOI: (10.1016/S0168-8278(03)00378-7)

 Natural course of chronic hepatitis B virus (HBV)
infection acquired perinatally and during infancy
The reactivion phase is similar in
every aspect to the immune-
clearance-phase, except for
HBeAg status. Adult-acquired
infection usually presents in the
immune-clearance or
reactivation phase (inset). The
events during the immune-
clearance and reactivation
phases could lead to cirrhosis
and hepatocellular carcinoma
(HCC) (adapted from Liaw21
with permission).
HBeAg=hepatitis B e antigen;
antiHBe=hepatitis B e antigen
antibody; pre C=pre core;
BCP=basal core promoter;
ALT=serum alanine
aminotransferase

Liaw Y-F, Chu C-M. Hepatitis B virus infection. Lancet. 2009 February 14, 2009;373:582-92.
Hepatitis B virus (HBV) replication and the outcomes
of chronic Hepatitis B infection

Note that Hepatitis B e antigen (HBeAg) seroconversion is followed by remission in most people but that HBeAg-
negative (–) hepatitis (HBV-DNA ≥ 2x103–2x10⁴ IU/mL) may develop. Patients who remain HBeAg seropositive or
develop HBeAg-negative hepatitis have a high occurrence of cirrhosis (~4 and ~3% per year). Most hepatocellular
carcinoma (HCC) develops in patients who have cirrhosis.
Liaw Y-F, Chu C-M. Hepatitis B virus infection. Lancet. 2009 February 14, 2009;373:582-92.
 Adjusted relative risks of cirrhosis in 3,582 hepatitis B
virus carriers stratified by baseline serum HBV DNA
levels in a population based prospective cohort study

Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting liver cirrhosis risk based on the level of circulating hepatitis B viral
load. Gastroenterology 2006;130:678–86
Kao J-H. Role of viral factors in the natural course and therapy of chronic hepatitis B. Hepatol Int. 2007;1:415–30
Hepatitis B Kronik pada Kehamilan
 Prevalensi Transmisi Hepatitis B di Eropa Tahun
2006-2012

Transmisi vertikal dari ibu ke anak menempati porsi

terbesar dalam transmisi Hepatitis B kronik

Duffell EF, Laar MJW, Amato-Gauci AJ. Enhanced surveillance of hepatits B in the EU, 2006-2012. Journal of Viral Hepatitis. 2015;22:581-89.
 Komplikasi Hepatitis B pada Kehamilan

Semakin muda usia saat terinfeksi, maka semakin tinggi

risiko Hepatitis B kronik

World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015.
Perjalanan Hepatitis B Kronik
 Manifestasi Hepatitis B pada Kehamilan

Hepatitis B
Akut

 Sering asimptomatik
Hepatitis B  Gejala yang dapat muncul adalah tanda-
tanda sirosis
Kronik  Perlunya deteksi dini

Tan YT, Sun C, Liu CX, Xie SS, Xiao D, Liu L, Yu JH, et al. Clinical features and outcome of acute hepatits B in pregnancy. BMC Infectious
Disease. 2014;14:368
 Deteksi Awal Infeksi Hepatitis B Kronik

Seluruh ibu hamil diperiksakan nilai HBsAg pada awal dan

trimester ketiga kehamilan

MchMahon BJ. Natural history of chronic hepatitis B-clinical implications. Medscape J Med. 2008;10(4):91
 Anamnesis pada Pasien dengan
HBsAg Positif

Tanda dan Gejala Sirosis Faktor Risiko Metabolik

Status Vaksinasi Hep B Riwayat KHS di keluarga

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
Tanda dan Gejala
Sirosis

Jaringan Hati Normal

Jaringan Sirosis Hati

 Faktor Risiko Metabolik

Lingkar Pinggang
• Asia : ≥ 90 cm (laki-laki) dan 80 cm
(perempuan)
• Eropa : ≥ 94 cm (laki-laki) dan 80 cm
(perempuan)

• Gula Darah Puasa (GDP) ≥ 100 mg/dL

• Sedang menjalani pengobatan untuk
DM Tipe 2

EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016
 Faktor Risiko Metabolik

• Tekanan darah ≥ 130/85 mmHg

• Sedang menjalani pengobatan untuk
hipertensi

• Kadar triasilglieserol > 150 mg/dL

• Kadar kolesterol HDL < 40 mg/dL
(pria) dan < 50 mg/dL (wanita)

EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016
 Pemeriksaan Laboratorium pada
Pasien dengan HBsAg Positif

Laboratorium Rutin Serologi/Virologi

• Darah Perifer Lengkap

(DPL) • HBeAg / anti-Hbe
• SGOT/SGPT • Kadar DNA-VHB
• Bilirubin total • Anti-HCV
• Alkaline fosfatase • Anti-HIV disarankan
• Albumin bagi mereka yang tidak
• Nilai INR pernah screening
• Alpha Feto Protein (AFP) sebelumnya
• Gamma GT

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Pemeriksaan Pencitraan pada
Pasien dengan HBsAg Positif

USG Abdominal

FibroScan

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Penegakkan Diagnosis Hepatitis B Kronik
pada Kehamilan

HBsAg positif selama 6 bulan

Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al. Asian-Pacific clinical practices guidelines on the management of hepatitis B:
a 2015 updated. Hepatol Int. 2016;10:1-98
 Faktor Risiko Infeksi VHB
• Multiple sexual partners
• Penggunaan obat intravena menggunakan jarum tidak steril
• Kontak dengan pasien yang terinfeksi atau pasien karier
hepatitis B kronik

Faktor Risiko Transmisi VHB

Faktor yang meningkatkan risiko transmisi :
• Status HBeAg (+) pada ibu
• Kadar DNA-VHB pada ibu (>200.000 IU/mL)

1. Tran TT, Ahn J, Reau NS. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016.
2. Borgia G, Carleo MA, Gaeta GB, Gentile I. Hepatitis B in pregnancy. World J Gastroenterol. 2012;18(34):4677-83
 Prevalensi HBeAg pada HBsAg Positif

Prevalensi HBeAg pada HBsAg positif tinggi pada perempuan < 30 tahun
(usia reproduksi)  risiko transmisi Hep B meningkat

Ott JJ, Stevens GA, Wiersma ST. The risk of perinatal hepatitis B virus transmission: hepatitis B e antigen (HBeAg) prevalence estimates for
all world regions. BMC Infectious Diseases. 2012;12:131
 Algoritma Diagnosis Hepatitis B pada Kehamilan

Pemeriksaan Awal Ibu Hamil :

Uji Hati Abnormal

Profil hepatoselular: AST/ALT Profil bilier: bilirubin/alkalin fosfatase

Eksklusi : Bilirubin ±
• IgM anti Alk.fosfatase ↑
• Hepatitis Viral alk.fosfatase ↑
HAV
• Infeksi Herpes
• HBsAg
• Penggunaan
• Anti HCV
obat-obatan Pencitraan Tidak ada
bilier follow up

Tidak ada bukti obstruksi

Tran TT, Ahn J, Reau NS. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016
 Perubahan Fisiologis selama Kehamilan

Tran TT, Ahn J, Reau NS. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016
 Algoritma Diagnosis Hepatitis B pada Kehamilan

Borgia G, Carleo MA, Gaeta GB, Gentile I. Hepatitis B in pregnancy. World J Gastroenterol. 2012;18(34):4677-83
 Definisi Transmisi Vertikal VHB

HbsAg atau DNA-VHB positif selama 6-12 bulan pertama

kehidupan pada bayi yang lahir dari ibu terinfeksi VHB

Gentile I, Borgia G. Vertical transmission of hepatitis B virus: challenges and solutions. InternationalJournal of Women’s Health. 2014;6:605-11
 HbsAg dan DNA-VHB (+) saat lahir :
- Sering hanya bersifat sementara (fenomena transien)
- Tidak menggambarkan transmisi

Papaevangelou V. Perinatal HBV Viremia in Newborns of HbsAg(+) mothers is a transient phenomenon that does not necessarily imply HBV
infection transmission. Journal of Clinical Virology. 2012; 54:202
 Anti Hbe dan anti Hbc (+) dari lahir hingga usia 2 tahun:
tidak berhubungan dengan infeksi VHB kronik

Karena anti-Hbe dan anti-Hbc

didapat dari ibuku melalui
plasenta

Papaevangelou V. Perinatal HBV Viremia in Newborns of HbsAg(+) mothers is a transient phenomenon that does not necessarily imply HBV
infection transmission. Journal of Clinical Virology. 2012; 54:202
 Tata Laksana Hepatitis B dan Pencegahan
Transmisi Vertikal

Pemberian Antiviral pada Ibu Hamil Vaksin Hepatitis B dan HBIg

Proses Kelahiran
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Indikasi Pemberian Antiviral pada Ibu Hamil

HbsAg (+)
Pemberian Antiviral
DNA-VHB > 200.000 U

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Penentuan Waktu Pemberian Antiviral

Pemberian Antiviral mulai diberikan pada

usia kehamilan 28-32 minggu

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Penghentian Pemberian Antiviral

Antiviral dihentikan

Pregnancy 3 bulan Setiap 3- 6 bulan

Pantau AST

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Pengaruh Antiviral terhadap Menyusui

Bukan
Kontraindikasi

Antiviral dieksresikan dalam ASI, namun belum ditemukan

adanya bukti toksisitas yang siginifikan

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Pemilihan Antiviral pada VHB Kronik

Telbivudine dan tenofovir

relatif aman untuk ibu hamil

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Rekomendasi AASLD 2015

Ibu hamil dengan

HbsAg (+) dan DNA-VHB ≤ 200.000 U
tidak disarankan untuk diberikan
antiviral

Benefit

Risk

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Immunoprofilaksis

• Vaksin Hepatitis B paling baik diberikan dalam waktu 12 jam

setelah lahir
• Hepatitis Immunoglobulin (HBIg) diberikan pada ekstremitas
yang berbeda
• Kombinasi vaksin dan Ig menurunkan risiko transmisi vertikal
dari >90% menjadi <10%

1. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
2. Rekomendasi Ikatan Dokter Anak Indonesia (IDAI). Jadwal Imunisasi Anak Umur 0-18 Tahun. 2014.
 Kegagalan Immunoprofilaksis

Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive
mothers. Journal of Viral Hepatitis. 2012.
 Per Vaginam atau Sectio Caesaria ?

Rekomendasi 8A

9. Seksio caesaria tidak diindikasikan dikarenakan kurangnya data dan

mempertimbangkan risk-benefit dari SC dibandingkan pervaginam.

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology. 2015: 1-23.
 Per Vaginam atau Sectio Caesaria ?
Meta-analisis Risiko Transmisi VHB pada section caesaria vs per vaginam

Chang MS, Gavini S, Andrade PC, Baltar JM. Caesarian section to prevent transmission of hepatits B: a meta-analysis. Can J
Gastroenterol Hepatol. 2014:28(8):439-44
 Peran Dokter Umum dalam Penanganan
Hepatitis B pada Ibu Hamil

Konsil Kedokteran Indonesia. Standar Kompetensi Dokter Indonesia. Edisi Kedua. 2012
 Peran Dokter Umum dalam Penanganan
Hepatitis B pada Ibu Hamil

Konsil Kedokteran Indonesia. Standar Kompetensi Dokter Indonesia. Edisi Kedua. 2012
 KEPUTUSAN MENTERI KESEHATAN REPUBLIK INDONESIA
NOMOR HK.02.02/MENKES/514/2015 TENTANG PANDUAN
PRAKTIK KLINIS BAGI DOKTER DI FASILITAS PELAYANAN
KESEHATAN TINGKAT PERTAMA
 Comparison of safety and efficacy of lamivudine,
entecavir, telbivudine, and tenofovir in pregnant women
with CHB.

Tavakolpour S, Darvishi M, Mirsafaei HS, Ghasemiadl M. Nucleoside/nucleotide analogues in the treatment of chronic
hepatitis B infection during pregnancy: a systematic review. Infect Dis (Lond). 2018;50(2):95-106.
 Grading and Staging of Acute Chorioamnionitis
Diagnostic Category
Maternal Inflammatory Response
Stage (Location)
1 (Early)
2 (Intermediate)
3 (Advanced)
Grade (Severity)
1 (Mild to moderate)
2 (Severe)
Fetal Inflammatory Response
Stage
1 (Early)
2 (Intermediate)
3 (Advanced)
Grade
1 (Mild to moderate)
2 (Severe)
Roberts DJ. Perinatal Infections. Diagnostic Pathology of Infectious Disease2018. p. 489-506.
Definition
Neutrophils in subchorionic fibrin, in chorionic plate, or
in chorionic epithelial layer of membranes
Neutrophils within chorionic or amnionic mesoderm
Stage 2 plus necrosis of amnionic epithelium and/or
neutrophils
Anything less than severe (grade 2)
Confluent or more than three foci ≥200 cells
Fetal inflammatory cells within chorionic plate vessel
walls or umbilical vein vessel wall or both
Fetal inflammatory cells within umbilical arteries ± vein
Necrotizing funisitis
Not severe (grade 2)
Confluent fetal inflammatory cells with
attenuation/degeneration of smooth muscle
 Antivirals for HBV vertical transmission in pregnancy

Antivirals used for vertical transmission prophylaxis, Food and Drug Administration
pregnancy categories, usual regimen, and additional information

Wong F, Pai R, Van Schalkwyk J, Yoshida EM. Hepatitis B in pregnancy: a concise review of neonatal vertical transmission
and antiviral prophylaxis. Ann Hepatol. 2014;13(2):187-95.
 Antivirals for HBV vertical transmission in pregnancy

Pregnancy
Antiviral Usual regimen Comments
category
100 mg/day at 28 weeks Most studied drug
Lamivudine C gestation to 1 month post High rate of HBV
partum. resistance.
600mg/day at 28 weeks Moderate rate of HBV
Telbivudine B gestation to 1 month post resistance.
partum.
300 mg/day at 28 weeks No reported resistance.
Tenofovir B gestation to 1 month post More research needed for
partum. further characterization.

Antivirals used for vertical transmission prophylaxis, Food and Drug Administration
pregnancy categories, usual regimen, and additional information
Wong F, Pai R, Van Schalkwyk J, Yoshida EM. Hepatitis B in pregnancy: a concise review of neonatal vertical transmission
and antiviral prophylaxis. Ann Hepatol. 2014;13(2):187-95.
 Antivirals for HBV vertical transmission in pregnancy

Antiviral Pregnancy Usual regimen Comments

category
100 mg/day at 28 weeks Most studied drug
Lamivudine C gestation to 1 month post High rate of HBV
partum. resistance.
600mg/day at 28 weeks
Moderate rate of HBV
Telbivudine B gestation to 1 month post resistance.
partum.
300 mg/day at 28 weeks No reported resistance.
Tenofovir B gestation to 1 month post More research needed for
partum. further characterization.

Antivirals used for vertical transmission prophylaxis, Food and Drug Administration
pregnancy categories, usual regimen, and additional information
Wong F, Pai R, Van Schalkwyk J, Yoshida EM. Hepatitis B in pregnancy: a concise review of neonatal vertical transmission
and antiviral prophylaxis. Ann Hepatol. 2014;13(2):187-95.
 Serologic response to acute hepatitis B Virus

Rac MW, Sheffield JS. Prevention and management of viral hepatitis in pregnancy. Obstet Gynecol Clin North Am.
2014;41(4):573-92.
 Interpretation of serologic test results for hepatitis B
virus

Abbreviations: Anti-HBc, antibody to hepatitis B core antigen; Anti-HBs, antibody to

HBsAg; HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.
Adapted from Centers for Disease Control and Prevention. Sexually transmitted disease
treatment guidelines 2010. MMWR Recomm Rep 2010;59(RR-12):1–110.

Rac MW, Sheffield JS. Prevention and management of viral hepatitis in pregnancy. Obstet Gynecol Clin North Am.
2014;41(4):573-92.
 Management of hepatitis B–positive mothers during
pregnancy

Degli Esposti S, Shah D. Hepatitis B in pregnancy: challenges and treatment. Gastroenterol Clin North Am. 2011;40(2):355-
72, viii.
 Birth defects associated with antiviral exposure
Antiviral Agent FDA Pregnancy Live Births Prevalence Birth
Category Earliest Exposure Defects (95% CI)
6 first trimester 0
Telbivudine B
8 second trimester 0
20 first trimester 1
Entecavir C
2 second trimester 0
3754 first trimester 3.0% (CI, 2.5%, 3.6%)
Lamivudine C
6080 second trimester 2.7% (CI, 2.3%, 3.2%)
981 first trimester 2.5 (CI, 1.6%, 3.7%)
Tenofovir B
584 second trimester 2.2 (CI, 1.2%, 3.8%)
39 first trimester 0
Adefovir C
0 second trimester 0

Degli Esposti S, Shah D. Hepatitis B in pregnancy: challenges and treatment. Gastroenterol Clin North Am. 2011;40(2):355-
72, viii.
 Comparison of safety and efficacy of lamivudine, entecavir,
telbivudine, and tenofovir in pregnant women with CHB
Nucleos(t)ide FDA Resistance rate in Number of found
analogue Category the literature studies/patients Safety Effectiveness Recommendation
LAM B High 17/794 Safe, but Effective Better to be started at the
(lamivudine) with a risk of last trimester of pregnancy to
resistance minimize the risk of
resistance. Breastfeeding
during the treatment should
be avoided.
ETV C Low 2/11 No enough Effective Using a category B drug is
(entecavir) evidence suggested. Breastfeeding
during the treatment should
be avoided.
LdT B Low 15/2338 Fairly safe Very effective Foetus/infants should be
(telbivudine) monitored for any side
effects and abnormalities.
Breastfeeding during the
treatment should be avoided.

TDF B Not reported 12/731 Safe in both Very effective In patients who develop HBV
(tenofovir) typical antiviral drug resistance could
and drug- be employed safely.
resistant Mothers and infants
patients monitored for possible
adverse events.

Tavakolpour S, Darvishi M, Mirsafaei HS, Ghasemiadl M. Nucleoside/nucleotide analogues in the treatment of chronic
hepatitis B infection during pregnancy: a systematic review. Infect Dis (Lond). 2018;50(2):95-106
 Diagnosis of hepatitis B
Serologic markers Clinical significance
HBcAb IgM (Hepatitis B core Acute infection
antibody IgM
HBeAg (Hepatitis B e antigen) High infectivity
HBeAb (Hepatitis B e antibody) Low infectivity
HBsAb (Hepatitis B surface antibody)
Immunity
HBcAb IgG and HBsAg Chronic infection
HBcAb IgG and HBsAb Resolved infection
HBV DNA level (May be undetectable Acute or chronic infection
in chronic inactive HBV infection)

Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J
Perinatol. 2014;34(12):882-91.
 Pregnancy outcomes with HBV
and HCV
HBV and HCV HCV
• Preterm birth • Cholestasis of
• Low birth weight pregnancy
• Premature rupture of • NICU admission
membranes • Neonatal abstinence
• Gestational diabetes syndrome
• Possible small increase in
congenital anomalies

Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J
Perinatol. 2014;34(12):882-91.
 Phases of chronic HBV infection

Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J
Perinatol. 2014;34(12):882-91.
 Pregnant women with HBV DNA levels >200 000 IU ml− 1 (>6 log10 copies ml− 1), or any
HBsAg-positive woman with a threatened abortion, are at high risk for MTCT and should
receive antiviral treatment in the third trimester.
Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J
Perinatol. 2014;34(12):882-91.
 European Association for Study of the Liver (EASL)
recommendation for antiviral therapy for HBV-infected
women who desire pregnancy
• Mild liver disease, low viremia (chronic inactive HBV)
→Pregnancy before treatment
• Moderate liver disease, no cirrhosis (chronic active HBV)
→Treatment before pregnancy; if responds, stop
treatment before pregnancy
• Advanced liver disease (advanced fibrosis-cirrhosis)
→Treatment before, during and after pregnancy
• Mild liver disease, very high viremia (immunotolerant)
→Treatment in last trimester with a ‘B’ category drug
with post-partum discontinuation

Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for care. J
Perinatol. 2014;34(12):882-91.
 Immunoprophylaxis of neonates

  HBV vaccine HBIG HBIG+HBV vaccine

MTCT of HBV 26–36% 15–20% 5–10%a
Abbreviations: HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; MTCT, mother-to-child
transmission. References: 23, 47. aA major risk for immunoprophylaxis failure is maternal HBV DNA level
>200 000 IUml − 1 (>6 log10 copies ml− 1).

Immunoprophylaxis of neonates with HBIG+HBV vaccine is superior to monotherapy

with either agent alone for prevention of MTCT of HBV infection

Dunkelberg JC, Berkley EM, Thiel KW, Leslie KK. Hepatitis B and C in pregnancy: a review and recommendations for
care. J Perinatol. 2014;34(12):882-91.
 Toxemia of pregnancy and associated disease.

Kia L, Rinella ME. Interpretation and management of hepatic abnormalities in pregnancy. Clin Gastroenterol Hepatol.
2013;11(11):1392-8.
Possible mechanisms leading to immunoprophylaxis failure

Cheung KW, Seto MT, Wong SF. Towards complete eradication of hepatitis B infection from perinatal transmission: review
of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy. Eur J Obstet Gynecol Reprod
Biol. 2013;169(1):17-23.
Distribution of HBV (a) among the HBeAg-positive group (n = 367)
DNA levels among
pregnant women
with different
HBeAg status

(b) among the HBeAg-negative group (n = 608).

Sun KX, Li J, Zhu FC, Liu JX, Li RC, Zhai XJ, et al. A predictive value of quantitative HBsAg for serum HBV DNA level among
HBeAg-positive pregnant women. Vaccine. 2012;30(36):5335-40.
 Serology Status and Vertical Transmission Rate of HBV

No immunoprophylaxis HBIg + vaccine

Infection rate Transient Persistent Persistent
infection (>6 infection (>6
infection (%) mo) (%) mo) (%)
HBeAg+a 10.1 78.8 7.4
HBeAg– eAb–a 9.1 6.8 3
HBeAg– eAb+a 9.3 1.5 3
HBcAg+ onlyb 6.6b NA 0
a
Different vertical transmission rate observed by Burk et al.
b
Transient infection that is based on detectable DNA and observed by Walz et al.

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, et al. An algorithm for risk assessment and intervention of
mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012;10(5):452-9.
 Risk Factors and Likelihood of MTCT
Infants received HBIg and vaccine on schedule
High risk HBeAg+ HBsAg+ DNA >200,000 IU/mL Threaten
labor
preterm

Genotype/ S
Moderate risk Genetic factors Mother education
mutation
Low risk or Amniocentesis Forceps/ vacuum Breastfeeding
inconclusive delivery

Infants missed or received delayed HBIg and/or vaccine

High risk HBeAg+ HBsAg+ DNA >200,000 IU/mL High titer of HBsAg
DNA 2000–200,000
Moderate risk HBeAg– HBsAg+ IU/mL Breastfeeding
Low risk or Amniocentesis DNA <2000 IU/mL Low titer of HBsAg
inconclusive

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, et al. An algorithm for risk assessment and intervention of
mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012;10(5):452-9.
 FDA Pregnancy Categories for HBV Antiviral Therapy
HBV therapy Pregnancy FDA description
category
A Adequate and well-controlled studies have failed to demonstrate a risk to
the fetus in the first trimester of pregnancy (and there is no evidence of risk
in later trimesters).
Telbivudine B Animal reproduction studies have failed to demonstrate a risk to the fetus,
Tenofovir and there are no adequate and well-controlled studies in pregnant women
or animal studies that have shown an adverse effect, but adequate and well-
controlled studies in pregnant women have failed to demonstrate a risk to
the fetus in any trimester.

Lamivudine C Animal reproduction studies have shown an adverse effect on the fetus, and
Entecavir there are no adequate and well-controlled studies in humans, but potential
Adefovir benefits might warrant use of the drug in pregnant women despite potential
risks.
D There is positive evidence of human fetal risk based on adverse reaction
data from investigational or marketing experience or studies in humans,
but potential benefits might warrant use of the drug in pregnant women
despite potential risks.
Interferon X Studies in animals or humans have demonstrated fetal abnormalities,
and/or there is positive evidence of human fetal risk based on adverse
reaction data from investigational or marketing experience, and the risks
involved in use of the drug in pregnant women clearly outweigh potential
benefits.

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, et al. An algorithm for risk assessment and intervention of
mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012;10(5):452-9.
 Hepatitis B Vaccine and HBIg Schedule for Infants Who
Are Born to Mothers With Chronic Hepatitis B
Full-term infants (>2000 g) Premature infants (<2000 g)
Single-antigen  Single-antigen + Dose Single antigen with or without
vaccine combination vaccine combination vaccine at age
Dose Age Dose Age Vaccinea Birth (<12 h)
1a Birth (<12 h) 1a Birth (<12 h) HBIgb Birth (<12 h)
HBIg Birth (<12 h)
b
HBIg b
Birth (<12 h)
1a 1 mo
2 1–2 mo 2 2 mo 2 2–3 mo
4 mo 3
3 c
7 mo
3c 6 mo 6 mo (Pediarix) or
4c Vaccine
12–15 mo (Comvax) Test for HBsAg and antibody to
outcome HBsAg after completion of vaccine
series at age 9–18 mo (next well-
child visit after the third dose)

a
Recombivax HB or Engerix-B should be used for the birth dose. Comvax and Pediarix cannot be administered at birth
or before age 6 weeks.
b
HBV globulin (0.5 mL) administered intramuscularly in a separate site from vaccine.
c
Final dose of vaccine series should not be administered before age 24 weeks (164 days).

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, et al. An algorithm for risk assessment and intervention of
mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012;10(5):452-9.
 Algorithm for risk assessment and prevention of MTCT of HBV

Tenofovir is a category B medication for pregnancy and might be an option in preventing

MTCT if the mother has chronic active hepatitis B and long-term treatment is indicated. The
safety data of tenofovir use during pregnancy are only available in women with HIV
infection.
Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, et al. An algorithm for risk assessment and intervention of
mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012;10(5):452-9.
 Maternal Hepatitis Virus B DNA Levels of Enrolled
Randomized Controlled Trials
Maternal HBV DNA* Before Treatment Maternal HBV DNA* After Treatment
  Lamivudine HBIG Control   Lamivudine HBIG Control
Li (2003) 7.49±0.54 7.38±1.17 7.05±1.29   5.33±1.34 5.28±2.77 6.23±3.66
Shi (2005) 8.72±0.69 — 8.93±1.12 6.59±1.06 — 9.05±0.26
Han (2005) 7.15±0.91 — >5.60 5.43±0.85 — >5.60
Li (2006) 6.89±0.82 — >5.00 5.08±0.76 — >5.00
Feng (2007) 8.34±1.23 — 8.26±1.87 4.85±1.27 — 8.56±1.08
Xiang (2007) 8.02±1.15 7.63±1.23 7.16±0.79 4.58±1.22 5.12±1.07 6.88±1.36
Yang (2008) 6.99±0.84 6.87±0.92 — 5.10±0.80 6.87±0.92 —
Yang (2008) 3.60±2.50 — 2.90±2.00 1.80±1.10 — 3.60±1.80
Shi (2009) 7.24±1.90 6.31±2.13 6.40±2.12 4.49±3.25 5.86±2.62 6.19±2.57
Xu (2009) 9.35±0.21 — 9.43±0.21   7.71±1.49 — 9.34±0.22

HBV, hepatitis B virus; HBIG, hepatitis B immunoglobulin.

* Log10 HBV DNA (meanstandard deviation).
Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a
systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147-59.
 Comparison of Lamivudine and Hepatitis B Immunoglobulin in
Interruption of Intrauterine Transmission of Hepatitis B Virus
Clinical Issues Lamivudine HBIG
Mechanism of interruption Decrease maternal hepatitis B viral load by Transplacental delivery of HBIG, passive
inhibition of HBV DNA polymerase immunization of the fetus
Efficiency in interruption of Yes, maybe better, but not significant, may
HBV intrauterine due to small number of patients Yes
transmission
Efficiency in decreasing Yes, significantly more efficient than HBIG Yes
maternal HBV level
Cost of medication (in $180–260, depending on prescription $100–200, depending on prescription
China)
Method of medication Oral 100 mg/d, 3–4 mo 200 international units/mo, three to
four injections total
Compliance to medication Yes Yes
Target population
HBV DNA positive pregnant women HBsAg positive pregnant women

Source of medicine
Blood-borne disease
infection
Higher drug-resistant
mutants rate
Imported from United Kingdom, same Different companies in China, different
company, same quality; chemically techniques and quality; plasma-derived
synthesized
No Possible
Possible, but not observed over 4 months Possible, but not observed over 4
of application months of application

Major congenital Not higher than CDC’s population

Z, Yang Y, Ma L, Li X, Schreibersurveillance
Shimalformation rate,
A. Lamivudine even
in late exposed to
pregnancy in interrupt
the first in N/A*
utero transmission of hepatitis B virus: a
trimester
systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147-59.
 Algorithm for
management of HBV
infection during
pregnancy

Buchanan C, Tran TT. Management of chronic hepatitis B in pregnancy. Clin Liver Dis. 2010;14(3):495-504.
Maternal serum HBV status and the outcome
of HBV infection in infants
Infant
Mother
No vaccination With immunoprophylaxis
HBeAg(+), HBsAg(+) >90% chronic Vaccine + HBIG10-15% chronic
infection
HBeAg(-), HBsAg(+) <5% chronic, with risk of <1% chronic infection and risk of
FH, AH FH, AH reduced
HBeAg(-), HBsAg(-) Not infected Not infected
FH, fulminant hepatitis; AH, acute hepatitis; HBeAg, hepatitis B e antigen; HBsAg,
hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin.

Chang MH. Hepatitis B virus infection. Semin Fetal Neonatal Med. 2007;12(3):160-7.
 Different strategies for HBV immunisation,
their costs and efficacy
  Maternal Infant Cost Efficacy Example
screening Vaccine HBIG

1. Active Only No Yes No Lower Modest Thailand

2. Active +
Passive

Infants of
Type I HBsAg and Yes HBeAg(+), Higher High Taiwan
HBeAg HBsAg(+)
mothers
Infants of
Type II HBsAg only Yes HBsAg(+) Highest High USA
mothers

Chang MH. Hepatitis B virus infection. Semin Fetal Neonatal Med. 2007;12(3):160-7.
 TENOFOVIR
PEG IFN-α LAMIVUDINE ADEFOVIR ENTECAVIR TELBIVUDINE DF
Route Subcutaneous Oral Oral Oral Oral Oral
180 µg/wk 100 mg/day† 10 mg/day† 0.5 mg/day† 600 mg/day† 300 mg/day†
Dose (1 if
lamivudine
resistant)
Duration (wk) 48 ≥48 ≥48 ≥48 ≥48 ≥48
Fair-poor: Good Good: follow Good Good Good: follow
Tolerability flulike renal function renal function
symptoms
HBeAg 27% 16%-21% 12% 21% 22% 21%
seroconversio
n
Undetectable 25%-63% 40%-73% 21%-51% 67%-90% 60%-88% 76%-93%
HBV DNA‡

ALT 38% 41%-75% 53% 72% 65% 74%

normalization
HBsAg loss 3% <1% 0% 2% <1% 3%

Viral None 15%-30% Minimal None§ 6% 0%

resistance
 Reduction of the HBsAg carriage rate in endemic
countries after introduction of vaccination

Pol S, Corouge M, Fontaine H. Hepatitis B virus infection and pregnancy. Clin Res Hepatol
Gastroenterol. 2011;35(10):618-22.
Shi Z, Li X, Ma L, Yang Y. Hepatitis B immunoglobulin injection in pregnancy to interrupt hepatitis B virus mother-to-
child transmission-a meta-analysis. Int J Infect Dis. 2010;14(7):e622-34.
 Profil obat-obat antiviral yang digunakan pada pasien
Hepatitis B kronik HBeAg (+) selama 1 tahun
Variabel Interferon Lamivudin Adefovir Entecavir Telbivudin Tenofovir
DNA VHB tak 19-70% 22-44% 13-21% 67% 56-60% 76-80%
terdeteksi Naik sampai
92% pada
pemakaian 3
tahun

Sero- konversi 20-32% 16-42% 12% 21-22% 22.5-26% 21%

HBeAg Naik sampai 27% Naik sampai
pada terapi 2 tahun 44% pada
dan 40% pada terapi pemakaian 3
3 tahun tahun

Sero- konversi 3-8% 0-1%, 0% 2-5.1% <1% 3%

HBsAg Mencapai 11% HBsAg loss mencapai
setelah 3 tahun 2.8% pada terapi 2
tahun
Normalisasi 39-59% 41-75% 48-61% 68-79% 70% 60-68%
ALT
Perbaikan 38% 49-62% 53-68% 72% 60-68% 67-74%
histologis
Resistensi 0% 15-30%, mencapai 0% 0% pada pasien 2.3-6% 0%
57% pada tahun naif
ketiga
* Data didapat dari referensi nomor 1,19,23,24,28,38,39,46-48,50,51,55,60, dan bukan merupakan perbandingan
langsung (head to head)
Perhimpunan Peneliti Hati Indonesia. Konsensus Nasional Penatalaksanaan Hepatitis B PPHI 2012
 Profil obat-obat antiviral yang digunakan pada pasien
Hepatitis B kronik HBeAg (-) selama 1 tahun
Variabel Interferon Lamivudin Adefovir Entecavir Telbivudin Tenofovir
DNA 19-53% 26-73% 51-63% 90% 88.3% 93%
VHB tak
terdeteksi
Sero- 4-6% 0% 0% 0% 0% 0%
konversi
HBsAg
Normalisasi 38-59% 71-79% 72-77% 78% 74% 76%
ALT
Perbaikan   61-63% 64% 70% 59% 71%
Histologis
Resistensi 0% 6-27%, 0%, 0% 2.3-2.7% 0%
mencapai Meningkat
57% pada sampai 11%
tahun ketiga pada tahun
ke-3
* Data didapat dari referensi nomor 1,19,23,24,28,38,39,46-48,50,51,55,60, dan bukan merupakan
perbandingan langsung (head to head)

Perhimpunan Peneliti Hati Indonesia. Konsensus Nasional Penatalaksanaan Hepatitis B PPHI 2012
Greenberg JM. Neonatal Morbidities of Prenatal and Perinatal Origin. Creasy and Resnik's Maternal-Fetal Medicine
Principles and Practice. 8th Ed, ed2019. p. 1309-33.e8.
 Estimates of Complication Rates Between Preterm and
Late Preterm Infants
Complication of Prematurity Incidence in Preterma Incidence in Late Pretermb
• 65% surf RX <1500g
• Respiratory distress syndrome • 5%
• 80% <27 weeks
• Bronchopulmonary dysplasia • 23% <1500 g • Uncommon
• Retinopathy of prematurity • ≈40% <1500 g
• Intraventricular hemorrhage with
ventricular dilation or parenchymal • 11% <1500 g • Rare
involvement
• Necrotizing enterocolitis • 5%–7% <1500 g • Uncommon
• Patent ductus arteriosus • 30% <1500 g • Uncommon
• Feeding difficulty • >90% • 10%–15%
• Hypoglycemia • NA • 10%–15%
• a
Defined as less than 32 weeks and/or less than 1500 g.
• b
Defined as 32–38 weeks and/or 1500–2500 g.
• NA, Not available; surf RX, surfactant treatment.

Greenberg JM. Neonatal Morbidities of Prenatal and Perinatal Origin. Creasy and Resnik's Maternal-Fetal Medicine
Principles and Practice. 8th ed, 2019. p. 1309-33.e8.