CURICULLUM VITAE :

dr. Yan O’Neil S Meliala, SpOG., Mkes

Bandung, 5 januari 1979
Pendidikan:
SDN Bojong Kacor I, Bandung 1986-1991
SMPN 2 Bandung. 1991-1994
SMANSA Bandung. 1994-1997
Univ. Kristen Maranatha Bandung. 1997-2003
Program Pasca Sarjana Unpad. 2007-2009
PPDS 1 OBGIN UNPAD. 2006-2009
 TRANSMISI VERTIKAL
COVID-19 PADA IBU HAMIL

dr. Yan O’Neil S Meliala, SpOG., MKes

RSUD 45 Kuningan
Jawa Barat
DEFINISI
Vertical Transmission atau Penularan Vertikal diartikan
sebagai penularan patogen infeksius dari ibu ke janin
selama periode antepartum, atau neonatus selama periode
postpartum melalui plasenta dalam rahim, kontak cairan
tubuh saat melahirkan atau melalui kontak langsung karena
menyusui setelah melahirkan.

Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis

 AKIBAT PADA KEHAMILAN
• Akibat yang di sebabkan oleh Covid-19 pada kehamilan dan janin sebagian besar masih
belum diketahui karena Covid-19 merupakan wabah penyakit yang baru. Wanita hamil
adalah kelompok yang berpotensi rentan terkena infeksi Covid-19.
• Trimester pertama dan ketiga kehamilan dapat dianggap sebagai periode aktivitas inflamasi
yang meningkat, sedangkan Trimester kedua adalah periode penurunan aktivitas kekebalan
secara keseluruhan.
• meskipun laporan awal dari wanita hamil yang terinfeksi Covid-19 pada trimester ketiga
menimbulkan kekhawatiran akan peningkatan risiko persalinan prematur
• Kelompok besar baru baru ini yang teridir dari 116 wanita di China dan 427 wanita di inggris
menunjukkan bahwa wanita hamil tidak mengalami peningkatan risiko aborsi spontan atau
kelahiran prematur spontan, Tetapi memiliki tingkat kelahiran seksio sesaria yang lebih
tinggi.

Mor G., Aldo P., Alvero A.B. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. 2017;17:469–482.
Liu H., Wang L.L., Zhao S.J., Kwak-Kim J., Mor G., Liao A.H. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod
Immunol. 2020;139:103122.
 SIKLUS VIRUS DAN KEHAMILAN
Mekanisme invasi SARS-CoV- Reaksi Tubuh thd SARS-CoV-2
2 ke sel Inang 
Innate immunity response 
• Epithelial, Macrophage, DC 
1. Attachment : SARS-CoV-2 - S protein
cleavage by TMPRRS2 ( S1 for binding to • T Cell response 
ACE2 Receptor)  • CD4 T cell --> Activate B -->
2.Penetration : membrane fusion -- S2 for virus specific Antibody Cells
fusion) -Endocytosis and membrane fusion 
CD8 --> Kill virus 
3.Biosynthesis : viral RNA the nucleus -->
mRNA is used to make viral protein  • Proinflammatory Cytokines
4.Maturation : New viral protein maturated  IL6, IL10, GCSF, Chemokines,
5.Released : release virus TNF a 
• Lung destruction 
• D-Dimer, 
• Fibrinogen decreased 
The characteristics unique to SARS-CoV-2 among
coronaviruses is the existence of furin cleavage site • Thrombosis, pulmonary
High Estradiol concentration augment CD4+ Th2 cell
(“RPPA” sequence) at the S1/S2 site.  response embolism 
Progesterone alter the balance between Th1 and Th2
Responses 
• Multiorgan failure
REKOMENDASI POKJA ISR PP POGI
badai sitokin , merupakan sebuah respon inflamasi sistemik tidak terkontrol
yg disebabkan oleh pelepasan sitokin dan kemokin pro-
inflamasi dalam jumlah sangat besar oleh sel-sel efektor imun
Related to pregnancy complication in COVID-19???

? Cytokine STORM/ BADAI SITOKIN

BRADIKININ STORM?? -->vasodilatasi, hipotensi

Cytokine Cytokine Cytokine

tipe I tipe II tipe I

Pregnancy loss, preterm birth, preeclampsia

 TINJAUAN SISTEMATIS SEBELUMNYA

tidak ada bukti penularan secara

vertikal

tidak ada kasus penularan vertikal

yang di temukan dengan Gejala yang
sama dengan MERS dan SARS

Fan C., Lei D., Fang C. Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry? Clin Infect Dis. 2020
Della Gatta A.N., Rizzo R., Pilu G., Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. 2020;223:36–41. 
Yang Z., Wang M., Zhu Z., Liu Y. Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review. J Matern Fetal Neonatal Med. 2020 
ang Z., Liu Y. Vertical transmission of severe acute respiratory syndrome coronavirus 2: a systematic review. Am J Perinatol. 2020;37:1055–1060.
NO EVIDENCE OF VERTICAL
TRANSMISSION

MARET 2020
MARET 2020 PENGARUH COVID-19 ➢ FETUS

• Kesimpulan: Berdasarkan data yang terbatas,

tidak ada bukti transmisi COVID-19 dari ibu
ke janin. (Maret 2020)

REKOMENDASI POKJA ISR PP POGI

KEMUNGKINAN TRANSMISI VERTIKAL
 MOTHER --> NP SWAB POSITIVE

NEONATAL 16 HOURS  NP SWAB POSITIVE

IgM & IgG  negative after 4 days  positive

REKOMENDASI POKJA ISR PP POGI

 PENGARUH COVID-19 ➢ FETUS
• Kesimpulan: Temuan menunjukkan
bahwa, kemungkinan transmisi
vertikal COVID-19 semakin
banyak dilaporkan. (April 2020)

• Adanya transmisi transplasenta tidak

bisa disingkirkan.

REKOMENDASI POKJA ISR PP POGI

• 936 neonatus dari ibu dengan covid-19,
• 27 neonatus positif untuk SARS-COV-2, test
RNA virus dengan nasopharyngeal
swab,menunjukkan proporsi 3.2% (95%
confidence interval, 2.2-4.3) untuk transmisi
vertikal.
• 2% (8/397) studi di China
• 2,7% (14/517) studi dari luar China
SAMPLE TESTING RNA FOR VERTICAL TRANSMISSION

• NEONATAL CORD BLOOD 2,9%

• PLACENTA 7,7%

• AMNIOTIC FLUIDS 0%
• URINE 0%

• FECAL/RECTAL SWAB 9,7%

• NEONATAL SEROLOGY 3,7%
KESIMPULAN :
sangat mungkin terjadi transmisi vertikal dan
beberapa kasus muncul pada trimester tiga
pada ibu hamil yg terkena Covid-19

The rates of infection are similar to those of

other pathogens that cause congenital
infections. 

No assessment can yet be made regarding

the rates of vertical transmission in early
pregnancy and potential risk for consequent
fetal morbidity and mortality.
NTANG TRANSMISI VERTIKAL
• The main receptor that COVID-19 binds to enter cell is the angiotensin-
converting enzyme 2 (ACE2) receptor, is expressed in placenta
• Found in the syncytiotrophoblast, cytotrophoblast, endothelium and vascular
smooth muscle from both primary and secondary villi
• ACE2 is expressed in gynecologic organs such as the ovary, uterus and vagina
• ACE2 expression is seen in numerous tissues that are direct communication
with a developing pregnancy

Levy A., Yagil Y., Bursztyn M., Barkalifa R., Scharf S., Yagil C. ACE2 expression and activity are enhanced during pregnancy. Am J Physiol Regul Integr Comp
Physiol. 2008;295:R1953–R1961.
Valdés G., Neves L.A., Anton L. Distribution of angiotensin-(1-7) and ACE2 in human placentas of normal and pathological
pregnancies. Placenta. 2006;27:200–207. 
Jing Y., Run-Qian L., Hao-Ran W. Potential influence of COVID-19/ACE2 on the female reproductive system. Mol Hum Reprod. 2020;26:367–373. 
ACE-2 receptor
 SINGLE CELL RNA SEQUENCING ANALYSIS

• ACE2 expression in stromal, perivaskuler, placental and decidual cells of the maternal fetal
interface
• Looking at the coexpression of ACE2 and transmembrane serine protein for virus spike (S)
protein priming, Transmembrane serine protease 2 (TMPRSS2) showed that only a minimal
number of placental cells express both proteins in any trimester.
• The chorioamniotic membranes from the third trimester exhibit minimal coexpression of both
proteins.
• The viral entry into placenta cells may still occur using combination of ACE2 and a
noncanonical cell entry mediators

Li M., Chen L., Zhang J., Xiong C., Li X. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell
transcriptome study. PLoS One. 2020;15
Pique-Regi R., Romero R., Tarca A. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? Elife. 2020;9:e58716.
• Study reported in Milan  31 pregnant women with
COVID-19 (+)
• In the three documented cases of vertical transmission,
SARS-CoV-2 infection was accompanied by a strong
inflammatory responses :
a. One in umbilicar cord blood
b. Two at-term placentas
• A case reported in Paris Saclay University Hospital : A 23 y.o G1P0A0 35-36 weeks of
pregnancy hospitalized with COVID-19 (+).
• A male neonate was delivered (gestational age 35-36 weeks; birth weight 2540 g). Apgar
scores were 4 and 7.
• RT-PCR on the placenta was positive for both SARS-CoV-2 genes.
• All RT-PCR results obtained in different maternal and neonatal specimens: viral load was
much higher in placental tissue, than in amniotic fluid and maternal or neonatal blood.
These findings suggest that:
1. Maternal viremia occurred and the virus reached the placenta as demonstrated by
immunohistochemistry;
2. The virus is causing a significant inflammatory reaction as demonstrated by the very high
viral load, the histological examination and the immunohistochemistry;
3. Neonatal viremia occurred following placental infection.
• The placenta showed signs of acute and chronic intervillous inflammation consistent with the
severe systemic maternal inflammatory status triggered by SARS-CoV-2 infection.
• As RT-PCR on the placental tissue was positive for SARS-CoV-2, and both maternal and
neonatal blood samples were also positive, the transmission clearly occurred through the
placenta.
• They screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women
who delivered between February 7 and May 15, 2020, including 15 tested positive for
SARS-CoV-2 RNA.
• SARS-CoV-2 S and N proteins were strongly expressed in the placenta of a COVID-19
pregnant woman whose newborn tested positive for viral RNA and developed COVID-19
pneumonia soon after birth.
• The placenta intervillous inflammatory infiltrate consisted of neutrophils and monocyte-
macrophages expressing activation markers.
 Immunohistochemical and RNA-in situ stains

• They detected viral S-protein and RNA

in villous syncytiotrophoblast.
• They found stronger expression of S-
protein in areas with dense monocyte-
macrophage inflammation, compatible
with a local activation of these immune
cells in response to the binding to anti-
Spike maternal IgG-virus immune
complexes, as shown in lung tissues.
 MARKER OF IMMUNOGLOBULIN M
• In addition to this biological plausibility, there are several lines of clinical evidence
concerning vertical transmission. Initial reports from China have documented
immunoglobulin M (IgM) antibodies in neonates born to mothers who had positive results for
COVID-19

• raising concerns for in utero transmission because IgM cannot cross the placenta

• Moreover, several recent case reports provided evidence that COVID-19 can infect the
placenta as confirmed by the presence of SARS-CoV-2 viral RNA and protein in the placenta
and evidence of virions found within the syncytiotrophoblast
Although the precise mechanisms employed by SARS-CoV-2 to cross the placental barrier are unknown so far, the following possibilities
have been considered:

1. Direct infection of syncytiotrophoblasts and breach through the syncytial layers via ACE2 and Fc receptor (FcR),

2. Passage through the maternal circulation to extravillous trophoblasts or other placental cells,

3. Passage through maternal immune cells,

And 4. Ascending infection via the maternal vaginal tract

• infection of syncytiotrophoblasts by SARS-CoV-2 must be rare because the incidence of viremia in symp-tomatic SARS-
CoV-2-positive adults was approximately 1%. In addition, the susceptibility and kinetics of SARS-CoV-2 in trophoblasts
are not well known. We should continue careful observation of pregnant women with COVID-19 and promote in vitro
studies with a trophoblast cell line or primary trophoblast.

• Transmission during vaginal delivery is another possible route of SARS-CoV-2 infection of the neonate. Recent
systematic reviews showed that 9.6% to 21.9% of COVID-19 pregnant patients delivered vaginally. A report from Italy
concluded that vaginal delivery may be associated with a low risk of intrapartum SARS-CoV-2 transmission to the
neonate. In Italy, some researchers recommend routine SARS-CoV-2 PCR assay testing with nasopharyngeal, vaginal and
rectal swabs in each pregnant patient before delivery to determine the indi-cation of safe vaginal delivery for patients with
negative PCR test results for vaginal and rectal samples. However, the low sensitivity of PCR examination, as well as the
financial cost, and limited medical resources make this approach impractical

• another possible mechanism of vertical transmission is via maternal immune cells. SARS-CoV-2 was reported to infect T
lymphocytes through spike protein-mediated membrane fusion, and maternal lymphocytes occasionally migrate into the
fetal circulation, which is observed as microchimerism.

Detection of SARS-CoV-2 in different types of clinical specimens, W. Wang, W. Tan, etc,J. Am. Med. Assoc. (2020)
Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis, E. Ferrazzi, I. Ceti, BJOG (2020)
SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion, X. Wan,  L. Lu, Cell. Mol. Immunol. (2020),
 Several reports of vertical COVID-19
transmission based on positive IgM antibodies in
cord blood samples collected at the time of
delivery
Due to its large molecular size, IgM cannot pass
the placental barrier. Thus, the presence of
specific anti-SARS-CoV-2 IgM antibodies
suggests intrauterine infection

DIAGNOSTIC OF
VERTICAL However, due to the high false positive rates of antibody testing, we must
TRANSMISSION be careful to correctly diagnose intrauterine infection for neonates without
any symptoms or positive PCR test results.

The detection of viral genomes or viral antigens in neonatal samples is stronger

evidence of vertical transmission.

However, the site of sampling is an important issue because neonates might be infected with SARS-CoV-2 via the maternal
bloodstream. They are not expected to secrete viruses in the sputum, saliva or stools in high copy numbers without
prominent inflammation
 VIRAL AND HOST IMMUNE FACTORS THAT
MIGHT AFFECT VERTICAL TRANSMISSION
1
• There have been several subtypes with different virulence and tropism. These mutations possibly explain different clinical outcomes and rates of mortality
between Asian and Caucasian people. In addition, several HLA haplotypes and polymorphisms of immunoregulatory genes, including Toll-like receptor
(TLR) promoters and interferon response genes, might affect the susceptibility of the patients, severity of the infection, and rates of vertical transmission

2
• The role of decidual and intervillous lymphocytes to control local viral transmission is unknown so far. Natural killer cells and cytotoxic T
cells are expected to destroy virus-infected cells, but several studies have suggested harmful roles of the cellular immune response and
subsequent tissue damage

3
• Antibody production might be another double edged sword because some antibodies neutralize viral particles, while others do not
inactivate them and are easily captured by Fc receptor-rich target cells, such as endothelial cells and syncytiotrophoblasts.
BREASTFEEDING AND COVID-19

Samples were tested for Covid-19 using qRT-PCR with results

demonstrating that all tests were negative. A slightly larger study
of 19 mothers did not find SARS-CoV-2 in breastmilk 
THERE HAVE BEEN PUBLISHED CASE REPORTS OF THE
PRESENCE OF COVID-19 RT-PCR IN BREASTMILK
SAMPLES

Recent investigations have found no evidence of SARS-CoV-2 in human breastmilk, but sample sizes were small .
 SARS‐CoV2 and pregnancy: An invisible enemy?

Schematic of SARS‐CoV‐2 mechanisms,

targets, and outcomes in pregnancy

American Journal of Reproductive Immunology, Volume: 84, Issue: 5, First published: 17 July 2020, DOI: (10.1111/aji.13308)
TAKE HOME MESSAGE
• POSSIBILITY VERTICAL TRANSMISSION
• ANTENATAL/intrauterine  Maternal sirculation, intraplacental, maternal immune cell
• CHILDBIRTH/intrapartum  Vaginal track, body fluid contact
• BREASTFEEDING/postpartum  human breastmilk

• DIAGNOSTIC OF VERTICAL TRANSMISSION

• EARLY TESTING ANTIBODY IgM (cannot cross placenta)

• MECANISM OF VERTICAL TRANSMISSION

• Co-expression of ACE2 and TMPRSS2 (transmembran serine protease2)

• These findings suggest that intrauterine, intrapartum and postpartum transmission is possible and
warrants clinical caution and further investigation.
 REFERENSI :
• buku pokja infeksi POGI
• Presentasi Dr. Muhammad Alamsyah Aziz, dr, SpOG(K), KIC, M.Kes
• Panduan Pengelolaan COVID-19 Dalam Bidang Obstetri, Divisi fetoMaternal
Terima Kasih

O’Neil Meliala, dr. SpOG., MKes