ART in The COVID-19 Era

ART in The COVID-19 Era
Patient preparations
www.marwanalhalabi.com
Marwan Alhalabi
Professor of Reproductive Medicine and Infertility,
Damascus University
Head of Assisted Reproduction Unit, Orient Hospital
Past President of Middle East Fertility Society
President of Syrian Society of Obstetricians and Gynecologists
MERK Webinar 2020

New
Serious
Unknowns
Unprepared
Pandemic
EBM

Most common symptoms of coronavirus

Ways of
Contamination
• Concentrations of viral particles
are high in the URT.
• Concentrations in non respiratory
specimen are very low.
• RNA titers (COVID patients)
positives:
• 29% in stool
• 01% in blood
• 00% in urine
• ?? Follicular fluid
Wang et al. JAMA 2020:
International Pulmonologist’s Consensus, COVID-19 April,2020

• Other coronaviruses do not efficiently
transmit through sex
• Covid-19 has not yet been found in
semen or vaginal fluid.
• Covid-19 has been found in feces of
people who are infected with the virus.
• If you or a partner may have Covid-19,
avoid sex and especially kissing.
COVID-19

Three
Strains
of
Corona
Virus

Spread of COVID-19 across the world
(8.5.2020)

Spread of COVID-19 in Syria (8.5.2020)

COVID-19 Receptor: ACE 2
97
improve over time and seem to be
related to hCG levels, which naturally
decline after 12 weeks. The most
common early pregnancy symptoms
are described in the table below.
takes over production of oestrogen and progesterone, secreting both
hormones in massive quantities. Progesterone levels are higher until
around 28 weeks, after which oestrogen levels dominate.
3ENDOMETRIUM
This is richly supplied with blood
vessels that carry the progesterone
and oestrogen directly to the tissue,
ensuring that it continues to thicken. The
implanting embryo will receive its first
nutrients directly from this lining.
Uterine
cavity
Blood vessels
Basal layer of endometrium
is not shed and generates
a new functional layer
each month
Progesterone and oestrogen
in blood maintain and thicken
endometrium
Functional layer of
endometrium is shed
during menstruation
Changes to the breasts begin soon after conception and include
an increase in breast size, sensitivity, and vascular patterns. Under
the influence of the early pregnancy hormones, the ductal system
is the first area to proliferate, with the glandular tissue increasing
much later in pregnancy. Breast soreness experienced within the
first trimester tends to ease as the pregnancy progresses.
An increase in blood flow to the kidneys and improvements
in their filtering capacity occur early in pregnancy. Urination
may occur more often as a result, although excessively high
frequency or pain on passing urine may indicate an infection
requiring help.
Spotting may occur at the time of implantation – this coincides
with the time that mensturation is due and can be confused with
a light period. The cervix also softens during pregnancy, and this
may lead to some spotting following intercourse.
A woman’s period should follow around two weeks after
ovulation unless fertilization has occurred; this is most likely if
sex took place near to ovulation. A pregnancy test at the time
of a missed period is sensitive enough to detect the presence
of an early pregnancy.
The exact cause of fatigue during the early weeks is unknown.
It does not affect all women and usually improves by 12 weeks.
Fatigue may be related to early hormonal changes and the body’s
gradual acclimatization to the pregnancy.
Commonly known as “morning sickness”, nausea and
vomiting are the classic early symptoms of pregnancy.
They can be present at any time of the day or night, and
may be exacerbated by certain foods or smells. Usually
it takes a mild form, but in rare cases the more severe
hyperemesis gravidarum can occur.
Changes to taste sensation, such as a metallic taste in
the mouth or the preference for certain foods, may be
experienced. These usually settle during the pregnancy or,
if not, very soon afterwards.
Progesterone prevents the uterus from contracting before term,
but it also slows down the contraction of all smooth muscle. This
causes digestion to be sluggish, leading to constipation.
PREGNANCY HORMONES
The above graph shows fluctuations
in the three main hormones that act
throughout a 40-week pregnancy.
ALLEVIATING NAUSEA
Morning sickness is extremely common and
can be highly disruptive. Eating regularly can
help to alleviate nausea, as can soothing herbal
teas, in particular mint or ginger teas.
BLOODLEVELS
AGE OF EMBRYO/FETUS (WEEKS)
HUMAN CHORIONIC
GONADOTROPIN (HCG)
OESTROGEN
PROGESTERONE
OVULATION
KEY
EARLY SYMPTOMS
4 8 12 16 20 24 28 32 36 400
Tender and
enlarged
breasts
Urinary
frequency
Spotting and
bleeding
Fatigue
Nausea and
vomiting
Metallic taste
in mouth
Constipation
Missed period
Unlikely COVID-19 will affect
reproductive system and fertility

Covid-19 And Male
Infertility : Summary
• So far, no study has confirmed that the
coronavirus can damage male testicles and
adversely hurt male fertility.
• As far as testis is rich in ACE2, the team
suggested men who get the virus might
consider getting tests on their semen quality
after 3 months .

Is There Any Risk of Viral Contamination to
Gametes& Embryos in The IVF Lab.?
84
DAY 17FERTILIZED EGG
The zona pellucida now
depolarizes, preventing further sperm from entering the
egg. The male and female pronuclei combine to produce
the “zygote”, which prepares for the ﬁrst cell division. In
rare instances, two sperm simultaneously fertilize the
egg, resulting in a molar pregnancy (see p.227).
DAY 18ZYGOTE
Within 24 hours of fertilization
the zygote duplicates the nuclear genetic material then
divides into two cells by mitosis (see p.50). Through a
sequence of rapid cell divisions, 16–32 cells, called
blastomeres, are produced. These form the morula,
which is Latin for “mulberry”.
DAY 20MORULA
The morula is still
contained within the zona pellucida at this
stage. This is possible because cell division
has occurred without cell growth. The morula
travels the length of the Fallopian tube to
emerge into the uterine cavity for implantation.
CONCEPTIONTOBIRTH
Fertilized egg
Cell has a
single nucleus
Zona pellucida
Membrane
prevents further
sperm entering
fertilized egg
Two cells
Egg divides
into two cells,
each with its
own nucleus
Goblet cell
Secretes mucus
into Fallopian tube
Cilia
Fallopian tube is lined
with tiny hairs that help
transport egg
Fimbriae
Ovary
Fallopian tube
Ampulla
Thin-walled, almost
muscle-free mid-section
is largest part of Fallopian
tube, where fertilization
often takes place
Blastomeres
Cells produced by
rapid division of
fertilized egg, each
with its own nucleus
Ovarian
ligament
Path of egg
084-085_conception_2.indd 84 23/04/19 7:22 PM
It is likely to be minimal (if at all). Why?
No ACE 2 Receptors, Zona Pellucida
Repeated washing steps

American Society for Reproductive
Medicine (ASRM)
April 13 to April 27, 2020
• Suspend initiation of new treatment cycles, including
ovulation induction, IUIs, IVF including retrievals and
frozen embryo transfers, as well as non-urgent gamete
cryopreservation
• Strongly consider cancellation of all embryo transfers
whether fresh or frozen.
• Continue to care for patients who are currently ‘‘in-cycle’’
or who require urgent stimulation and cryopreservation.
• Suspend elective surgeries and non- urgent diagnostic
procedures;
• Minimize in-person interactions and increase utilization of
telehealth.

European Society of Human Reproduction
and Embryology (ESHRE)
March 17, 2020
• All fertility patients considering or planning
treatment, even if they do not meet the
diagnostic criteria for COVID-19, should avoid
becoming pregnant at this time.
• For those patients already having treatment, it is
suggested to consider deferring pregnancy with
oocyte or embryo freezing for later embryo
transfer.

Covid-19 Joint
Statements
(Syria)
• suspend fertility treatments except urgent fertility
preservation in oncology patients
• In case started freeze –all.
• Centre’s can see patients who are currently in
treatment for any essential appointments such as
monitoring ultrasound scans, OHSS checks or early
pregnancy monitoring.
• Recommendation that hospitals suspend elective
surgeries during the COVID-19 crisis pandemic.
• Obstetric and gynecologic procedures for which a
delay will negatively affect patient health and safety
should not be delayed.

Covid-19 Joint
Statements (Syria)
Adaptations of ART
services
Sanitation
Limitation of the
number of persons
simultaneously
present in the center
Provision of personal
protective
equipment
Redesign the waiting
rooms and working
spaces
Use of a triage
questionnaire

Why?
To avoid complications of ART& pregnancy.
To avoid potential Covid-19 related complications
during pregnancy.
To decrease the unknown risk of vertical
transmission in Covid-19 positive patients.
To support the necessary reallocation of healthcare
resources
To observe the current recommendations of social
distancing.
To minimize any risk of transmission by travelling to
clinic

What to do?
• Use this time to prepare your body for the
forthcoming Treatment and pregnancy
• Important to prepare Physically, Mentally and
Emotionally
• Healthy Lifestyle
• Eat balanced diet
• Daily routine of exercise
• Continue your vitamins:
especially, folic acid and
Vitamin D
• Studies show that being
overweight or underweight
can negatively affect your
fertility and increase health
and safety risks during IVF
treatments
Physically
Body mass index (BMI)

Nervous
Women
freezing Their
eggs over
Covid-19
fears
• Many women are rushing to get their eggs frozen
among fears of the coronavirus. A top fertility clinic
says it’s been streamed with women begging to
freeze their eggs during the pandemic.

COVID-19 here to stay.
resuming fertility treatments
restarting IVF

Patients Journey
Through the Pandemic
and Beyond
Patient preparations

Pillars of GMP proposed for the
restart of activity in the ART centers.
1) Discussion, agreement and consent to
the start of treatment
2) Staff and patient triage
3) Access to advice and treatment
4) Adaptation of ART services
5) Treatment cycle planning
6) Code of Conduct for staff and patients

Discussion,
agreement
and
consent to
start
treatment
High-risk patients:
• Diabetes,
• Hypertension,
• Using immunosuppressant therapy,
• Past transplant patients,
• Lung, liver or renal disease
should not start ART treatment
until it is deemed safe to do.

Discussion,
agreement
and
consent to
start
treatment
Patients must be comprehensively informed,
clearly understand:
the risks related to
COVID-19 disease
the increased risks
in case of infection
during pregnancy
how to reduce the
risk of infection in
general.
All patients should be offered a choice to
proceed with or postpone their ART
treatment. In both cases patient preference
should be clearly documented.

ART Triage Questionnaire (1)
Have you been sick in
the last two weeks?
Do you have fever
(over 37,5°C)?
Do you have a sore
throat?
Have you lost your
sense of smell or
taste?
Have you been in
contact with
somebody who has any
of these symptoms?
Have you travelled to
an area at high risk for
COVID-19, nationally
or internationally?

ART Triage
Questionnaire
(2)
1) Do you work in a hospital/nursing home or healthcare
facility?
2) Have you been in contact with somebody who has
COVID-19?
3) Have you been you diagnosed with COVID-19?
4) Do you live in a household with somebody who has
been diagnosed with COVID-19 infection or has COVID-
19 symptoms (fever, cough, loss of smell)?
5) If you have been COVID-19 positive and recovered, do
you have certified medical evidence of clearance ?
6) Do you have a severe medical condition like diabetes,
respiratory disease, chronic kidney disease, etc.? (this
question can be skipped when using the ART triage
questionnaire for staff)

Procedure for staff (1) : Risk Assessment
Suspected Undergo COVID-19 IgM/IgG testing
Test positive
Receive health advice
go into self quarantine
Symptomatic
Medical advice and testing, should not re-
attend work until the infection is cleared
Triage information regarding health status,

Procedure for staff (2)
• Contact tracing and testing
should be routine if a staff
member is diagnosed with
COVID-19 infection.
• Depending on the size of the
unit, staff should be
subdivided in “mini-teams”
with minimum interactions
among them.

Summary
Figure
Staff
Triage

During Consultations
Routine disinfections of surfaces (door handles, etc…)
Social Distancing appointments
Body temperature measurements
Screening questionnaire
Spacing patients (if more than two couples waiting)
No hands shake
Keep face mask

For ultrasound
• Routine disinfection of surfaces (door
handles, desks, ultrasound, etc…)
• Prevention
• Surface disinfection
• Triage (body T°, questionnaire)
• Ventilation of ultrasound room
• 20 m between each exam (for
ventilation)
• Surgical mask with hand wash after
each exam
• gloves single time use

For surgery
• Routine disinfection
• Prevention:
• Anesthesia (protocol applied by the anesthesiologist)
• Surgery: surgery for infertility, (oocytes retrieval)
• Surgeon processing:
• Donning (after wash hands, masks, operative gown, gloves)
• Operating field (as usual disinfection)
• Doffing (gown, gloves, wash hands, remove googles, change
mask)
• Working with a High-Efficacy Particulate Air (HEPA) filter equipment
combined with PPE provide adequate protection. (Negative
pressure).

For ART
• IUI, embryo replacement.
• Prevention:
• Surface disinfection
• Triage (body T°, questionnaire)
• Ventilation of the room
• 20 m between each procedure (for
ventilation)
• Surgical mask with hand wash after
each exam
• (gloves single time use)

Procedure for patients (1)
triage
questionnaire of
both partners
two weeks
before starting
the ART.
A further triage
during ovarian
stimulation.

Procedure for patients (2)
• Get regular COVID-19 IgM/IgG testing
• Additional testing can be considered
Suspected of
infection
• Present medical evidence of clearance
• in order to be eligible for treatment
Previous
confirmed
COVID-19
• Provide evidence of assessment
• medical specialist report.
Respiratory
support during
the COVID-19

Both patients
are triaged as
low risk
[include]
Negative clinical
history
Lifestyle compatible
with minimal risk
Both patients are
asymptomatic

Patients who have
recovered from a
previous COVID-19
infection
• Proven by certified
medical evidence of
clearance,
• Should have COVID-19
IgM/IgG testing prior to
starting treatment.

Presence of
non-specific
symptoms in
one of the
partners
before starting
ovarian
stimulation:
[be open minded]
Repeat
the triage at the beginning of ovarian
stimulation
Continue If negative: Continue the treatment
Perform
If symptoms persist : Perform COVID-19
IgM/IgG testing to decide
Continue
If IgM/IgG negative: Continue the treatment
Postpone
If IgM/IgG positive: Postpone the treatment
and refer for further testing.

Non-specific
symptoms arising
during ovarian
stimulation
• Perform COVID-19 IgM/IgG
testing
Ø If IgM/IgG negative: Continue the
treatment
Ø If IgM/IgG positive: Postpone the
treatment and refer for further
testing.

Exclude
• If patients and/or
partners are
symptomatic or COVID-
19 positive, postpone
the treatment and refer
for further testing and
follow-up.

Access to
advice and
treatment
Tutorials on the
use of personal
protective
equipment (PPE),
if required.
Social distancing
and avoidance of
unnecessary
human physical
contact.
Information
about COVID-19
(symptoms or
exposure
occurrence).
Agreement that
treatment can be
discontinued if
the patient
encounters high-
risk situation

Adaptation of
ART services
• The treatment of each patient should be completely re-
thought and individualized.
• In order to reduce unnecessary visits and staff-patient
contact, telemedicine should be used for treatment
steps that do not require the physical presence of
patients at the center.

Sanitation
• Routine sanitation of all areas
should be performed according
to local protocols.
• Specific COVID-19 sanitation
procedures should be
implemented in case of COVID-19
positive patients or staff
members.

Staff and centre
adaptation
COVID-19-
specific training
COVID-19-specific
standard operating
procedures
Adjusted
work shifts
Emergency
agreements
between ART
centers

Access
procedures
(1)
Limitation of the number of
persons present in the center
Provision of protective screens for
administrative staff
Provision of personal protective
equipment and sanitation devices
Restriction of access for partners
and accompanying persons

Access
procedures
(2)
Redesign of waiting rooms and working
spaces to guarantee appropriate distancing
Management of appointments according to
specific timetables
Subdivision of staff into mini-teams to
reduce unnecessary exposure of patients
Follow-up of patients three weeks after
oocyte retrieval and/or embryo transfer

Treatment cycle
Ovarian stimulation monitoring
• Minimal exposure for both staff and patients.
• Isolation of staff showing symptoms of infection
• Use of personal protective equipment (PPE) by staff
• Minimal number of visits and optimised number of blood tests

Oocyte retrieval
• Follow standard procedures unless changes occur between
ovulation trigger and oocyte retrieval
• If positive re-triage : consider COVID-19 IgM/IgG and/or RT-PCR
testing for COVID-19. Based on the result, decide whether to
continue the treatment or to postpone it.
• If the patient tests positive for COVID-19, before ovulation
trigger or embryo thawing, postpone treatment, refer and
isolate.
• Exceptions : patients at high risk of OHSS. In this case, oocyte
retrieval could be performed and unit sanitation should follow .

Laboratory
• Routine good laboratory practice should be
followed and laboratory staff should wear
masks and gloves.
• Staff should be organized in mini-teams.
• Extra care should be taken to reduce
exposure to native follicular fluid and sperm
by dilution and safe disposal of fluids, as
quickly as possible.
• Should a patient become suspect or
positive for COVID-19 during embryo
culture, a freeze-all policy should be
adopted.

Embryo
transfer
Limit the number of staff members in the
transfer roomLimit
Restrict access for accompanying person(s)Restrict
Perform transfer only in cases of low
risk/asymptomatic patients and partnersPerform
Apply a freeze-all policy for all patients
and/or partners who became
symptomatic after the oocyte retrieval.
Apply

Summary Figure
treatment cycle

Some
considerations
could include:
The impact of delay on patient prognosis
due to medical factors, such as age, ovarian
reserve or endometriosis.
The number of patient visits required (e.g.
treatments that are associated with the
fewest visits may be prioritized first).
The impact of treatment delay on the
mental and emotional well-being of
patients.
The impact of delay on patient ability to
access treatment due to insurance coverage
or employment status.

• Together we can save
this world by
following
precautionary
measures and taking
care of each other …
• Thanks!

Polymerase Chain
Reaction (PCR)
• mostly Real-Time Reverse
Transcription-Polymerase Chain
Reaction (rRT-PCR)
• amplifies the viral genetic material
if present
• the most reliable test
• requires centralized labs for
analysis, so it can take several days
• can test a variety of samples like
urine, blood, saliva, sweat, serum,
and other fluids

Rapid diagnostic
test (RDT)
• typically qualitative (positive or
negative)
• can be used at point of care (POC)
• may use blood samples, saliva
samples, or nasal swab
• colored lines indicate positive or
negative
• for IgG and IgM or viral antigen

Enzyme-linked
immunosorbent assay (ELISA)
• lab-based test
• qualitative or quantitative
• whole blood, plasma, or serum
samples
• if the patient has antibodies to the
tested viral protein, they bind
together
• present protein complex measured
in the lab

Neutralization assay
• patient antibodies prevent
viral infection of cells in a lab
• can tell if a patient has
antibodies that are active
and effective against the
virus
• whole blood, serum, or
plasma samples
• depends on cell culture

Chemiluminescent
(Fluorescence)
immunoassay
• typically quantitative
• lab-based
• whole blood, plasma, or serum samples
• IgG, IgM, and IgA
• mixing samples with a known viral protein, buffer reagents, and specific
enzyme-labeled antibodies that release a light when bound
• amount of light is measured to calculate the number of antibodies present

Conclusions (1)
• Our practice is considered at low risk
• However a general prevention measures
should always be applied during the
pandemic
• Triage before entering the center or the
consultation office
• Face mask well positioned ( surgical masks )
• Patients gloves removed before entry and
hands disinfection
• Distancing appointments and patients in
waiting room

Conclusions (2)
• Surface disinfection of furniture and medical
material
• Appropriate prevention in operating rooms
(Donning and Doffing PPEs )
• Adequate ventilation of the examination rooms
• Distancing the procedure of ART
• Appropriate handling of specimens and
materials
• Keep PPEs available with respect of efficacy
duration ( 4 hours for surgical masks , single
time use of gloves).
• Appointed ‘person responsible’ for monitoring
the Policy

Pregnant women
• Vulnerable populations
• Physiological and mechanical changes
• Cardiopulmonary systems
• Changes in immune system
• Hypercoagulable state
• There are no data to inform whether pregnancy increases susceptibility to COVID-19
• No vertical transmission
• No data suggesting an increased risk of miscarriage
• There is no evidence currently that the virus is teratogenic

Our concern: (COVID-19)
Specificity:
Highly infectious
during
asymptomatic
incubation period
Low concentration
of viral RNA in
blood
High
concentration of
viral RNA in URT
Inactivation:
Acid PH (variety of
alcohol,
hydroalcoholic
gel) > 80% alcohol
Basic PH (soap
cleaning
solutions) 20”
time
Heat: 60° for 15-
30 minutes.

Enhanced control
measures to
prevent
nosocomial
transmission of
COVID-19
AAMI: Association for the Advancement of Medical Instrumentation
Control Measures Caring COVID19+ Triage station Aerosol
generating
procedures
Other patients’
areas
Other
Hand wash Required Required Required Required Required
Choice of mask N95 N95 N95 Surgical mask Surgical mask
Isolation gown AAMI level3 AAMI level1-3 AAMI level3 Standard
precautions +/-
Transmission based
precautions
Not Required
Disposable gloves Required Required Required Not Required
Eye protection Goggles, face
shield
Goggles, face
shield, eye visor
Goggles, face
shield
Not Required
Hair cover Optional Optional Optional Not Required

COVID-19
pregnancy
Morbidity
and
Mortality
Vertical
transmission
Congenital
Anomalies
Abortion

ART in The COVID-19 Era

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