Clinical and laboratory guidelines
for assisted technologies
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We believe that infertile couples have the right to establish a family.
Infertility is a sickness that gives physical and psychological pain that
needs treatment. This is stated by WHO.
At Nordica we know that we can cure 75% or more of the infertile
couples.
The treatment might consist of 1 or more attempts.
The nature has a chance of 20%. We offer a higher percentage of 30%
or more.
All issues involving patient treatment and research is considered and
approved by Nordica Advisory Board which consist of one doctor
from each clinic.
Nordica clinics are in accordance with the law of their country and the
public attitude in the future.
Nordica clinics are not involved in human cloning.
Nordica clinics are committed to inform patients about the treatments
and the expected outcome. We inform patients that fertilization is
decreasing for women from the beginning of the thirties.
Nordica wants to share our knowledge in human reproduction with
colleagues and public institutions.
Abbreviations and Definitions
IUI-D
Intra Uterine Insemination with Donor sperm
IUI-H
Intra Uterine Insemination with Husband’s sperm
ART
Assisted Reprodictiove Technologies
ESHRE
European Society of Human Reproduction and Embryology
ET
Embryo Transfer
Gamete
Oocyte or spermatozoa
HCG
Human Chorionic Gonadotropin
HIV
Human Immundidiciency Virus
HSG
HysteroSalpingoGraphy
ICSI
Intra Cytoplasmic Sperm Injection
IFFS
International Federation of Fertility Societies
IVF
In Vitro Fertilisation
Pre-Embryo Conceptus from the two-cell stage until 14days after conception
Pronuclei
Nuclei derived from the spermatozoa and the oocyte before fusion in the oocyte
QA
Qyality Assurance
QC
Quality Control
OHHS
Ovarian HyperStimulation Syndrome
1. The aim
The aim of the guidelines is to provide a framework for both the clinic and laboratory aspects of
assisted reproduction and for the use of local laboratory manuals and procedures. Therefore, the
guidelines are not to be considered a manual and do not provide recommendations on how to
perform the specific procedures. The guidelines should rather be seen as minimal standard
recommendations. The Nordica Advisory Board understands that the legal situation differs in the
countries. However, the Board believes that these guidelines could serve as a minimal standard,
common to all Nordica clinics.
3. Clinical guidelines
3.1 Clinical Manual
All clinical activities must be described in a Clinical Manual. The manual should provide the
contents of these guidelines, describing in detail the clinical work in the specific clinic and the
responsibility of each person working in that clinic. The manual must be kept accurate and up-todate at all times. Therefore, changes in the clinical practices approved by the Medical Director must
always be recorded in the manual.
In the manual, the responsibility for the handling of complaints from patients should be described.
Complaints can be resolved, filed and closed at different levels in the unit, as determined by the
medical director.
3.1.1 General Patient Information
An information or booklet brochure for couples considering treatment at the unit should include
specific information on the clinic:
 each treatment modality offered (background, performance and risks)
 volume of activities
 predicted results (including the incidence of abortion, ectopic pregnancy and multiple
pregnancy)
 patient selection criteria
 cost and reimbursement polices
 waiting list regulations
 the availability of professional psychological counselling
 presentation of the personnel involved
3.1.2 Detailed Treatment Schedule for patients
A treatment schedule providing detailed information should be issued to all couples undergoing the
different treatment modalities. This schedule should be different from the general information
booklet or information brochure described above. It should provide very practical information on
the treatment, timing, blood sampling procedures etc. Covering all the practical aspects of a
complete treatment.
3.1.3 Patient consent Form
All the concerned individuals must sign a complete set of forms used in the clinic for the received
treatment. This is especially important when previously frozen pre-embryos are being thawed and
transferred. In these cases, several years may have elapsed since the last IVF cycle, and must be
assured that it is the wish of both partners to have the pre-embryos thawed and transferred.
Informed consent should be considered with standard IVF, ICSI IVF, natural cycles, IUID and
IUIH. In addition, the use of spare pre-embryos for research must receive the consent of the couples
concerned.
3.1.4 History and Pre-treatment Assessment
History: The following important information must be collected for the assessment of each couple’s
suitability for assisted reproduction treatment:
 a well defined medical diagnosis of the infertility (including observations and PCO, myomas,
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endometriosis and sactosalpinges) and a decision on whether or not to intervene with these
findings before actual treatment takes place)
any concurrent disease of potential importance
evaluation of psycho-social situation
age of the woman and the man
duration of infertility
previous pregnancies and outcome
previous infertility treatments and outcomes
Immediate pre-treatment assessment: The immediate pre-treatment assessment deals especially with
sperm quality (assessed by sperm quantity, motility, morphology) the uterus and the uterine cavity
(assessed by ultrasound of the uterus including sonohysterography or HSG, in selected cases) and
ovarian reserve (assessed by cycle day 3 (2-4) monitoring of gonadotrophin levels). Also tests for
HIV, hepatitis B and C, and rubella should be considered for inclusion in the assessment.
Access to professional psychological counselling should always be available, if needed or
requested.
3.1.5 Individual Prognosis and treatment Plan
The pre-treatment assessment should form the basis for formulating an individual treatment plan
and an individual prognosis. Treatment alternatives should be identified. For each of the alternatives
the prognosis, risk, cost and time frame should be defined. All this information should be
documented in the couple’s individual record.
3.1.6 Monitoring of Ovarian Stimulation
Ultrasound monitoring is mandatory. Also, ready access to oestradion determination must be
avaolable when considered necessary. The monitoring is done to ensure appropriate adjustment of
hormone doses, timing of hCG injection and to allow cycle cancellation in cases of suspected OHSS
or in low responders.
3.1.7 Oocyte retrieval
Sufficient facilities and qualified personnel must be present during each oocyte retrieval procedure
to ensure the woman’s safety in case of an emergency. Sufficient pain-relief should be offered.
Correct handling of the oocytes retrieved must be assured.
3.1.8 Embryo Transfer
Normally, a maximum of two pre-embryos should be transferred. In exceptional cases three preembryos can be transferred. The clinic’s policy for selecting those cases where three pre-embryos
could be transferred should be clearly stated in the clinical manual. Factors to be considered here
include age of the woman, oocyte quality and the effect of freezing and thawing the pre-embryos.
The transfer of only one pre-embryo should be considered in selected cases.
Any delay in the transfer of the pre-embryos from the incubator to the uterus should be avoided.
3.1.9 Post treatment follow-up
Pregnant women should be monitored until the number and the site(s) of implementation(s) can be
determined. Thereafter, a referral to a specialist pregnancy follow-up should be considered.
For non-pregnant couples the treatment outcome should be discussed in detail. Post-treatment
consultation must be available for those who wish it, including psychological consultation.
3.1.10 Monitoring of Ovarian Stimulation without IVF
In cases of ovarian stimulation without IVF, intensive monitoring is mandatory, including ultrasound, to ensure that no more than three mature follicles exist when HCG for ovulation is given. If
more than three follicles develop cancellation of the cycle or transformation to an IVF cycle could
be considered. Aspiration to reduce the number of follicles may also be a possibility. Monitoring to
determine the number and the site(s) of implantation(s) is mandatory.
4 Laboratory Guidelines
4.1 Laboratory Manual
A Manual describing all laboratory procedures for the assisted reproductive technologies
undertaken should be available in each laboratory. The purpose of this manual should be to describe
standard operating procedures and to describe the laboratory procedures in sufficient detail to assure
reproducibility and competence in all aspects of the duties performed by the laboratory personnel.
The manual must be kept accurate at all times, and should be reviewed and revised at regular
intervals (e.g. every 6-month). The Laboratory Director must always approve changes in laboratory
practices. All personnel should be updated and trained on the revised procedures. It is important that
personnel receive continual training and education. The manual should include the following
information:
4.1.1 Procedures
The manual should include detailed operating procedures on all activities undertaken by the
laboratory. These are e.g. preparation of culture media, identification of oocytes, assessment of
oocyte quality, sperm preparation, culture conditions including insemination of oocytes,
determination of fertilisation and selection of pre-embryos) for each treatment modality (e.g. IVF,
microinsemination, microdroplets, AID, AIH etc.).
The manual should contain detailed lists of equipment and material, including the sources of
materials.
4.1.2 Record keeping and communication
The manual should include detailed procedures for keeping records, reporting results and
communication within the laboratory and with the clinical team.
4.1.3 Laboratory cleaning
The manual should include detailed procedures for cleaning rooms, material and equipment, and
procedures describing how to handle disposable waste, especially potentially infectious material.
4.1.4 Equipment
The manual should include detailed instructions for the maintenance and calibration of each piece
of laboratory equipment, including whether daily, weekly, monthly, or annual
maintenance/calibrations have to be performed. Records have to be complied at frequent intervals in
order to document maintenance/calibration and whether any corrective actions have been taken. The
manufacturers' guidelines for quality control, calibration, cleaning etc. should be noted.
4.1.5 Treatment policy
The manual should include detailed information on the legal aspects and the local policy regarding
assisted reproductive technologies,
4.2 Monitoring laboratory results
Monitoring of the laboratory results should include, but not necessary be limited to, the following:
Cumulative patient data
Frequency of:
* Oocytes in different quality and maturity grading categories (scoring)
* Fertilisation rate (number of oocytes showing two pronuclei per total number oocytes
inseminated)
* Pre-embryo development (cleavage rate)
* Pre-embryo’s in different pre-embryo grading categories (scoring)
* Developmental stage of pre-embryo's transferred (scoring)
* Embryo implantation (fetal heart activity) per pre-embryo replaced (i.e. implantation rate)
* Spare pre-embryo's suitable for cryopreservation
* Fertilised oocytes with 3 or more pronuclei (i.e. polyploidy)
* Pre-embryos used for research purposes.
Tracing all oocytes from aspiration to final disposition (i.e. transfer, cryop reservation, discharged
after culture and/or donation to research) must be possible.
5 Responsibility
The chain of responsibility for all the clinical and laboratory activities in the unit must be written
down and known to everyone working at the unit. The Clinical Manual and the Laboratory Manual
should clearly state the responsible person whom to contact during normal and odd-working hours.
The manuals should also state the competence required to per-form each of the procedures
undertaken by the clinic and the laboratory, and which persons are authorised to make changes in
the manuals.
A "Medical Director", specialist in obstetrics and gynaecology with at least two years of experience
in assisted reproduction, must be responsible for all medical activities of the unit.
A "Laboratory Director" with an academic degree in a related field and at least one year of
experience with laboratory procedures in the field of assisted reproduction should be responsible for
all the laboratory activities of the unit. The Laboratory Director should preferentially be either
employed or formally affiliated to the clinic. However, the Medical Director and the Laboratory
Director may be the same person.
6 Quality Control
A quality control program should be in place in each unit. Such a program should assure periodic
monitoring and control of all technical equipment such as ultrasound machines, oocyte retrieval
pumps, incubators laminar airflow benches and freezers as well as registration of all new batch
numbers of drugs, culture media, medical devices etc.
7 Quality Assurance
Quality must be assured by preventive measures relying on the documentation and evaluation of
clinical outcome data and by periodic conferences, where clinical outcome and laboratory
performance are complied and evaluated. Also, an Annual Report, compiling all data for each
specific year, should be issued for both internal and external use.
Each unit should establish a detailed quality assurance system (QA). It is important to realise that
most assisted reproductive technologies comprise many different disciplines, and a successful
program is a result of team work. It is therefore important to establish a formulated feedback system
whereby everyone in the team is frequently informed about data and results.
The QA-system should be in operation continuously and should include mechanisms to review and
analyse data in order to identify problems related to the quality of the service. In addition, the
QA-system should include warning systems, which when alarmed, require specific measures to be
taken to correct the problem. The system should permit continuos troubleshooting in order to obtain
optimal results. However, except for the birth of healthy children, there does not seem to be a single
or a few key parameters indicating how successful the assisted reproductive technologies are
performed.
8 Identification and labelling
8.1 Patient Identification: The Clinic
This should be performed at all stages throughout the treatment procedures. Identification should be
verified in such a way that it Is open to the couples.
8.2 Patient Identification: The Laboratory
Each laboratory should have a formulated procedure on how to identify patients, i.e. how do
personnel from the laboratory identify a woman who is to undergo oocyte retrieval or have
pre-embryos replaced.
8.3 Labelling
Each laboratory should have a formulated procedure on how biological material (e.g. blood, serum,
semen, follicular fluid, sperm, oocytes, pre-embryos etc.) should be labelled throughout all
procedures. The procedures should secure the identity of all biological specimens and ensure that an
interchange between patients cannot occur. It should be defined whether sperm samples also should
be labelled with the spouse's name, and how straws containing pre-embryos for cryopreservation
should be labelled. It should be considered how mistakes - if they should occur - are recorded, and
what measures should be taken to correct them.
9 Log-book
In order to establish trace ability of all activities undertaken, the clinic and laboratory should each
keep a Logbook. The book states for each day the personnel on duty, what activities were
undertaken, whether any deviations were made from the manual and if so why or whether any
extraordinary measures were taken.
10 Facilities
Sufficient facilities for patient care with appropriate rooms for different phases of the treatment
must be at hand. The geographical relation to the IVF laboratory must be such that gametes and
pre-embryos are properly handled and sufficiently protected. Equipment for resuscitation must be
*In place for emergency situations, which might occur during or after oocyte retrieval. Testing of
this equipment and training in its use must occur periodically.
The embryology laboratory should have adequate space to follow good laboratory practice. The
construction of the laboratory should assure aseptic and optimal handling of gametes and
pre-embryos during all phases of the treatment. Separate office space should be provided for
administrative work, such as record keeping and data entry. A general wet area in which washing of
equipment, sterilisation, etc., is performed, should be separate from the embryo laboratory. The
equipment used should be adequate for laboratory work and be easy to clean and disinfect.
A specific endocrinological laboratory should be identified to serve the unit when needed.
11 Protection
All utensils are disposable
It is important to realise that all assisted reproductive technologies involve handling biological
material, and pose a potential hazard of transmitting diseases to personnel. Each unit should
establish procedures and policies for the safety of personnel, both in the clinical and the laboratory
part, taking national and/or local safety regulations into consideration. These procedures can be
included into a safety plan, covering procedures regarding personnel protection, fire protection, etc.
The purpose of the protective measures is also to ensure aseptic conditions for gametes and
pre-embryos. The procedures should deal with, but not be limited to, the following:
Personnel Protective Equipment
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Use of laboratory clothing
Use of gloves and masks
The use of glasses or goggles
Shoe cover, scrubs and gowns
Equipment
Use of laminar-flow benches
Use of mechanical pipetting devices
Location for carrying out specific procedures, such as sperm preparation
Disinfecting and sterilisation of potentially infected equipment
Vaccinations Personnel
Vaccination against Hepatitis B is recommended
Patients
Screening for HIV, Hepatitis B/C and other sexually transmitted diseases before treatment should
be considered.
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Documentation of Results - Data Collection
-Annual Report -
The clinic must document the number and the proportion of pregnancies, abortions, ec- and multiple
pregnancies per started treatment cycle, per oocyte retrieval and per transfer. The outcomes should
be presented according to the age of the woman and the treatment indication. For the children birth
weight, pregnancy week at delivery and any malformation should be documented. All side effects
must be documented, Short-term side-effects concern the woman and include the incidence of
allergic reactions, intra abdominal bleeding, infections, and cases of OHSS. Long term side-effects
concern the woman, the man and the infant. Follow-up on long side effects is preferably the
responsibility of research projects or national initiatives. Recommendations on caryotype
determinations in cases of new treatment modalities (such as ICSI) should be considered.
The treatment volume (number of started and cancelled cycles, retrievals and transfers and number
of couples treated) must be stated.
Each clinic should issue an Annual Report containing the outcome documentation outlined above.
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Data Collection for National, Regional and Global Purposes
In the Nordic countries, different laws regulate data collection procedures on a national basis. Data
collection requests from regional bodies such as ESHRE or from global bodies such as IFFS, should
also be met.
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