This chapter should be cited as follows:
Hasaballah A, Mocanu EV, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421143

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 15

Reproductive medicine for the obstetrician and gynecologist

Volume Editors: Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS

Published in association with the
International Federation of
Fertility Societies

Chapter

Patient Advice Prior to Medically Assisted Reproduction

First published: November 2024

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ABSTRACT

Couples who are unable to conceive after 1 year of regular unprotected intercourse are considered subfertile. While many causes of male and/or female subfertility are medically or surgically manageable in primary or secondary care facilities, the remaining patients who cannot achieve a pregnancy will require medically assisted reproduction (MAR) interventions in order to conceive.

Prior to MAR, the couples must be fully investigated and etiological therapies provided when the likelihood of achieving a pregnancy without MAR is realistic. The recommendation for MAR should only be made after all other therapies have been exhausted. Couples must be given a clear diagnosis and receive counseling with evidence-based information regarding MAR interventions, success rates, complications, failure rates, risks to “child to be” and costs.

INTRODUCTION

Fertility rates are falling at a far faster rate than expected with 50% of countries with rates below the replacement rate of 2.1.² As such, the investigation and treatment of infertility are becoming a global priority for all stakeholders. One in six couples worldwide is estimated to struggle to conceive, infertility lifetime prevalence being 17.5%.³ MAR treatments are well-established interventions that help patients who cannot conceive otherwise. Since 1978 when Louise Brown was born, more than 12 million babies have been brought into this world after the use of MAR therapies.⁴ The procedure is the only option in couples where natural conception is not possible, i.e., both Fallopian tubes have been removed or no sperm present in the ejaculate (azoospermia).

The MAR uptake is well below the global need, yet the trend is upwards due to changing attitudes in relation to family building, and couples deciding to have a family much later in their lives resulting in increased need for intervention. The ICMART Glossary¹ is the up-to-date reference for definitions of MAR in the field. A list of relevant definitions is presented below.

Medically assisted reproduction (MAR)

All interventions that include the in vitro handling of both human oocytes and sperm for the purpose of reproduction. This includes, but is not limited to, IVF and embryo transfer (ET), intracytoplasmic sperm injection (ICSI), embryo biopsy, pre-implantation genetic testing (PGT), assisted hatching, cryopreservation, and embryo donation. Thus, MAR does not include intrauterine insemination (IUI).

In vitro fertilization (IVF)

A procedure in which laboratory processed sperm are used to fertilize the oocyte in vitro.

Intracytoplasmic sperm injection (ICSI)

A procedure in which a single spermatozoon is injected into the oocyte cytoplasm.

Pre-Implantation genetic testing (PGT)

A test performed to analyze the DNA from oocytes (polar bodies) or embryos (cleavage stage or blastocyst) for HLA-typing or for determining genetic abnormalities. These include: PGT for aneuploidies (PGT-A); PGT for monogenic/single gene defects (PGT-M); and PGT for chromosomal structural rearrangements (PGT-SR).

Assisted hatching

An MAR procedure in which the zona pellucida of an embryo is either thinned or perforated by chemical, mechanical or laser methods.

Cryopreservation

The process of slow freezing or vitrification to preserve biological material (e.g., gametes, zygotes, cleavage-stage embryos, blastocysts or gonadal tissue) at extreme low temperature.

Intrauterine insemination (IUI)

A procedure in which laboratory processed sperm are placed in the uterus to attempt a pregnancy.

Testicular sperm aspiration/extraction (TESA/TESE)

A surgical procedure involving one or more testicular biopsies or needle aspirations to obtain sperm for use in ICSI.

As the MAR field remains a high-tech medical intervention and many of the definitions and procedures might seem difficult for patients to comprehend, appropriate information, counseling and time to digest the information offered are paramount before asking for consent and enrolling patients in such programmes. This chapter deals with the immediate steps before MAR, practitioner-patient dialog, information exchange, consent and risk analysis. It is intended to be a reflection of current good clinical practice prior to commencing MAR.

ADVICE PRIOR TO CONSENT

For an informed consent to be taken, the information and decisions between the clinician and the patient has to be shared in a diligent and robust way. Both partners of the couples have to understand the nature of the procedure, steps, risks, prognosis and alternatives, if any available. The consequences of not proceeding have to be discussed as well.

The key principles for consent to be valid are:

• Capacity to make an informed decision
• Competency to give consent
• Ability to understand the information provided
• Ability to communicate own decision.

An integral part of the MAR decision-making process is that patients should have the opportunity to make informed decisions regarding their care and treatment via access to evidence-based information provided by the services that treat them. Couples should be seen together because both partners are affected by decisions surrounding investigations and treatments. Verbal and written information should be provided as well as audio-visual media, if available. Special care should be supplemented to people who have additional needs, such as physical, cognitive or sensory disabilities, and people who do not speak or read the country language.⁵

So, what information should patients be provided prior to seeking consent for MAR?

The diagnosis

All patients should receive a final diagnosis and a recommendation for MAR based on the likelihood of a pregnancy establishing without MAR. While no MAR treatment is guaranteed to work, there is no obligation for any patient to undergo MAR either.

Preventive reproduction

• Female age is one of the most important indicators. Increasing female age is negatively correlated with MAR success. Subsequent pregnancy risks include increased miscarriage and early pregnancy loss, preterm delivery, gestational diabetes, hypertensive disorders, intrauterine growth restriction (IUGR), antepartum/postpartum hemorrhage, and cesarean section.⁶
• BMI. A normal range is considered (18.5–24.9 kg/m²). Overweight or underweight women have increased procedural risks and subsequent pregnancy risks, including early pregnancy loss, gestational diabetes mellitus, and IUGR.
• Medical conditions. Optimization of female and male health remains a pre-MAR priority. Occasionally, the need for multidisciplinary advice should be recognized early and offered before starting the procedure. Many disorders may interact with the procedure and/or the subsequent pregnancy: endocrine-metabolic disorders (e.g., diabetes, thyroid disorders), gynecological conditions (e.g., endometriosis), auto-immune disorders (e.g., multiple sclerosis, systemic lupus erythematosus), thrombophilia, previous abdominal surgery, single organ or systemic diseases, to name just a few.
• Infectious diseases. Where a partner is diagnosed with a transmissible disease, treatment of the condition and prevention of horizontal and vertical transmission is essential as part of optimization prior to MAR treatment.⁷
• Alcohol and smoking significantly reduce the likelihood to conceive after MAR, irrespective of which partner smokes. Smoking cessation should be advised for all patients planning MAR.
• Vitamins and folate repletion reduces the risk of spina bifida in the offspring. All females trying to conceive should take folic acid daily or a multivitamin that contains folate. Where a family history exists or medical conditions that justify a higher dose (epilepsy, diabetes, high body weight), 5 mg folate daily must be prescribed.

Why the procedure is needed (indication)

While no MAR treatment is guaranteed to work, there is no obligation for any patient to undergo MAR. Unless a pregnancy is impossible (no sperm, no uterus, no tubes, no intercourse) there is always a theoretical chance that a pregnancy will establish in the absence of MAR. The practitioner has a deontological duty not to recommend MAR if the likelihood of pregnancy is negligible. The main indications for MAR are detailed in Table 1.

What the procedure involves (female and male)

MAR technologies are complex therapeutic intervention combining clinical and laboratory processes.

For IUI the medical intervention includes daily injections with follicle stimulating hormone (FSH), ultrasound monitoring and triggering with human chorionic gonadotropin (hCG), semen preparation in the laboratory and transcervical insertion of the prepared semen into the uterus.

The clinical steps for IVF/ICSI include hormonal stimulation, monitoring of the follicular development with ultrasound scans and bloods, oocyte pick-up (OPU), extraction of the oocytes through the vagina). The first laboratory process includes insemination of oocytes either by In IVF, an intervention where oocytes and sperm are placed in a culture medium and allowed to interact without interference or ICSI when a male factor is present and a single sperm needs to be injected into a single mature egg, in turn. The laboratory activity also includes fertilization check and embryo culture/development assessment, intrauterine ET, and/or cryopreservation.

The hormonal ovarian stimulation for IVF uses FSH administered subcutaneously, daily and an additional injection or nasal spray to prevent spontaneous ovulation due to endogenous LH release (gonadotropin releasing hormone (GnRH) antagonist or GnRH agonist). A hCG injection is used to mature the eggs before the surgical transvaginal procedure to remove the eggs. Afterwards the eggs and sperm are processed in the laboratory in the hope of a normally developed embryo to be inserted in the uterus after 2, 3, 5 or 6 days of in vitro development. Any additional normal appearing embryos can be preserved by snap freeze (vitrification) and stored in liquid nitrogen for a recommended, sometimes law determined, duration.

For frozen embryo replacement (FER) cycles there are two options: using the natural cycle and transferring the thawed embryo a few days after spontaneous ovulation or using an HRT stimulated cycle (where no spontaneous ovulation occurs) where estrogens are used to proliferate the endometrium and progesterone is added to induce secretory changes followed by embryo thaw and transfer.

Donor oocytes therapies involves the use of oocytes from a donor, the patient does not require FSH stimulation and only follows the protocol of a FER treatment.

In surrogacy therapies the surrogate offers her uterus as an incubator for the embryo belonging to the couple that need surrogacy. The embryo could be created with either their own genetic materials (own oocytes and sperm) or donor gametes.

When the man has no sperm in the ejaculate, a testicular biopsy is recommended to identify the presence of sperm and attempt to freeze a sample if quality allows. A cut is made in the testicle(s) and the tissue is sent to the MAR laboratory where it is analyzed for the presence of sperm and a histological diagnosis is also pursued. Any healthy sperm identified can be frozen and subsequently used for ICSI.

Advanced laboratory techniques such as pre-implantation genetic assessment encompass an embryo biopsy (removal of cells from the outer embryonic layers that will form the placenta, [i.e., trophoblastic cells]) and subsequent advanced analysis of the genetic material of these cells to either screen for known abnormalities or detect new ones. It is indicated to exclude affected embryos where familial genetic risks exist or to select a genetically competent (euploid) embryo prior to implantation.

For single women, in case of sperm and/or egg donation and surrogacy, the genetic legacy of the “child to be” must be discussed and incorporated in the consent.

The opportunity to freeze gametes and embryos is part of the consent discussion and details such as method of freeze and storage, duration of storage and destiny of the stored material in different life circumstances (death, separation, divorce, force majeure) must be thoroughly discussed.

As the consent has to cover the multiple facets of the MAR intervention, the discussion prior to obtaining consent must be as comprehensive as possible and applicable to the clinical scenario.

MAR RISKS

No medical intervention is 100% safe. The main risks related to the MAR procedures are detailed below:

• Side-effects or allergy to medication – rare but possible. Discontinuation of therapy is required and alternatives proposed.
• Ovarian hyperstimulation syndrome (OHSS) – an excessive ovarian response to FSH stimulation, characterized by the growth of a large number of follicles.⁸ Females diagnosed with PCOS should receive an antagonist protocol to reduce and eliminate (if freezing all embryos) the risk of OHSS.⁹ Potential complications are venous or arterial thromboembolism, pulmonary edema and acute respiratory distress syndrome, renal failure, ascites and even death. Cancelation of a treatment cycle is sometimes needed.
• Injuries at oocyte pick up – the procedure is performed under sedation and an ultrasound guided needle is inserted through the vagina directly in each ovary. Bladder, blood vessel or bowel injury are possible (risks less than 1 : 1000) particularly in high BMI patients or in patients with previous major abdominal or pelvic surgery.¹⁰ Pelvic inflammatory disease is also possible as the vagina is not a sterile environment.
• Testicular infection, failure – if the man requires a testicular biopsy to obtain sperm.
• Failure to fertilize – when sperm and eggs are mixed together there is a 5% chance that no eggs fertilize. This means there will be no transfer during this procedure and injection of sperm into the egg (ICSI) is recommended in a new cycle.
• Embryo demise – can occur after the sperm injection or after embryo biopsy.
• Genetic misdiagnosis – a 5% risk after embryo biopsy and genetic analysis.
• No embryos to transfer – even if fertilization occurs there is no guarantee that a healthy appearing embryo will form after culture in vitro. The risk is about 1 : 200
• Multiple pregnancy – if more than one follicle at IUI or more than one embryo transferred during IVF/ICSI/frozen transfer the likelihood of a multiple pregnancy increases significantly. A single embryo transfer is recommended in all suitable cases.
• Early pregnancy complications – are the same as after a spontaneous pregnancy establishing. Both miscarriage and ectopic pregnancy are possible after MAR, risk of ectopic 1 : 100.
• Related to pregnancy and the children born – the patients that require IVF/ICSI are a highly selected population. Their risk of having a child with a congenital anomaly is higher than for couples that spontaneously conceive within 12 months of trying. Singletons conceived through MAR have increased risk compared to singletons spontaneously conceived. In a recent meta-analysis¹¹ showed that among IVF/ICSI conceived children, pooled estimates were 10.9% (95% confidence interval (CI) 10.0–11.8) for preterm birth, 2.4% (95% CI 1.9–3.0) for very preterm birth, 8.7% (95% CI 7.4–10.2) for low birth weight, 2.0% (95% CI 1.5–2.6) for very low birth weight, 7.1% (95% CI 5.5–9.2) for small for gestational age, 1.1% (95% CI 0.9–1.3) for perinatal mortality, and 5.7% (95% CI 4.7–6.9) for congenital malformations. the main malformations have been shown by Chen et al.¹² to be cardiac, musculoskeletal and genitourinary. These risks increase further when multiple gestation occurs after MAR therapies.

MAR success rates

Clinical pregnancy is commonly used for measuring the success of MAR. It is defined as ultrasound visualization of one or more gestational sacs or definitive clinical signs of pregnancy. Without specification of the location of the pregnancy, this definition includes ectopic pregnancy.^1,13

The average birth rate from IVF using fresh embryo transfers increased from 8% per embryo transferred in 1991 to 22% in 2021. Patients aged 18–34 had the highest delivery rate per embryo transferred at 33% in 2021.¹⁴ We quote the Human Fertilisation and Embryology Authority (HFEA) data as they collect compulsory outcomes from a large cohort of clinics and treatments provided.

From a patient perspective the most relevant measure of success is the livebirth rate (LBR). While the medical background plays a role also, figures from the HFEA show a constant decrease in LBR as female age advances (Table 2).

COSTS

Where the public purse does not pay for IUI/IVF/ICSI or other MAR therapies patients need to be made aware of the costs (many times significant) of paying for these medical interventions. Costs of treatments vary significantly according to the country where the treatment takes place, whether the medications are included or not, techniques used, patient age and the need for donor sperms/ovum. For IVF/ICSI figures span from 2000 $ in India and many low- and middle-income countries¹⁵ to 30,000 USD in United States.¹⁶

CONCLUSIONS

Patients where MAR is the next medical intervention are vulnerable and require adequate information and discussion in order to decide whether they should pursue the treatment and give informed consent. Indications for MAR must be clear and based on history, examination and investigations. The information to be provided includes risks of the MAR procedure, ethical aspects (freezing, donor, single embryo transfer), success and failure rates, pregnancy risks and child risks. Health optimization of all patients is a major priority, especially as it has a major impact on the outcome of treatments and outcome of pregnancy. The recommendation to proceed with MAR carries some responsibilities from both the practitioner (to provide all information necessary, ensure information is understood, obtain consent) and the patient (to understand and be informed prior to consent, follow the advice). MAR therapies are now recognised as routine medical interventions and have allowed patients the opportunity to have a healthy child where a pregnancy cannot establish naturally.

PRACTICE RECOMMENDATIONS

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