Keywords

18.1 Introduction

The human species is biologically distinguished by low fertility.

In fact, with each menstrual cycle, a couple at the peak of their reproductive capacity has only about a 30% chance of conceiving. This percentage, already quite modest, is significantly reduced in the presence of factors that can reduce reproductive capacity. The World Health Organization (WHO) states that it is the decision of each individual and couple, according to their conscience, to determine whether they intend to have a pregnancy and if so, when they wish to have a child, as well as determining the size of the family unit. However, fertility problems may affect the possibility of pregnancy. The WHO states infertility as “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse” [1] It is reported that one in four couples in developing countries has been affected by infertility. In 2012, infertility in women remained within a similar range over 20 years, from 1990 to 2010. However, in 2019, infertility increased worldwide, as it was found that the age-standardized infertility prevalence rate increased by 0.37% per year for women and by 0.29% per year for men. Since a significant percentage of couples manage to have a child after at least 2 years of trying, many prefer to talk about infertility after 24 months. The term “sub fecundity”, on the other hand, indicates a fertility index three or four times lower: this means that some couples will have to wait longer to conceive. Although it is difficult to assess the impact of the various factors on the causes of infertility, the data regarding the incidence and the main causes of infertility are similar worldwide. About 20–30% of infertility cases are due to male infertility, 20–35% are due to female infertility, and 25–40% are due to combined problems in both parts. In 10–20% cases, no cause is found.

Common contributory factors-causes of female infertility, include:

  • Ovarian disorders and hormonal imbalances (e.g., polycystic ovarian syndrome-PCOS), premature ovarian failure (POF), hypothalamic dysfunction, hyperprolactinemia.

  • Fallopian tubal damage (including previous tubal ligation).

  • Pelvic inflammatory disease (PID) caused by infections like tuberculosis.

  • Age-related factors.

  • Uterine problems (benign polyps fibroids).

  • Cervical disorders (benign polyps or tumors and cervical stenosis).

  • Endometriosis.

  • Advanced maternal age.

The main cause of male infertility is low semen quality. In men who have the necessary reproductive organs to procreate, infertility can be caused by low sperm count due to endocrine problems, drugs, radiation, or infection. There may be testicular malformation, hormone imbalance, or blockage of man’s duct system.

Male and female infertility: in some cases, both the man and woman may be infertile or subfertile, and couple’s infertility arises from the combination of these conditions. In other cases, the cause is suspected to be.

Infertility due to unknown cause (idiopathic): In the US, up to 20% of infertile couples have unknown (unexplained) infertility. In these cases, abnormalities are likely to be present but not detected by current methods.

18.2 Assisted Reproductive Technology

Assisted reproductive technology (ART) consists of all treatments or procedures that include the in vitro handling of both human oocytes and sperm or of embryos, for the purpose of establishing a pregnancy. Increasingly, couples are turning to ART for help with conceiving and ultimately giving birth to a healthy live baby of their own. In July 1978, Louise Brown was the first child successfully born after her mother received IVF treatment. Brown was born as a result of natural-cycle IVF, where no stimulation was made. The procedure took place at Dr. Kershaw’s Cottage Hospital (now Dr. Kershaw’s Hospice) in Ryton, Oldham, England. Robert G. Edwards was awarded the Nobel Prize in Physiology or Medicine in 2010. The physiologist codeveloped the treatment together with Patrick Steptoe and embryologist Jean Purdy, but the latter two were not eligible for consideration as they had died and the Nobel Prize is not awarded posthumously. Since the first baby was born after in vitro fertilization (IVF) in the United Kingdom in 1978, assisted reproductive technology (ART), including IVF and embryo transfers (ETs), has been widely used for infertility treatment worldwide. The International Committee for Monitoring Assisted Reproductive Technologies reported that more than one million babies were born after ART between 2008 and 2010.

18.3 Art Techniques and Indications

The techniques are usually divided into three broad categories:

  • First level techniques: the simpler and less invasive ones, such as intrauterine insemination (IUI) with or without ovarian stimulation.

  • Second level techniques the more complex and more invasive ones that can be performed under local anesthesia or deep sedation, which differ from the basic techniques as they involve manipulation of female and male gametes and because they require in vitro fertilization. Among these techniques, the IVF (In Vitro Fertilization and Embryo Transfer), ICSI (Intracytoplasmic Sperm Injection), and the possible cryopreservation of male and female gametes and embryos.

  • Third level techniques procedures that require general anesthesia with intubation, including:

    • laparoscopic egg retrieval, intra-tubal transfer of male and female gametes (GIFT), zygotes (ZIFT) and /or embryos (TET) laparoscopically;

    • microsurgical sampling of gametes from the testicle: Testicular Sperm Extraction (TESE), Microsurgical Testicular Sperm Extraction (microTESE), Testicular Sperm Aspiration (TESA);

    • microsurgical sampling of gametes from the epididymides: Percutaneous Epididymal Sperm Aspiration (PESA) and Microsurgical Epididymal Sperm Aspiration (MESA).

In all assisted reproduction techniques, the seminal fluid receives a treatment able to induce capacitation “in vitro” so that the activated spermatozoa, at the threshold of the acrosomal reaction, can interact with the mature oocytes.

The goal of the preparation is twofold:

  1. 1.

    Separate sperm from seminal plasma which contains decapacitating factors, bacteria, leukocytes, and cell debris.

  2. 2.

    Concentrate as many spermatozoa as possible with good progressive motility in a small volume.

18.3.1 First Level Technique: Intrauterine and Intracervical Insemination IUI/ICI

Intrauterine insemination is used most often in couples who have:

  • Donor sperm treatment.

  • Unexplained infertility.

  • Endometriosis stage I –II-related infertility.

  • Mild male factor infertility (subfertility).

  • Cervical factor infertility.

  • Ovulatory factor infertility.

In an IUI cycle, the male partner’s sperm is prepared and placed directly in the womb around the time of ovulation. The sperm can be inseminated in natural cycles or in cycles with ovarian stimulation.

In natural cycles, the timing of insemination may be determined by measuring urinary luteinizing hormone (LH). Detection of a rise in the LH level can also be done in the clinic, with daily blood samples. Finally, transvaginal ultrasound, in combination with the administration of human chorionic gonadotropin (hCG), may be used to time the insemination [2]. In cycles with OH, women receive clomiphene citrate, an antiestrogen, or gonadotrophins to induce the growth of up to three follicles. The timing of insemination is determined by transvaginal ultrasound, combined with hCG-triggered ovulation.

When the follicle reaches an estimated size of 15–20 mm, human chorionic gonadotrophin (hCG) is administered intramuscularly and final maturation of the oocyte is thereby induced [3]. Many sperm preparation procedures are available, but there are three main methods (Fig. 18.1) used to select the best spermatozoa from native sperm (Fig. 18.1a).

Fig. 18.1
figure 1

Description of the compared sperm preparation procedures (a) Native sperm; (b) Swim-up; (c) Density Gradient Centrifugation, and (d) Centrifugation with washing

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18.3.1.1 Sperm Preparation Techniques

  • Swim-up: The spermatozoa may be selected on their ability to swim, known as the “swim-up technique” (Fig. 18.1b). This technique is performed by layering culture medium over the liquefied semen. Motile spermatozoa then swim into the culture. The upper part of the supernatant is then carefully removed for further use.

  • Density gradients The second method of selecting spermatozoa is by the use of density gradients (Fig. 18.1c). The semen sample is pipetted on top of the density column and then centrifuged. Density gradient centrifugation separates spermatozoa according to their density. This way you can select the motile, morphologically spermatozoa in the solution with the highest concentration of gradient, which is aspirated for further use [4].

  • The third method is the conventional wash method in combination with centrifugation (Fig. 18.1d). The semen sample is diluted with a medium and centrifuged. Subsequently, the pellet is resuspended in a bit of medium and incubated until the time of insemination.

Concerning IUI outcomes, recent evidences suggest that treatment with IUI with ovarian stimulation probably results in a higher live birth rate, compared to expectant management without ovarian stimulation, in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle [5]. At present, the most important indication for IUI is in donor sperm treatment. In these cases, the sperm can be introduced by intrauterine insemination (IUI) or by intracervical insemination (ICI). The main difference between IUI and ICI is the processing of the sperm [6].

18.3.2 Second Level Techniques: In Vitro Fertilization (IVF)

Fertility treatments are complex, and each cycle consists of several steps. If one of these steps is incorrectly applied, conception may not occur.

18.3.2.1 Indications

In vitro fertilization is indicated in couples who are unable to conceive for:

  • Tubal-peritoneal factor (acquired or congenital tubal disease).

  • Moderate male infertility when medical-surgical treatment or previous intrauterine inseminations have failed or have been judged inappropriate.

  • Severe male factor infertility.

  • Grade III or IV endometriosis.

  • Immunological factor.

  • Idiopathic infertility if the previous intrauterine insemination treatment did not give results or was not judged appropriate for that couple.

  • Cryopreserved semen, in relation to semen quality after thawing.

  • Repeated abortion.

  • Genetic Diseases/Preimplantation Genetic Screening or Diagnosis (PGT-A or PGT-M).

The following steps make up an IVF cycle:

  • Drugs are initiated to stimulate growth of multiple ovarian follicles, while at the same time other medications are given to suppress the natural menstrual cycle and downregulate the pituitary gland.

  • After ovarian stimulatory drugs are initiated, monitoring is undertaken at intervals to assess the growth of follicles. When the follicles have reached an appropriate size (19–20 mm), a drug is administered to bring about final maturation of the eggs (known as ovulation triggering). The next step involves egg collection (usually with a transvaginal ultrasound probe to guide the pickup) and, in some cases of male infertility, sperm retrieval.

  • Next is the fertilization process, which usually is completed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

  • Embryos are then placed into the uterus. Issues of importance here include endometrial preparation, the best timing for embryo transfer, how many embryos to transfer, what type of catheter to use, the use of ultrasound guidance, need for bed rest, etc.

Then comes luteal phase support, for which several options are available, including administration of progesterone, estrogen (E2), and human chorionic gonadotrophin (hCG).

Finally, adverse effects, such as ovarian hyperstimulation syndrome, can be associated with the assisted reproduction process.

18.3.2.2 Controlled Ovarian Stimulation in IVF

Controlled ovarian stimulation comprises three basic elements.

  1. 1.

    Exogenous gonadotrophins to stimulate multi-follicular development.

  2. 2.

    Cotreatment with either gonadotropin-releasing hormone (GnRH) agonist or antagonists to suppress pituitary function and prevent premature ovulation.

  3. 3.

    Triggering of final oocyte maturation 36–38 h prior to oocyte retrieval.

Gonadotrophin preparations available for use include human menopausal gonadotrophin (hMG), a urinary product with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity, purified FSH (p-FSH) and highly purified FSH (hp-FSH), and various recombinant FSH (rFSH) and LH (rFSH/rLH) preparations. In addition, IVF in an unstimulated cycle with the anticipation of only collecting a mature single egg is offered by some clinics, but this practice is not widely established [7].

GnRH agonists or antagonists have been used in a number of different protocols. In the so-called ‘long protocol’, the GnRH agonist is started at least 2 weeks before stimulation and continued up until oocyte maturation is achieved. Alternatively, a ‘short protocol’ is used in which the GnRH agonist is commenced simultaneously with stimulation and continued up until the day of oocyte maturation trigger. Yet another option is the use of GnRH antagonists. These involve a shorter duration of use compared with the agonist ‘long protocol’ and are started a few days after initiation of stimulation, continuing up until administration of a drug to trigger oocyte maturation.

18.3.2.3 Controlled Ovarian Stimulation and Ovarian Response

On the basis of ovarian response patients are classified into normoresponders, poor responders, and hyperresponders. Although no unequivocal definition of the poor responders has been universally accepted, the Bologna classification [8] defines poor responders by two of the following characteristics:

  • Maternal age 40 years or older, or other risk factors for poor ovarian response (such as excision of bilateral ovarian endometriomas)

  • Poor ovarian response in previous IVF cycle(s) (defined as retrieval of three or fewer oocytes in a conventional stimulation IVF protocol).

  • Low antral follicle count (AFC) (less than5–7 follicles), or low anti-Müllerian hormone (AMH) below 0.5–1.1 ng/mL (3.5–8 pmol/L).

Hyperresponders patients, with a prior risk for development of hyperstimulation (OHSS), are those with polycystic ovaries (PCOs), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations [7]. Ovarian stimulation protocols are chosen on the basis of the expected response of patients. Duiring controlled ovarian stimulation, the number and size of follicles, visualized at transvaginal ultrasound sonography, provide an estimate of ovarian response and hCG is used to trigger ovulation when a certain number of follicles reach a certain size. Estradiol, which is produced by developing follicles, provides additional information which is believed to further improve the decision making process; follicle maturity is supported by adequate estradiol levels while there is an increased risk of OHSS in the presence of very high levels. At the end of the stimulation phase of an IVF cycle, a drug is used to trigger the final oocyte maturation, which is used to mimic the natural endogenous LH surge and initiate the process of ovulation before the mature eggs are collected from the woman and fertilized with sperm in the laboratory. Two drugs are currently used: human chorionic gonadotropin (HCG), which is the most common drug, or GnRH agonist in an antagonist protocol.

18.3.3 IVF—ICSI: Laboratory Phase

In Vitro Fertilization (IVF) and Intracitoplasmatic Sperm Injection (ICSI) are laboratory techniques that both involve the aspiration of oocytes from the follicles. Therefore, the therapy to be carried out by the patient and the egg retrieval are absolutely the same in the two techniques. Which technique to adopt is a decision that is made “in the laboratory” after the egg retrieval.

18.3.3.1 In Vitro Fertilization

IVF consists of placing the spermatozoa close to the oocyte and letting one of these fertilize it naturally (Fig. 18.2). This technique can be used when sperm has the adequate number of spermatozoa with sufficient motility to fertilize the egg.

Fig. 18.2
figure 2

(a) IVF: Sperms are placed along with eggs and leave them to their natural process of fertilization. (b) Microscopic sperm cells around human egg

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18.3.3.2 Intracitoplasmatic Sperm Injection (ICSI)

In vitro fertilization with ICSI is an assisted reproduction technique that allows to inseminate an oocyte (female reproductive cell) by microinjection into it of a single sperm. The ICSI requires a sperm to be selected and injected into the oocyte, forcing its fertilization (Fig. 18.3).

Fig. 18.3
figure 3

ICSI procedure: a single spermatozoa is injected directly into an egg to achieve fertilization

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Once fertilized, the oocyte becomes a preembryo and is transferred inside the uterus so that it continues its development (Fig. 18.4).

Fig. 18.4
figure 4

Stages of embryo development from zygote (day 1) to blastocyst (day 5)

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ICSI is a complementary tool to conventional in vitro fertilization. The previous and subsequent stages are the same as those of insemination (stimulation of the ovaries, follicular puncture, and embryo transfer); only the insemination technique changes. This technique is used when the spermatozoa are in very small numbers and their motility is very low. With this technique, there is an evident saving of sperm: only one sperm is needed for each oocyte, while in conventional IVF, between 50,000 and 100,000 sperm are needed. IVF technique reproduces more faithfully than ICSI what probably occurs in nature; allowing the sperm to enter in a very natural way, without having to create a microtrauma on the oocyte wall (the microinjection of ICSI). Let the sperm that fertilizes the egg be “selected by nature”. However, we do not yet know for sure whether this selection process is better than the one performed in the laboratory with ICSI. Since sperm and oocytes remain in contact for a long time, the slightly immature oocytes develop and be fertilized even many hours after pick-up. On the other hand, ICSI technique is the only technique through which it is possible to obtain pregnancy when the seminal damage is severe or when the spermatozoa must be retrieved directly from the testicle and not from the ejaculate. It ensures that if there is a problem where the sperm is unable to “pass” the egg wall, it is overcome by microinjecting the sperm beyond the wall. It is the only technique that fertilizes oocytes if the frosted oocytes are used. It is therefore clear that in some cases the choice of ICSI is an opportune and obligatory choice which has revolutionized the world of assisted procreation, allowing fertilization with very badly damaged seminal fluids. It is also true that in cases where it is applicable, IVF remains an effective and highly successful technique. Therefore, the use of routine ICSI is not indicated but only in specific cases. The most appropriate technique will therefore be chosen according to the clinical situation of the couple.

18.3.4 Third Level Techniques: IVF in Azoospermic Patients

The absence of sperm in semen does not necessarily mean that they are not produced at all. In the case of azoospermia, crypto-azoospermia, necrozoospermia, and anejaculation, the spermatozoa can be identified in other sites—testis or epididymis—and even if in small numbers they can be collected using various techniques. Testicular Sperm Extraction (TESE) and Microsurgical Testicular Sperm Extraction (microTESE) or Testicular Sperm Aspiration (TESA) allow the recovery of spermatozoa from the testicles; other techniques as Percutaneous Epididymal Sperm Aspiration (PESA)and Microsurgical Epididymal Sperm Aspiration (MESA) from the epididymides. What are the main withdrawal techniques in details:

  • PESA, MESA, and TESA are procedures performed by needle aspiration: the sampling is carried out with different techniques in the epididymis.

  • TESE and micro TESE are surgical procedures: the collection takes place through the skin of the testicle.

TESE: is a biopsy of testicular tissue, a procedure that allows the recovery of spermatozoa from a small fragment of surgically removed testicle tissue. TESE can be performed under local, locoregional anesthesia, or deep sedation. The surgeon cuts into the tissue covering the testicle (tunica albuginea) and takes a section of the seminiferous tubules the size of an orange seed. The removed fragment is delivered inside a sterile test tube to the biologists for the extraction of spermatozoa. The sampling can be single or multiple in the same testicle. A histological examination is also routinely performed which allows for a precise diagnosis of azoospermia and to intercept occult tumor forms, frequent in nonobstructive azoospermia. Sperm recovery success rates: In obstructive azoospermias (OA), in obstructive crypto-azoospermias, in necrozoospermia, and in anejaculation, the recovery rate of “useful” spermatozoa for ICSI is close to 100%. In nonobstructive azoospermias (NOAs) and secretory crypto-azoospermias, the recovery rate of “useful” spermatozoa is 50%. Generally, it is performed before carrying out the ovarian stimulation in the female partner, cryopreserving the spermatozoa, to optimize the time and avoid hormonal treatments to the woman in case of absence of spermatozoa.

18.3.5 Genetic Diseases/Preimplantation Genetic Testing

One additional indication for IVF is to provide genetic testing on embryos prior to implantation. Preimplantation Genetic Screening (PGS) and Preimplantation Genetic Diagnosis (PGD) are highly specialized procedures which involve removing three to four cells from a 5–6 days old blastocyst and testing it for chromosomal abnormalities prior to transferring the embryo into a woman’s uterus. Following a revision of definitions used in infertility care, the previous terms of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) have been replaced by the term PGT, including PGT for aneuploidies (PGT-A), PGT for monogenic/ single gene defects (PGT-M), and PGT for chromosomal structural rearrangements (PGT-SR) [9]. PGT was first clinically applied in the early 90s, and was initially utilized in sexing cases for couples who were at risk of transmitting an X-linked recessive disorder [10]. Since that time, the number of diseases diagnosed has increased dramatically, as have the different patient groups who use PGT to achieve a healthy pregnancy. At present, PGT is considered as an alternative to prenatal diagnosis [11], while the related method known as preimplantation genetic screening (PGS) is employed to increase success rates of ART. PGD is indicated in the following categories of patients: (1) Carriers of single gene disorders, dominant and recessive, autosomal or X-linked. (2) Carriers of structural chromosome abnormalities, reciprocal and Robertsonian translocations, inversions, deletions, insertions, etc. In most cases, these can lead to chromosomal rearrangements not compatible with life or result in repeated miscarriages (3) Women of advanced maternal age, to avoid having chromosomally abnormal offspring. (4) Couples with repeated implantation failure following assisted reproduction treatments (ART). (5) Couples with repeated unexplained miscarriage. PGT-A and PGT-M techniques permit the selection and subsequent transfer of embryos which are less likely to have chromosomal abnormalities or free of a known single gene disorder, hence increasing the chances for a successful pregnancy, decreased risk of miscarriage, and healthy baby.

Patients who need PGT-A or PGT-M undergo a typical IVF cycle. After the patient’s eggs are retrieved, they are fertilized with the husband’s or donor sperm in the laboratory. The lab waits for fertilization to occur and lets the embryos develop for 5–6 days into the 80–100 cell blastocyst stage. Trophectoderm biopsy (Fig. 18.5) has replaced cleavage-stage biopsy as the preferential method for biopsy for PGT-A and for concurrent PGT-M. This shift in the biopsy method is linked to the implementation of comprehensive genetic testing.

Fig. 18.5
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Blastocyst trophectoderm biopsy

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At the blastocyst stage, embryologists remove three to four cells from each embryo after creating a precise microscopic hole in the outer shell with a laser (embryo biopsy) and then these cells undergo the chromosomal analysis. Once chromosomally normal embryos are confirmed, patients receive a frozen embryo transfer after appropriate ovarian suppression and uterine preparation using hormonal stimulation. The frozen embryo transfer can occur as soon as 5–6 weeks after initial egg retrieval, but this is dependent on several factors. In most cases, it will subsequently only transfer at the most two blastocysts, and in most cases, recommend transfer of one chromosomally tested normal blastocyst in order to avoid the increased risk of higher order multiples. According to the last data report of the ESHRE PGT Consortium, the top five of PGT-M indications are: cystic fibrosis, Huntington’s disease, and myotonic dystrophy type 1 that remain frequent indications, while testing for hereditary breast cancer syndromes and neurofibromatosis has become more frequent than analyses for hereditary haemoglobinopathies and fragile X [12]. The efficiency of diagnostic testing is high (over 94%) for PGT-SR, PGT-A, and concurrent PGT-M/SR and PGT-A, whereas a slightly poorer efficiency (88%) is obtained for PGT-M. It remains to be seen whether in the coming years efficiency can be improved with new comprehensive techniques.

18.3.6 IVF Outcomes in European Countries

According to data reported from the European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE), the clinical pregnancy rates (PR) per aspiration and per transfer are 28.0% and 34.8%, respectively. After ICSI, the corresponding rates are 24% and 33.5% (Table 18.1) [13]. The pregnancy and delivery rates are higher for frozen embryo replacement (FER) cycles than for both fresh IVF and ICSI cycles. When considering the stage of replaced embryos, data showed PR for blastocyst transfers to be higher: 41.7% vs. 29.4% for cleavage stage embryos, for fresh IVF and ICSI cycles, respectively. Regarding treatment modalities, while ICSI remains the most applied with a trend to stabilization of its use during recent years, frozen embryo replacement is the second most used technique and there is a progressive increase in the proportion of transfer of frozen embryo relative to fresh IVF and ICSI cycles .

Table 18.1 Pregnancy and delivery rates (DR) after IVF or ICSI and after FER (after both IVF and ICSI) reported in European countries in 2017
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18.4 Art Complications

ART can alleviate the burden of infertility on individuals and families, but it can also present challenges to public health as evidenced by the high rates of multiple delivery, preterm delivery, and low birth-weight delivery experienced with ART. Monitoring the outcomes of technologies that affect ART has become an important public health activity. The potential health risks for both mothers and infants are described as follows.

18.4.1 Ovarian Hyperstimulation Syndrome (OHSS)

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology. The syndrome is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space due to increased capillary permeability and ovarian neoangiogenesis. Its occurrence is dependent on the administration of human chorionic gonadotrophin (hCG). To understand OHSS and its management, one must first be aware of its classifications of severity [14].

Grades of OHSS are described as follows:

  • Mild OHSS

    • Grade 1—Abdominal distention and discomfort

    • Grade 2—Grade 1 disease plus nausea, vomiting, and/ or diarrhea plus ovarian enlargement from 5 to 12 cm.

  • Moderate OHSS

    • Grade 3—Features of mild OHSS plus ultrasonographic evidence of ascites.

  • Severe OHSS

    • Grade 4—Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax and breathing difficulties.

    • Grade 5—All of the above plus a change in the blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function.

18.4.1.1 Prevention of OHSS: Effective Interventions

Dopamine agonist is effective for prevention of moderate or severe OHSS in women at high risk of OHSS. However, dopamine agonists might increase the risk of adverse events, such as gastrointestinal symptoms [15]. Moreover, the use of gonadotrophin-releasing hormone antagonists (GnRHa) compared with long GnRHa protocols is associated with a large reduction in OHSS, and no evidence suggested a difference in live birth rates [16]. OHSS rates are reduced with GnRHa triggering. However, a lower live birth rate, a reduced ongoing pregnancy rate, and a higher miscarriage rate are registered among women who received GnRHa versus hCG [17].

18.4.2 Multiple Pregnancies and Preterm Birth

Because multiple embryos are transferred in most ART procedures, ART often results in multiple-gestation pregnancies and multiple births. In Europe, according to data of the last report of the European IVF-monitoring Consortium (EIM) [13], as a result of decreasing numbers of embryos replaced per transfer, the proportion of both twin and triplet deliveries continued to decrease. In 2017, twin and triplet rates for fresh IVF and ICSI cycles together were 14.2% and 0.3%, respectively. Corresponding results for frozen embryo replacement were 11.2% and 0.2%. Risks to the mother from a multiple-birth pregnancy include higher rates of caesarean delivery, maternal hemorrhage, pregnancy-related hypertension, and gestational diabetes. Risks to the infant include preterm birth, low birth weight, death, and greater risk for birth defects and developmental disability. Further, also singleton infants conceived with ART might have higher risk for low birthweight and prematurity than singletons not conceived with ART [18]. According to data reported from CDC ART surveillance [19], in the United States, although rates of ART-conceived preterm and low birthweight infants have been declining steadily, the percentage of infants born with low birthweight and preterm is higher among ART-conceived infants than among all infants. The percentage of preterm births is higher among infants conceived with ART (29.9%) than among all infants born in the total birth population (9.9%). ART-conceived infants contribute to 5.3% of all preterm (gestational age <37 weeks) infants.

18.4.3 Long-Term Effects of ART on Women

Hormonal and reproductive factors are involved in the etiology of breast cancer and cancers of the female genital tract. Many studies have not been able to reach solid conclusions. In a large-scale cohort study in The Netherlands, after a follow-up of 5 ± 8 years, no increased risk of breast and ovarian cancer was found in women who had undergone IVF, as compared with subfertile women who had received no IVF [20]. For endometrial cancer, an increased risk was observed in those exposed to IVF as well as in the unexposed group, suggesting a subfertility-related effect which needs further evaluation.

18.4.4 Long-Term Effects of ART on Offspring

Much concern has been expressed about the health of children born after ART. In particular, the risk of boys born to couples with male factor subfertility has drawn attention, since in a substantial number of male factor subfertility cases, a genetic cause can be suspected. These include Y-chromosomal microdeletions, X-chromosomal and autosomal aberrations (i.e., Robertsonian translocations), syndromal disorders featuring infertility (i.e., Kallmann’s syndrome), and ultrastructural sperm defects with a genetic basis (Meschede et al., 2000). Theoretically, with ICSI these defects may be transmitted to the following male generation. Moreover, according to recent statements, [21] the use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins. The use of ICSI further increases this risk, the most with male factor infertility. These findings support the correct use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study [21].

18.5 Art Legislation and Regulation in European Countries

Thirty-nine European countries reported specific legislation on ART; Accessibility is legally restricted to heterosexual couples in 11 countries: Albania, Bosnia and Herzegovina, Czech Republic, France, Italy, Lithuania, Poland, Slovakia, Slovenia, Switzerland, and Turkey. A total of 30 countries offer treatments to single women and 18 to female couples. In five countries, ART and IUI are permitted for treatment of all patient groups, being infertile couples, single women, and same sex couples, male and female. Use of donated sperm is allowed in 41 countries, egg donation in 38, the simultaneous donation of sperm and egg in 32, and embryo donation in 29. Embryo donation is not allowed in 14 countries (Austria, Armenia, Belarus, Bosnia and Herzegovina, Bulgaria, Denmark, Iceland, Italy, Kazakhstan, Norway, Slovenia, Sweden, Switzerland, and Turkey). Information on individual principal countries is shown in Table 18.2. Preimplantation genetic testing (PGT) for monogenic disorders or structural rearrangements is not allowed in two countries, and PGT for aneuploidy is not allowed in 11; surrogacy is accepted in 16 countries. With the exception of marital/sexual situation, female age is the most frequently reported limiting criteria for legal access to ART, minimal age is usually set at 18 years, and maximum ranging from 45 to 51 years with some countries not using numeric definition. Male maximum age is set in very few countries. Where permitted, age is frequently a limiting criterion for third-party donors (male maximum age 35–55 years; female maximum age 34–38 years). Other legal constraints in third-party donation are the number of children born from the same donor (in some countries, number of families with children from the same donor) and, in 10 countries, a maximum number of egg donations. The legislations of 6 principal european countries are reported in Table 18.2.

Table 18.2 Principal countries in Europe and their ART regulations
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