Assisted fertilization

Pre-implantation diagnosis (PGT) in Italy, how and where it takes place under the NHS

What does Pre-Implantation diagnosis consist of, who is it for and where can it be done in Italy even at the cost of the national health system?

What is PGT (Pre-Implantation Genetic Testing)?

Pre-implantation genetic diagnosis (PGT)  is the earliest form of prenatal diagnosis and allows for the identification of anomalies of the genetic heritage in the embryos produced in vitro.  According to the latest scientific studies carried out, the “gold standard” for carrying out pre-implantation diagnosis is a biopsy (taking a few cells) of the trophoblast at the blastocyst stage (5th-6th day of embryonic development in vitro).

The sampling does not cause any damage to the subsequent implantation and embryonic development, because the trophoblast cells are the ones that will form the placenta and do not become part of the constitution of the future fetus/child.

During the genetic analysis, the embryos always remain frozen (cryopreserved by vitrification) and, once it has been established which embryos are not carriers of a genetic anomaly, they are thawed and transferred in a suitable number into the patient’s uterus, while the remaining (healthy or sick ) remain, by law, frozen.

What applications does PGT have?

In the context of pre-implantation diagnosis, it is possible to identify two distinct applications:

  1. Identification of specific genetic anomalies in couples at risk of transmission of Mendelian diseases (caused by the defect of a single gene), and in this case we speak of PGT-M, or known chromosomal pathologies (numerical or structural, such as translocations), and in this case we talk about PGT-SR. The technique allows genetically/chromosomally abnormal embryos to be excluded from transfer to the uterus.
  2. Analysis of the chromosomal structure aimed at identifying numerical anomalies (aneuploidies) of the embryo, and in this case we speak of PGT-A, (e.g. Down’s Syndrome) in couples with fertility problems deriving from age advanced maternal , multiple miscarriages , repeated implant failures after assisted conception , poor sperm quality. This diagnostic is commonly called PGS (Pre-ImplantationGenetic Screening).

 Who is it aimed at?

The PGT for known genetic disease  (indication 1 or PGT-M)  is aimed at couples, fertile or infertile, who are healthy carriers of a specific gene or chromosomal defect, or in which one of the partners is affected by a specific genetic disease or is carrier of a chromosomal abnormality, usually a balanced translocation.

It is possible to diagnose the embryo for all genetic diseases for which the gene and specific mutation are known, or the haplotype at risk (portion of chromosome involved in the disease). As far as genetic anomalies are concerned, the most frequent indications are:

Cystic Fibrosis, Beta Thalassemia, Spinal Muscular Atrophy, Myotonic Dystrophy, Neurofibromatosis, Charcot Marie Tooth, Duchenne-Becker Muscular Dystrophy, Hemophilia A or B, Fragile-X Syndrome.

However, PGT is applicable to virtually all genetic disorders due to known cause.

PGT cannot be applied to some de novo mutation genetic diseases, to diseases for which the gene or chromosomal locus is unknown, and to most mitochondrial DNA mutation diseases .

As regards chromosomal abnormalities (indication 1 or PGT-SR)  , the most frequent indications are represented by balanced, reciprocal and Robertsonian translocations.

It is recommended to perform PGT-SR only if the detected genomic alteration, confirmed at the germline level, has been proven to be the cause of the pathological phenotype.

Therefore, couples carrying genomic variants of benign or uncertain significance should be excluded from the PGT-SR.

A careful evaluation must be made for those genomic anomalies with low or variable penetrance (e.g. 1q21.1; 3q29; 15q11.2; 15q13.3; 16p11.2; 16p13.1; 22q11.2), to evaluate the real benefit the use of a PMA technique with PGT-SR to obtain a euploid conceptus.

It is to be evaluated whether to include in the PGT-SR the couples carrying the common pericentric heterochromatin inversions (1, 9, 16, Y), inv(2)(p11q13), inv(3)(p11-13q11-12), inv( 5)(p13q13), inv(10)(p11.2q21.1), since the risk of imbalance in term is negligible, while the risk of imbalance in the early stages of embryonic development is not known.

The PGT-A for the identification of numerical chromosomal anomalies  (indication 2)  is aimed  at couples in which:

1) is performed on that couple another type of PGT (eg for monogenic disease), in order to optimize the evaluation of the embryo by transferring an embryo not affected by genetic disease without chromosomal aneuploidies.

2) the woman has an advanced maternal age (AMA) > 35 years. Recent publications have called for PGT-A to be performed in all couples who perform MAP, regardless of the age of the female partner. As widely reported, in fact, even the young women we consider to have a good prognosis have a percentage of aneuploid embryos that varies between 25 and 35%.

3) the couple had repeated failed implantation (RFI) in several cycles of standard PMA (≥3 transfers with good quality embryos or ≥10 embryos transferred in multiple transfers). RFI is defined as the absence of an ultrasound gestational sac 5 or more weeks after embryo transfer.

4) the couple with normal karyotype had repeated first trimester spontaneous abortions (≥2 abortions), not due to “mechanical” causes such as uterine pathologies (e.g. fibroids, congenital malformations, etc.), or other factors (e.g. coagulation defects, autoimmunity, etc.). It is important to underline that couples with a history of multiple abortions have a high probability of conceiving spontaneously and reaching term of pregnancy within 12 months, therefore it is advisable to evaluate each individual case especially in relation to the age of the woman and the residual ovarian reserve.

5) the male partner has a serious male factor (severe oligoasthenoteratospermia, cryptospermia or non-obstructive azoospermia, who have to resort to sperm collection from the seminal tract using the microsurgical techniques of MESA and TESE).

6) one of the partners has chromosomal mosaicism (abnormal karyotype given by the presence of different mosaic cell lines,)

7) one of the partners, especially the woman, has undergone cycles of chemo-radiotherapy or has had proven occupational or environmental exposure to ionizing radiation or chemical pollutants.

In fact, it is possible to verify the normality of the karyotype (chromosomal arrangement) of the embryos and to transfer only those with normal chromosomes, in order to obtain a full-term pregnancy in the shortest possible time.

Phase 1

The couple with genetic disease who decide to access PGT techniques is initially subjected to genetic, gynecological and andrological counseling , in which the most appropriate path to follow is explained to the couple in order to obtain the best chances of pregnancy of a child not affected by the disease genetics.

For PGT indications, the benefits and limitations of the technique are explained to the couple, in order to optimize their chances of pregnancy at term. Furthermore, the gynecologist and andrologist, through appropriate visits and tests, establish the suitability of the couple for assisted fertilization. This phase lasts at least 30 days.

Level 2

In the case of PGTD for monogenic disease (PGT-M), the pre-conceptional measurement is carried out with DNA analysis of the couple (direct analysis) and, possibly, of the family members (indirect analysis). This phase lasts approximately 45-60 days. In the case of PGT-A or a balanced constitutional chromosome abnormality this step is usually not necessary.

phase 3

The couple undergoes assisted fertilization treatment, during which the biopsy of the embryo (blastocyst) and subsequent analysis is carried out. This stage lasts about 10-15 days.

Phase 4

The couple is informed by the team (gynecologist, embryologist, geneticist) of the outcome of the PGT analysis and of the embryo quality, and one or more embryos are transferred.

Where can the PGT be carried out in Italy?

At present, PGT in Italy can be carried out at PMA Centers affiliated with the NHS, where you pay the cost of the ticket for PMA and an amount ranging from 1500 to 3000 euros in solvency, or at private PMA Centers , where the cost is entirely borne by the couple.

The first Italian public center was recently opened where pre-implantation diagnosis can be carried out through the National Health System
It is located at the Arco Hospital (TN).
  • Mangiagalli hospital but only for 3 genetic diseases
  • Hospital in Siena only for some pathologies
  • Microcitemico of Cagliari pre-implantation diagnosis for thalassemia
  • Humanitas of Rozzano: it is possible to carry out the PMA cycle in an agreed form (only ticket payment) while the PGT is paid by the couple.

There are about 50 private centers in Italy that carry out pre-implantation diagnosis but rely on two main laboratories for the analysis,

What are the differences between PGT and PGS?

PGT is recommended when one or both parents are carriers of a genetic abnormality and the diagnosis focuses on chromosomes implicated in this anomaly.

Preimplantation Genetic Screening (PGS ) is recommended when both parents have normal karyotypes and no known genetic disorders but have a history of previous failed IVF or ICSI. With PGS all the chromosomes of the embryos obtained in vitro are examined by evaluating the aneuploidies and anomalies in the structure of the chromosomes.

Kathryn Barlow is an OB/GYN doctor, which is the medical specialty that deals with the care of women's reproductive health, including pregnancy and childbirth.

Obstetricians provide care to women during pregnancy, labor, and delivery, while gynecologists focus on the health of the female reproductive system, including the ovaries, uterus, vagina, and breasts. OB/GYN doctors are trained to provide medical and surgical care for a wide range of conditions related to women's reproductive health.

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