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In vitro fertilization (IVF)

Introduction

Today in vitro fertilization, or IVF, is one of the basic ways of treating infertility in the whole world. Now IVF allows to treat all types of sterility – tubal, endocrinic, immunological, linked to the so-called ‘male’ factor, as well as idiopathic, or the so-called ‘unexplained’, sterility in which no reasons preventing a woman from achieving pregnancy can be relieved. In IVF the rate of achieving a pregnancy is considerably higher (approximately 35%) than in achieving pregnancy naturally (not higher than 25%). IVF within surrogacy and donation programmes makes it possible for all couples to have babies of their own. Within just 30 years after the birth of Louise Brown, the first in vitro child, more than 3 million in vitro babies have been born. Scientific evidence provided on this subject has made it clear that IVF children are in no way inferior to ‘natural’ ones and sometimes they are even more advanced in their development.

IVF is a modern and highly-efficient technique to treat sterility. Its efficiency is highly dependant on the laboratory equipment where all the processes related to programmes take place. Vitanova has an embryological laboratory that is equipped with the latest devices allowing to guarantee successful treatment even in most complicated cases.

History

In vitro fertilization has been the subject of many scientists for several centuries already and it has been in practice since 1978. In 1677 the inventor of microscope, the Dutch scholar Anton van Leeuwenhoek, examined human semen and was the first to discover spermatozoa. He made a suggestion that a spermatozoon was a kind of seed, and a woman’s uterus created a favourable environment for its ‘sprouting’.

In 1784 an Italian scholar Lazzaro Spallanzani carried out the first in history artificial insemination of a dog who delivered three healthy puppies in 62 days after the procedure. Six years later a prominent Scottish surgeon and venereologist John Hunter (1728-1793) injected a man’s semen into his wife’s vagina with a syringe to overcome sterility. By doing this, he implemented the first artificial human insemination in history. Due to his experiment, the woman became pregnant and later gave birth to a healthy child.

In 1880 the first IVF attempt in history was tested on guinea pigs. 10 years later, in 1890 an English scientist Walter Heape and a surgeon Samuel Buckley carried out a successful IVF and transferred an embryo from one guinea rabbit to another one, thus realizing the first surrogacy programme in history.

In 1893-97 V. Gruzdev (1866-1938) suggested a theory of importance of egg’s maturity for conception to take place, and he was also the first to apply his patented method to rabbits. Later on his theory laid down the principles of GIFT (gamete intrafallopian transfer; egg cells are removed from the woman's ovary, mixed with sperm, and introduced into one of her Fallopian tubes). Starting with the 1920s artificial insemination with the husband’s or a selected donor’s sperm has become a widely-spread practice in sterility treatment.

The first IVF involving human reproductive materials was conducted in 1944 by Harvard gynecologists John Rock and Miriam Minkin. They cultivated a human egg and inseminated it in vitro which resulted in the development of a 2-cell embryo. In 1954 the first pregnancy was achieved through cryoconserved sperm insemination.

Despite all these early discoveries, the IVF pioneers are considered to be two distinguished British researchers – biologist Robert Edwards and gynecologist Patrick Steptoe. Edwards had his first success in fertilizing a human egg in vitro in 1967. The first ‘alien child’ pregnancy (which unfortunately turned out to be extrauterine) was registered in 1976, following 9 years of continuous research and experiments. On November 10, 1977 when the amount of IVF failures had exceeded 600, the doctors carried out an 8-cell embryo transfer which was accepted by the mother’s organism. On July 25, 1978 in the English town of Oldham Louise Brown, the first ‘test tube’ child, was born. It took more than 600 IVF attempts for Louise to make her historic entry into the world.

Another ‘test tube’ baby followed soon after. In 1980 in Melbourne (Australia) 8 years after intensive research in Carl Wood’s and Alex Lopata’s laboratory a ‘test tube’ boy was born, and in 1981 Elizabeth Carr, the first US in vitro baby, was born. The first successful human egg fertilization attempts in the Soviet Union were made at the end of the 1960s by B. Leonov in Moscow and A. Nikitin in Leningrad.

The first Soviet ‘test tube’ baby Lena was conceived at Leonov’s laboratory in Moscow and born in February 1986 just a few years before the famous Perestroika. A few months later another IVF child Kirill, Lena’s brother, was born in St. Petersburg.

Boris Leonov can be rightfully considered as the founding father of IVF and reproductive technologies in Russia. In the period of the Soviet stagnation, when there was no Internet, and other communication means were quite poor, when the country was almost isolated from its European neighbours and the information flow was more than poor, he managed to work out and lay down the principles of IVF basing on his scattered knowledge about IVF attempts in the West, and he did his best to start implementing similar programmes on the territory of the USSR. He was a real pioneer in this obscure ‘start-up’ field in the Soviet science. It is his persistence and ability to persuade people that made it possible to open the first Soviet IVF clinic – the Ministry of Health agreed to allocate $500,000 (a hefty sum of money at that time) for this purpose. Thus, it would be fair to call B. Leonov the ‘Godfather’ of thousands of IVF children who made their entry into this world due to his programmes and techniques.

Just in 30 years after Louise Brown’s birth more than 3 million in vitro children have been born in the world. Many of them, as well as Louise Brown, have become parents themselves and in their cases they did not turn to reproductologists for help. On December 20, 2006 in Bristol she bore her own son Cameron conceived naturally. The first Russian in vitro child Yelena Dontsova became mother in April 2007.

Indications and contra-indications

Certain medical indications are necessary to be suited to IVF. These requirements have been set up by Order 67 On appliance of assisted reproductive technologies (ART) in male and female infertility treatment issued by the Ministry of Healthcare of the Russian Federation on February 26, 2003.

Indications for IVF:

  • Recurrent infertility treatment failures. If there are no contra-indications, any couple (or unmarried woman) is entitled to apply for IVF with any form of infertility. Sterility is diagnosed in case if attempts to achieve pregnancy end in a failure with a year’s term of regular sexual activity without contraceptives. It is believed that each fifth couple in the world suffers from sterility.

Contraindications for IVF:

  • somatic and mental diseases contraindicative to child bearing and child birth;
  • innate uterine malformations or acquired uterine deformities precluding any embryo implantation or child bearing;
  • ovarian tumors;
  • benign uterine tumors requiring operative treatment;
  • acute inflammatory diseases, wherever located;
  • malignant neophytes, wherever located, including those in anamnesis.
  • Screening before carrying out an IVF

    For the woman:

    Compulsory:

    • general and special gynecological examination;
    • ultrasound examination of small pelvis;
    • blood type and Rh identification;
    • clinical blood sample testing, including coagulation time (results are valid for 1 month);
    • blood sample testing for syphilis, HIV, Hepatitis B and Hepatitis C (results are valid for 3 months);
    • testing of samples taken from urethra and cervical channel for microflora and testing of actual vaginal cleanness;
    • general practitioner’s report on the actual state of health and chances for child bearing.

    Per indications:

    • Examination of uterus and uterine tubes (hysterosalpingography or hysterosalpingoscopy and laparoscopy);
    • endometrial biopsy;
    • bacteriological testing of samples taken from urethra and cervical channel;
    • cytological testing of samples taken by way of uterine cervix smears;
    • blood sample testing for FSG, LG, Е2, Prl, T, cortisol, P, Т3, Т4, NNG and STG;
    • examination for antispermal and antiphospholipid antibodies;
    • examination for infections (chlamydiosis, uro- and mycoplasmosis, herpes simplex, cytomegaly, toxoplasmosis, rubella);
    • per-indication reports from other specialists.

    For the man:

    Compulsory:

    • blood sample testing for syphilis, HIV, Hepatitis B and Hepatitis C (results are valid for 3 months);
    • spermogramme.

    Per indications:

    • blood type and Rh identification;
    • andrologist’s consultation;
    • examination for infections (chlamydiosis, uro- and mycoplasmosis, herpes simplex, cytomegaly).

    For patients over 35 years old a genetic screening is normally required.

    IVF stages

    A classical IVF consists of the following stages:

      • patients’ medical screening;
      • induction of superovulation;
      • monitoring of follicle genesis and endometrial development;
      • ovarian follicle puncture;
      • collecting and preparing the sperm;
      • insemination of oocytes and in vitro cultivation of embryos;
      • transfer of embryos into the uterine cavity;
      • maintaining of the lutein phase within the stimulated menstrual cycle;
      • diagnostics of early-stage pregnancy.

      IVF can also be conducted within the natural menstrual cycle without any induction of superovulation.

      Superovulation induction

      To increase chances of successful fertilization hormonal medication stimulating the follicle genesis is prescribed to patients. Thus, the patient’s ovaries produce more than one oocyte.

      To induce superovulation only drugs that are registered in the Russian Federation can be used. Selection of specific stimulation patterns and medication, as well as adjustment of dosage and introduction of modifications into the induced superovulation protocol are performed on an individual basis.

      As a rule, the stimulation starts on the 2nd or 3rd day of the cycle and lasts for 10-12 days. The following drug groups can be used here: selective modulators of estrogen receptors (SMER); gonadotropines (human menopausal gonadotropine – hMG; follicle stimulating hormone – FSH; recombinant FSH – rFSH; recombinant luteinizing hormone – rLH; chorionic gonadotropine – CG); agonists of gonadotropine releasing hormone (a-GnRH); antagonists of gonadotropine releasing hormone (ant-GnRH).

      Monitoring of follicle genesis and endometrial development

      During the stimulation regular ultrasound and hormonal monitoring is carried out. Ultrasound monitoring allows to estimate the ovarian response to the stimulation, determine the number of follicles, their rate of growth, modify the stimulation pattern if needed and choose the best moment to induce CG – medication that finalizes the stage of follicle growth.

      Ultrasound monitoring is the principal method to carry out dynamic control over the development of follicles and endometrium during superovulation induction. Ultrasound monitoring makes it possible to precise the number of follicles available and their average diameter (as per sum total of two measurements made) and to measure the endometrial thickness.

      Hormonal monitoring implies dynamic identification of estradiol (Е2) and progesterone (Prg) concentrations in blood and, therefore, is a supplement to ultrasound examination results to estimate the maturity of the follicles.

      Criteria of the completion of superovulation induction and prescription of CG

      The induction of superovulation is completed at the moment when the leading follicles become more than 17 mm in diameter and the endometrial thickness exceeds 8 mm. Some other indicators to complete the induction depend on how active steroid genesis (Е2 concentrations in blood plasma) is.

      To finalize the process of oocyte maturing, CG is induced (recommended dosage: 5,000 – 10,000 IU at a time, intramuscularly).

      Follicle puncture and oocytes retrieval

      Puncture of ovarian follicles and aspiration of oocytes are carried out 32-40 hours after CG’s induction. It can be done on-site, in a minor-operation room, usually through transvaginal access under ultrasound control, with special needles designed for puncture purposes. In case transvaginal puncture is not possible (ovaries are located atypically, etc.), oocytes can be retrieved through laparoscopy.

      The puncture does not take more than 15-20 minutes and is not dangerous for the patient. After the operation the woman stays in a special post-care unit for 1,5-2 hours under surveillance of the medical staff. After that she can be released home.

      If there are necessary medical indications, a donor’s oocytes can be used. An anonymous donor is chosen by the patients basing on the phenotypic description provided by the clinic.

      Sperm collection and registration for IVF

      Specially prepared husband’s or donor’s sperm is used in IVF. Sexual abstinence of 3-5 days is recommended for the man before sperm collection. The sperm is collected through masturbation. Sterile container intended for collection of the ejaculate should be marked appropriately. Sperm collecting is to be performed in an appropriate room with a separate entrance, appropriate interior design and lavatory with a washbasin. The sperm may be frozen for a later use.

      An anonymous donor is chosen by the patients basing on the phenotypic description provided by the clinic.

      Oocyte insemination and in vitro embryo cultivation

      Follicular liquid obtained after the follicle puncture is placed into a Petri dish. The material is examined by a stereomicroscope. At this stage qualitative estimate of the retrieved oocytes is carried out. Then they are transferred into a cultivation environment. The dish is placed into an incubator imitating the uterine flora and environment.

      Both fresh and cryconserved spermatozoa should be washed of any seminal plasma before use. Fraction of morphologically normal and top-mobile spermatozoa should be separated from all other spermatozoa. Today 2 principal methods for sperm processing are used: flotation centrifugation and density centrifugation.

      If the spermogramme results are not sufficiently good, ICSI (intracytoplasmic sperm injection) is then recommended which ensures conception even if there are few viable spermatozoa.

      Presence of fertilized oocytes is usually estimated 12-18 hours later, when male and female pronuclei become clearly visible. Zygotes are put into a fresh cultural medium, where initial embryo development takes place. Embryos are cultivated in a special incubator during 2-5 days.

      Embryo transfer into the uterine cavity

      Embryos can be transferred into the uterine cavity at various stages, starting from the zygote stage and up to the blastocyte stage, which is usually formed in humans 5-6 days after fertilization.

      It is recommended to transfer not more than 3 embryos into the uterine cavity. However, it is possible to transfer a greater number of embryos, if expected implantation probability is low. Embryos are transferred with special catheters that are induced into the uterine cavity through the cervical channel.

      In case of the cervical channel permeability impairment which cannot be treated, embryo transfer can be performed through the uterine wall (transmyometrally). Mandrin-containing needle can be put into the uterine cavity transvaginally, transabdomenally or transurethrally.

      To increase the chances of implantation the so-called assisted hatching can be used. In this procedure the outer layer of the embryo is hatched out in order to help it implant into the uterus.

      Maintaining of lutein phase within the stimulated menstrual cycle

      Lutein phase within the stimulated menstrual cycle is usually maintained by progesterone or its analogues.

      In case there is no risk of ovarian hyperstimulation syndrome (OHS), maintaining of the lutein phase can include inducement of CG-based drugs, normally prescribed on the embryo transfer date, and, afterwards, each 2-4 days (on the individual basis).

      Diagnostic of early-stage pregnancy

      Pregnancy diagnostic methods involving identification of beta-CG content in blood or in urine are performed 12-14 days after the embryo transfer date. The first ultrasound screening can be carried out 21 days after the embryo transfer date.

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