IVF and assisted reproduction

Assisted reproduction is an umbrella term for techniques in which eggs, sperm or embryos are handled outside the body to help conception: superovulation, artificial insemination, embryo transfer, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) among them. Many were first developed in laboratory and farm animals, and the history of the field runs in parallel through animal breeding and human medicine.

Animal roots

The first successful transfer of mammalian embryos, from one female to another, was reported in 1890. It then took roughly 60 years before significant progress was made with the technique in cattle, and by the early 1970s methods were reliable enough for commercial embryo transfer programmes to be founded in several countries. Today superovulation, embryo recovery and transfer, cryopreservation and IVF are used in cattle breeding businesses worldwide. Interestingly, the average number of embryos obtained by superovulating a cow has changed little in 40 years, even though hormonal protocols have improved.

In parallel, scientists showed that rabbit eggs could be fertilized in culture dishes and still give rise to offspring. Those experiments encouraged the idea that the same might be possible with human eggs, which turned out to have a very different maturation cycle from rabbit eggs.

From the laboratory to the first IVF baby

The British physiologist Robert Edwards began studying the biology of fertilization in the 1950s. With several co-workers he worked out how human eggs mature, how hormones regulate that maturation, when eggs can be fertilized and under what conditions sperm become able to fertilize them. In 1969 a human egg was fertilized in vitro for the first time. Edwards then joined forces with the gynaecologist Patrick Steptoe, a pioneer of laparoscopy, who collected eggs that had matured in the ovary. After the Medical Research Council declined to fund the project, a private donation kept the work going. The world’s first IVF baby was born on 25 July 1978. Edwards received the 2010 Nobel Prize in Physiology or Medicine for the development of IVF; by then approximately four million people had been born after the treatment. The European Society of Human Reproduction and Embryology (ESHRE) now puts the total at more than ten million.

A second turning point came in 1992, when a team including Gianpiero Palermo and André Van Steirteghem reported pregnancies after injecting a single sperm directly into an egg, in couples with severely impaired sperm for whom IVF had failed. ICSI has since become the most common fertilization technique, used in about 73% of treatments worldwide according to ESHRE.

How treatment works

The UK Human Fertilisation and Embryology Authority (HFEA) describes a typical IVF cycle in four stages:

• Ovarian stimulation: fertility drugs encourage the ovaries to produce several eggs, monitored by blood tests or ultrasound.
• Egg collection: eggs are retrieved under sedation or general anaesthetic.
• Fertilization: eggs are mixed with sperm in the laboratory, or injected with sperm by ICSI, and the resulting embryos are monitored.
• Embryo transfer: an embryo is placed in the uterus two to five days after fertilization; good-quality embryos that are not transferred are normally frozen.

The quality of the embryo and the receptivity of the uterus both matter; the biology behind them is described on the page on early embryo development and implantation, and the freezing of eggs and embryos on the page on cryopreservation and fertility preservation.

What the numbers show

ESHRE estimates that around four million assisted reproduction cycles are performed each year worldwide, leading to about one million births. In Europe in 2020, the average pregnancy rate per embryo transfer was 33.2% after IVF, 33.0% after ICSI, 35.9% after frozen embryo transfer and 51.3% after egg donation, with higher rates in women under 35. Worldwide data for 2020 put the cumulative delivery rate at 32.3% for each egg collection, counting all embryos transferred from it.

The main safety concerns are well known. Multiple pregnancies carry serious risks for mother and babies, and the trend has been toward transferring fewer embryos: in Europe, the multiple delivery rate per transfer fell from 26.9% in 2000 to 11.1% in 2020. Ovarian hyperstimulation syndrome, a severe reaction to fertility drugs, is the most common complication, reported in fewer than 0.2% of cycles.

Established practice and open debates

IVF and ICSI are established treatments, and infertility is common: ESHRE estimates that one in six couples experience some form of infertility problem at least once during their reproductive lives. Causes are spread across partners: physiological causes in men explain 20–30% of cases, in women 20–35%, problems in both partners 25–40%, and in 10–20% no cause is found. Use of treatment varies widely: Europe initiates about half of all reported cycles, and in several European countries more than 5% of babies are conceived through assisted reproduction, compared with slightly over 1% in the United States. Most treatments take place in women aged 30 to 39. Much else remains contested. Clinics offer many optional “add-ons” claimed to improve success, and the HFEA rates them on the strength of the evidence using a traffic-light system. Time-lapse imaging, for example, is rated as showing no effect on outcomes, endometrial scratching as unclear, and preimplantation genetic testing for chromosome abnormalities (PGT-A) and endometrial receptivity testing as raising potential concerns about safety or effectiveness. The HFEA notes that for most patients proven treatment works well without such extras.

Longer-term questions are also studied in animals. In cattle, abnormal pregnancies associated with embryos produced in vitro have not been satisfactorily explained, and the possible role of altered epigenetic marks continues to be researched. Monitoring the health of people conceived through assisted reproduction, now that many of them are adults and some have become parents themselves, remains an important part of the field.