IUI vs IVF vs ICSI: The Infertility Treatment Ladder

IUI vs IVF vs ICSI is not a standalone choice: all three sit on an infertility treatment ladder that runs from lifestyle change through medicines and surgery to assisted reproduction. IUI places washed sperm in the uterus and suits mild problems; IVF fertilises eggs in the laboratory; ICSI injects a single sperm into each egg for severe male infertility. If three IUI cycles fail, the couple should move to IVF.

Dr. Soma Singh, Associate Director - IVF & Infertility, Max Super Speciality Hospital, Noida, India, walked through each rung of this ladder, setting standard practice beside the newer techniques now in use at her centre: dual stimulation, PICSI and EmbryoGlue. This article covers treatment. The series overview is recent advances in the management of an infertile couple, and the tests that decide where a couple starts on the ladder are in the infertility workup and male infertility evaluation.

Lifestyle modification: the first rung

Treatment starts with the couple's lifestyle. Dr. Singh's analogy is that only a healthy seed grows into a healthy plant. Her advice for both partners:

• Diet and exercise, which go a long way towards managing weight.
• Stop smoking and alcohol. Both reduce sperm function; in the woman, they affect egg quality and reduce the embryo's ability to implant.
• Limit caffeine to no more than 250 mg a day.
• Avoid recreational drugs.
• Yoga and meditation to reduce stress.

Medical management in the woman: ovulation induction

In a natural cycle, a single dominant follicle grows in one ovary under the influence of FSH from the pituitary, and a surge of LH triggers ovulation. Fertility drugs alter this process in two distinct ways, and Dr. Singh draws a clear line between them:

• Ovulation induction and superovulation aim for one egg, or a small number of eggs, followed by timed intercourse or IUI.
• Controlled ovarian stimulation is used in IVF. The aim is as many eggs as the woman's ovarian reserve allows, but under control, so that she does not develop ovarian hyperstimulation syndrome (OHSS), a potentially serious overreaction of the ovaries to injected hormones.

In stimulated cycles, an injection of hCG stands in for the natural LH surge. After this trigger, the couple tries for a pregnancy by timed intercourse, or the woman has IUI or egg collection for IVF.

The drugs Dr. Singh listed:

• Clomiphene and letrozole, oral ovulation-inducing agents.
• Follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG), injectable gonadotropins.
• hCG, used as the trigger in place of the LH surge.
• Gonadotropin-releasing hormone (GnRH) and its analogues, now also used as a trigger and to down-regulate the pituitary during IVF.
• Dopamine agonists such as cabergoline and bromocriptine, for women with high prolactin.
• Insulin-sensitising agents for women with diabetes or PCOS.

The male side of medical treatment, which helps a smaller and more specific group of men, is covered in the male infertility article.

Fertility-enhancing surgery

Fertility-enhancing surgery corrects a structural problem so that the couple can conceive naturally or with simpler treatment. Dr. Singh's centre performs these procedures by hysteroscopy, laparoscopy and robotic surgery:

Hysteroscopic (through the cervix, inside the uterus):

• removal of uterine fibroids and polyps;
• tubal cannulation, which reopens a tube blocked near the uterus;
• adhesiolysis for intrauterine adhesions;
• resection of a uterine septum.

Laparoscopic or robotic (keyhole surgery in the abdomen):

• excision of endometriosis;
• myomectomy (removal of fibroids);
• tubal recanalisation;
• ovarian drilling in selected women with PCOS.

In men, surgery repairs a severe varicocele associated with abnormal semen, and relieves obstruction such as a midline cyst in the lower genital tract. Costs at partner hospitals are listed on the hysteroscopy procedures and myomectomy cost pages. For a detailed view of when fibroids and endometriosis should be operated on before IVF, see Dr. Shelly Singh's article on fibroids, polyps and uterine surgery before IVF.

IUI vs IVF vs ICSI: assisted reproductive technology compared

Assisted reproductive technology (ART) is any treatment that achieves conception by a means other than vaginal intercourse. It includes IUI, IVF and ICSI.

IUI: intrauterine insemination

In IUI, the semen is washed in a special medium, which concentrates the motile sperm and removes antisperm factors, and the prepared sperm are placed in the uterine cavity around the time of ovulation. It works only if the woman has at least one open fallopian tube and the semen is not severely abnormal.

Dr. Singh's indications for IUI:

• mild male factor infertility;
• sexual dysfunction, such as erectile dysfunction;
• unexplained infertility;
• cervical factors, including antisperm antibodies;
• mild endometriosis;
• couples in which the man has HIV and the woman does not, using specially prepared sperm;
• donor sperm.

IUI success rates and when to move to IVF

Dr. Singh's figures for IUI:

The cumulative pregnancy rate reaches at most about 30% and does not increase after three cycles. Her rule is therefore clear: if three IUI cycles have not succeeded, the couple should move to IVF rather than continue.

When IVF is indicated

IVF is the next step after failed IUI, and the first step in several situations:

• Tubal disease: both tubes blocked, or tubes that are open but do not function because of previous pelvic inflammatory disease or surgery.
• Moderate to severe endometriosis.
• Severe male factor infertility, which needs ICSI.
• Fertility preservation in cancer patients: freezing eggs, sperm or embryos before treatment.
• An unexpected high response. When a woman with PCOS given gonadotropins for IUI suddenly produces many follicles, converting the cycle to egg collection and IVF avoids cancelling it.
• Donor eggs, for which IVF is the only option.
• Surrogacy.

The steps of an IVF cycle

An IVF cycle has five steps: ovarian stimulation, egg retrieval, fertilisation, embryo culture and embryo transfer. Dr. Singh emphasised that the field has moved from one-size-fits-all to tailor-made protocols, with doses and regimens individualised to each woman.

Ovarian stimulation, and why it does not deplete the reserve

Normally only one egg matures each month, while many others in the same cohort die. A woman loses these eggs every month whether or not she is pregnant or ovulating. Stimulation injections rescue eggs that would otherwise have been lost; they do not deplete her ovarian reserve. The number of eggs that respond depends on her reserve.

The two conventional regimens are the long agonist protocol and the shorter antagonist protocol, which ESHRE now recommends as the standard for most women.

Dual stimulation (DuoStim)

The classic teaching was that a single wave of follicles is recruited in each menstrual cycle. It is now known that several waves are recruited within one cycle. Dual stimulation takes advantage of this: the ovaries are stimulated and the eggs collected, then stimulation restarts about four to five days later and a second collection follows, all within the same cycle. Dr. Singh uses DuoStim for:

• women with diminished ovarian reserve;
• cancer patients who have very little time to preserve as many eggs as possible;
• women who must collect the maximum number of eggs in limited time, such as international patients or women with low reserve who want to bank eggs before they get older or before they travel.

During stimulation, follicular scans track how many eggs are growing, so that OHSS can be avoided.

Egg retrieval

Egg collection, also called ovum pick-up, is a simple day-care procedure performed under ultrasound guidance through the vagina. Under the microscope each egg appears as a dark dot surrounded by a hazy cloud of supporting cells, the cumulus-oocyte complex.

Fertilisation: conventional IVF, ICSI and PICSI

Conventional IVF, once called the test tube baby technique, places each egg in a drop of culture medium with a large number of motile sperm, 20 to 30 million, and lets fertilisation happen by natural selection: the fittest sperm reaches and fertilises the egg.

ICSI (intracytoplasmic sperm injection) is used when sperm are very weak or very few. The egg is stripped of its supporting cells, and a mature (metaphase II) egg is held with a holding pipette while a fine injecting pipette places a single sperm directly into its cytoplasm.

PICSI (physiological ICSI) is the newer refinement. The prepared sperm are placed in a special dish with microdots of hyaluronan, a substance naturally present around the egg. Only mature sperm with good DNA integrity and sperm function bind to the hyaluronan, and those bound sperm are picked for injection. Dr. Singh finds PICSI very helpful in unexplained infertility, recurrent pregnancy loss and men with high levels of reactive oxygen species. In a large randomised trial, hyaluronan-based sperm selection did not increase live birth rates overall, and the European Society of Human Reproduction and Embryology (ESHRE) does not recommend it for routine use.

Embryo culture: day one to day five

Embryos are cultured in the laboratory and assessed each day:

1. Day 1: two pronuclei show that fertilisation has occurred; later in the day the embryo divides into two cells.
2. Day 2: four cells.
3. Day 3: eight cells.
4. Day 4: compaction, as the cells draw together.
5. Day 5: the blastocyst, with a fluid-filled cavity, an inner cell mass and an outer layer of cells.

Embryo transfer

Embryo transfer is simple. In almost all cases no anaesthesia is needed, and it is done as an outpatient procedure, much like IUI. The woman lies with a partially filled bladder, and the embryos are passed into the uterus through a soft catheter under ultrasound guidance. The embryos are loaded between two small air bubbles: embryos are microscopic, but the bubbles are visible on ultrasound and show exactly where they have been placed.

EmbryoGlue for recurrent implantation failure

Among the newer laboratory add-ons, Dr. Singh singles out EmbryoGlue, a transfer medium rich in hyaluronan. Implantation requires the embryo to attach to and then penetrate the lining of the uterus, and hyaluronan supports that attachment. She finds it useful for couples with recurrent implantation failure, who produce good embryos that repeatedly fail to implant. Evidence on hyaluronan-enriched transfer media is mixed, and laboratory add-ons in general remain under review by professional bodies.

Luteal phase support

After transfer, every IVF patient needs progesterone support. During IVF the corpus luteum, which would normally produce progesterone, depends on pituitary stimulation that the drugs suppress, whether an antagonist or an agonist protocol is used. Progesterone is therefore given from outside to support the lining.

A case: severe male factor after two failed IVF cycles

An international couple came with primary infertility and two failed IVF cycles elsewhere. The woman, in her mid-thirties, had PCOS with a good ovarian reserve and an otherwise normal pelvis and uterus. Her husband, in his fifties, had diabetes and abnormal liver function from heavy drinking. His semen showed severe oligoasthenoteratozoospermia (a low count, poor motility and abnormal forms), and his DFI was high.

ICSI was the only option, and because the DFI was high, Dr. Singh advised PICSI. One egg collection yielded 16 mature eggs. The embryos were grown to blastocysts and, because her PCOS ovaries were hyperstimulated, all were frozen rather than transferred fresh. The couple returned two months later for a frozen embryo transfer of two blastocysts, and she conceived a singleton pregnancy at the first transfer. She was in her fourth month at the time of the masterclass.

Risks of embryo transfer

The transfer procedure itself has essentially no complications; the risks lie in what follows and in how many embryos are transferred.

• Failure to implant. Not every embryo implants. The implantation rate is about 30 to 40%, which is the main reason IVF does not succeed every time.
• Multiple pregnancy. Transferring more than one embryo, such as two blastocysts or three or four day-two or day-three embryos, raises the pregnancy rate but makes twins or triplets far more likely than with natural conception.
• Ectopic pregnancy. Dr. Singh stresses that the risk depends on the operator's skill: placing too many embryos, pushing too much fluid or placing the embryos too close to the tube all increase it. Registry data show a modestly higher ectopic rate after IVF than after natural conception, particularly with fresh transfers and in women with tubal disease.
• Heterotopic pregnancy, in which one embryo implants in the uterus and another in the tube. It is rare, but more frequent after IVF than after natural conception.

The audience's questions on embryo transfer risks and on pregnancy after menopause are answered in full in the Live Discussion from this masterclass. Costs for IVF and ICSI at partner hospitals are summarised on the IVF and fertility treatment cost page. For the WHO's view of stepped treatment in unexplained infertility, see Dr. Hrishikesh Pai's article on unexplained infertility treatment from IUI to IVF.