Unexplained Infertility Treatment: From IUI to IVF

Under the WHO guideline, infertility treatment follows the cause and escalates in steps. Unexplained infertility treatment moves from expectant management to stimulated intrauterine insemination (IUI) and then to IVF. Hydrosalpinx is removed or disconnected before IVF, uterine fibroids and septa are corrected surgically, and clinical varicocele is treated in men with abnormal semen. IVF is the final step, and its success depends above all on the woman's age.

Dr. Hrishikesh Pai, Director of Fortis Bloom IVF Centre, has practised IVF for 35 years, and his message to referring doctors was that most couples never need it. In his estimate, a clinic with good ultrasound, an IUI laboratory and access to laparoscopy and hysteroscopy can bring around 80% of couples to pregnancy without IVF; only about 20% need it. This article sets out his treatment ladder, cause by cause. The tests that lead to each diagnosis are in the WHO infertility workup article, and the guideline itself in the complete guide to the WHO infertility guidelines.

Unexplained infertility treatment: what WHO recommends

For couples with unexplained infertility, WHO suggests expectant management (continuing to try naturally, with advice on timing) rather than unstimulated IUI. Where expectant management has not worked, WHO suggests IUI in a stimulated cycle, that is, with medication to stimulate the ovaries.

Dr. Pai's own sequence is slightly more active, and most centres in India skip straight to stimulation:

1. Timed intercourse for three to six months, with clomiphene to stimulate ovulation and monitoring to time intercourse.
2. Stimulated IUI, usually three cycles. Some clinicians go to six, which he considers reasonable, but most now stop at three.
3. Laparoscopy and hysteroscopy if IUI fails, to find endometriosis, adhesions or genital tuberculosis before committing to IVF.
4. IVF.

Dr. Pai's IUI stimulation protocol

IUI places washed sperm directly into the uterine cavity around the time of ovulation. Dr. Pai's stimulation regimen for couples who have already tried clomiphene alone:

• Clomiphene citrate 50 mg, two tablets a day, from day 2 to day 6 of the cycle.
• Human menopausal gonadotropin (HMG) 150 IU on day 7 and day 9.
• Monitoring by transvaginal ultrasound until the leading follicle reaches 18 to 20 mm.
• Trigger with an hCG injection to complete egg maturation.
• Insemination: the semen sample is collected and washed, and the best-quality sperm are placed in the uterine cavity.

The exception is a woman with polycystic ovaries. Dr. Pai avoids HMG in these patients because it can provoke ovarian hyperstimulation, and uses letrozole instead, as explained in the PCOS and ovulation induction article.

IUI success rate, and why it suits African clinics

Dr. Pai puts the success rate of IUI at about 10% per cycle: of every ten women who undergo it, one conceives. Because it is inexpensive, repeating it three or four times is practical, and across a course of IUI cycles about 30% of couples conceive.

That makes IUI the treatment he most wants to see delivered close to patients. An IUI laboratory costs about $1,000 to $2,000 to set up, and he offered to help train African clinicians in the technique so that couples do not travel to India unnecessarily. Only patients with a clear indication, he argued, should make the journey.

Hydrosalpinx and tubal disease before IVF

Treatment depends on the severity of tubal damage:

• Severe tubal disease or hydrosalpinx (a blocked tube distended with fluid): Dr. Pai removes the damaged tube and goes straight to IVF.
• Mild tubal disease: IUI is possible, but these women carry a higher risk of ectopic pregnancy, so they need close monitoring.

Sequencing surgery around IVF

His usual order is to perform IVF first and freeze the embryos, then remove the hydrosalpinx laparoscopically before transfer. Sometimes the diseased tube is densely stuck to the bowel, and separating them risks a bowel injury. In that case he disconnects the tube from the uterus on both sides instead, which stops the fluid reaching the cavity, and then proceeds with embryo transfer.

Catching an ectopic pregnancy early

Any woman with tubal disease, a hydrosalpinx on ultrasound or a history of pelvic inflammatory disease is told to come in as soon as she misses a period. Dr. Pai then measures beta-hCG, the pregnancy hormone, every 48 hours. In a normal early pregnancy he expects it to double, or at least to rise by 60%; a smaller rise raises the suspicion of an ectopic pregnancy and calls for an ultrasound, transvaginal where possible and abdominal where not. Current ACOG guidance sets the minimum 48-hour rise for a potentially viable pregnancy lower, at about 35%, because some normal pregnancies rise slowly.

An early ectopic pregnancy seen on ultrasound can be treated with methotrexate, avoiding surgery. Dr. Pai will also give methotrexate empirically when hCG is positive but no pregnancy is visible in the uterus by six to seven weeks. International guidelines reserve that approach for cases in which serial hCG measurements and ultrasound have reliably excluded a viable pregnancy inside the uterus.

Fibroids, adenomyosis and a uterine septum

A uterine septum (a wall of tissue dividing the cavity) is cut through a hysteroscope, a simple procedure. Fibroids and adenomyosis are the commonest problems Dr. Pai sees in women referred from Africa; drawing on 12 years of visiting Nairobi to perform IVF, he described fibroids in African women as frequently large and multiple. His centre removes even very large fibroids laparoscopically.

He uses two sequences, depending on the size of the fibroids:

1. Large fibroids: surgery first. The fibroids are removed and the patient flies home within five to ten days. She then tries to conceive naturally for about six months, and many women do. If she has not conceived within five or six months, she returns for IVF.
2. Smaller fibroids: IVF first. IVF is carried out and the embryos are frozen; the fibroids are then removed laparoscopically. The patient goes home for three months to heal and tries naturally for three or four months. If she does not conceive, she returns and the frozen embryos are transferred.

The second sequence secures frozen embryos before the operation, so the healing period after surgery does not hold up egg collection. Costs for both procedures are on the myomectomy cost page and the hysteroscopy cost page.

Varicocele treatment for male infertility

A varicocele is a cluster of dilated veins around the testis. For men with infertility and a clinical varicocele, WHO suggests surgical or radiological treatment; the recommendation applies to men with abnormal semen parameters who are not undergoing IVF. Dr. Pai prefers surgery by high ligation. Indicative prices are on the varicocelectomy cost page. Men with no sperm in the ejaculate need a different approach, surgical sperm retrieval with ICSI, which is described in the complete guide.

IVF success rates by age

Asked what reduces the success of IVF, Dr. Pai named the woman's age as the biggest single factor. Every major registry reports results by age band, including the Society for Assisted Reproductive Technology (SART) in the United States and the Human Fertilisation and Embryology Authority (HFEA) in the United Kingdom. The per-cycle success rates he gave:

As age rises, a larger share of eggs is genetically abnormal. Embryos still form, but many of the pregnancies they produce end in miscarriage.

Across repeated cycles the picture improves. Dr. Pai cited European data showing that among women younger than 34 who start IVF, around 70% achieve a pregnancy within three cycles and 89% within six. Among women aged 35 to 39, around 70% conceive within four cycles. For women under 35 a single cycle succeeds roughly one time in three.

Asked about the complications of IVF, Dr. Pai answered that the main one is failure to conceive. His other answers to participating doctors, on IUI stimulation and IVF success, are in the masterclass Live Discussion.

Embryo freezing changes the economics

Modern freezing means one stimulation cycle often produces enough embryos for several attempts. If the first transfer fails, embryos are thawed and transferred without repeating stimulation and egg collection. Couples who succeed often return years later for a second child from the same frozen embryos.

Preimplantation genetic testing

For women with repeated failures, Dr. Pai uses preimplantation genetic testing (PGT). Embryos are grown to the blastocyst stage, a few cells are biopsied and tested, and only a genetically normal blastocyst is transferred. His centres see couples who have had ten or more failed cycles elsewhere.

Poor ovarian reserve and the limits of treatment

The second major obstacle is a woman with very few eggs, with AMH values as low as 0.3 or 0.4 ng/mL. Dr. Pai's advice to these women is egg donation or adoption. Many refuse to use donor eggs and insist on trying with their own. For them he offers platelet-rich plasma (PRP), prepared from about 30 mL of the patient's blood and injected into the ovaries under ultrasound or at laparoscopy, or stem cell treatment, while telling them plainly that in his view these technologies do not work. Neither has proven benefit in controlled trials, and ESHRE recommends against their routine use. When he uses the laparoscope, he also looks for genital tuberculosis, which can itself reduce ovarian reserve.

Donor eggs, surrogacy and the timing of referral

Egg donation is widely used by Dr. Pai's international patients, many from the Middle East and Africa: a donor's eggs are fertilised with the husband's sperm and the embryo transferred to the patient's uterus. Surrogacy is a different matter: Dr. Pai noted that surrogacy in India is not available to foreign nationals.

On timing, he was direct. Many African patients reach his centre only after repeated failures elsewhere, when their egg numbers have already fallen. Couples who need IVF do better when they are referred early.

Reducing the time abroad

The length of stay is often the real barrier for international patients, and Dr. Pai proposed a pathway around it. Ovarian stimulation could be started at home: medicines can be supplied to the referring clinic through pharmaceutical companies that distribute in Africa, the local doctor gives the injections under his team's instructions, and the patient travels to India around day 7 or 8 of stimulation for monitoring and egg collection. A diagnostic laparoscopy needs about five to seven days in India. Costs for the full cycle are on the IVF and fertility treatment cost page.