By Dr Mohamed Ashraf Parenthood undeniably used to be the most desired goal of adulthood. Sub-fertility or infertility is the legacy of modern era of ever increasing aspirations, which has led childbirth to be a requirement to be fulfilled only when there is spare time. Hence, the ever increasing problem of infertility.Worldwide prevalence of infertility is 5–15%. Childless couples require medical help to conceive which may vary from medicine for ovarian induction (egg production) to more advanced artificial reproduction techniques (ART). ART involves special procedures to bring wife’s egg and husband’s sperm close to each other in order to form an embryo, and subsequent transfer of this embryo inside the uterus. The cumulative chance of having a live baby after in vitro fertilisation(IVF) varies from 20% to 50-70% depending on the woman’s age and other varied factors. We say cumulative because not all couples conceive after the first IVF cycle and many may require multiple attempts. Possible reasons behind repeated IVF cycle failures The main causes of multiple IVF failures are: a) Poor response to medications used for ovarian stimulation b) Repeated failure of fertilisation (embryo formation)c) Repeated difficult embryo transfer procedure d) Repeated implantation failure Ovarian stimulation is the process of induction of multi-follicular growth by giving gonadotrophins. Those women who fail to show adequate response despite maximum dose of gonadotrophin stimulation constitute the category of poor responders. In these patients either the eggs obtained are too less, or of poor quality. There are set criteria to define these poor responders. Women with advanced age (40 and above), raised FSH and decreased AMH (markers of ovarian egg reserve) and less number of ovarian follicles on ultrasound can be expected to have poor response. The oocyte quality can be improved by adding various adjuvants. A new option which has become available in recent time is egg freezing, in which egg produced from multiple cycles can be frozen and fertilised in single sitting, thereby decreasing the cost involved in multiple cycles and increasing the chance of egg being chromosomally normal. Fertilisation involves entry of a sperm inside an oocyte and fusion of genetic material to form an embryo. Repeated fertilisation failure is a challenge. Although fertilisation failure during IVF can be overcome in most of the cases with ICSI, which is the process of injecting the sperm directly inside the oocyte under microscope; fertilisation failure following ICSI is also known to occur. This poses a challenge as it involves as yet poorly understood genetic and molecular factors. These are usually associated with severe male factor infertility. Repeated difficult embryo transfer is not an uncommon problem. Embryo transfer is done by passing a cannula with the embryos in it inside the under, ultrasound guidance. The embryo is extremely sensitive to changes in temperature, pH and environmental toxins. Once the embryo is outside the incubator, it is to be transferred inside the uterus within 120 seconds; any delay will put the embryo at risk. The embryo is very sensitive to blood, so any bleeding during embryo transfer is to be avoided. Recurrent implantation failure of the embryo transferred inside the cavity to result in a pregnancy accounts for more than 50% repeated IVF attempts. Anatomical abnormalities of uterus, fallopian tube, endometrial (lining of the uterus) and/or immunological abnormalities could be responsible for this.To diagnose abnormalities, it is mandatory to do a detailed ultrasound evaluation preferably with 3-D scan in all cases. If no abnormality is detected, a hysteroscopy (a procedure involving visualisation of inner lining of uterus with a thin tubular instrument) should be undertaken if not already done.Detailed screening for antibodies and other genetic disorders should be performed in all cases. This should include chromosomal testing of the couple to begin with. Thrompophilias are inherited conditions of increased blood thickness. These can be diagnosed by various investigations and treatment of these disorders depends on the type of abnormality. Also, testing for autoimmune diseases is needed in these patients. How to treat abnormalitiesMost of the anatomic abnormalties are amenable to treatment; septum can be excised hysteroscopically; fibroid and polyp can be removed surgically by laparoscopy; hydrosalpinx can be blocked or removed. The presence of adhesions inside the uterine cavity, depending on their severity, is trickier to treat. Although it has a long recovery curve, a combined treatment with surgery and hormones is usually successful. Tuberculosis can be treated with multi-drug therapy, but in rare cases, it may lead to permanent scaring of the endometrium.The persistent thin endometrium or failure of the endometrium to grow can be due to insufficient blood supply or other underlying factors. The blood supply can be improved by medications like sildenafil. Local endometrial injury leads to alteration in gene expression and inflammation which leads to release of growth factors which aids in growth of endometrium. LMWH (low molecular weight heparin) is usually given to those women with increased blood coagulability. It acts not only in decreasing blood thickness but also has an immune modulating action.If no obvious cause could be diagnosed, empirical treatment might be needed. This includes HLT injections, pre-IVF endometrial injury to aid implantation, ovarian stimulation with moderate intensity aiming at 5-8 eggs and doing a blastocyst transfer on day 5.Also, embryos can be frozen and transferred later to make sure that the hormone levels are controlled.Lastly, there is growing evidence regarding utility of pre-implantation genetic diagnosis (embryo biopsy) for unexplained cases of IVF failure. This can help to detect the chromosomally normal embryo and selective transfer of these. *** The author is MBBS, MD, DGO, DPS (Germany) and will be visiting Aster Medical Centre Hilal this week.