Complications
The main side effects of clomifene therapy are related to a decreased cerebral perception of oestrogen. Women often complain of hot flushes, headaches, and visual changes. Lowering the effect of oestrogen in the uterus can result in poor endometrial development and low implantation rates. Clomifene has been associated with a decreased cervical mucus score that results in poor sperm-mucus interactions. This means some clinicians advocate performing post-coital tests in women undergoing clomifene induction cycles or routinely performing intrauterine inseminations.
The reported incidence of ectopic pregnancy after IVF and embryo transfer (IVF-ET) ranges from 1.8% to 8.6%, compared with an incidence in natural conception between 2% and 4%.[202][203][204] Risk factors for ectopic pregnancy after IVF-ET include tubal factor infertility, history of pelvic surgery or prior ectopic pregnancy, transfer of multiple embryos, cleavage stage embryo transfer, fresh embryo transfer, and artificial cycle protocols.[202][203]
Multiple gestation is a common side effect of infertility treatment. Ten percent of clomifene cycles and 30% of gonadotrophin and IVF cycles end in multiple gestations. The frequency of higher-order multiple gestation is decreasing by closer monitoring and transferring fewer embryos during IVF.
Internationally, policies are in place to reduce multiple pregnancy rates and their sequelae from IVF by elective single embryo transfer. The success of such policies however are dependent on several factors, including a successful freezing programme and the availability of public funding.[170][171][200][201]
Assisted reproductive technology (ART) is associated with a slightly increased risk of congenital anomalies, with a relative risk of 1.33 (95% CI 1.24 to 1.43) compared with natural conception in one meta-analysis.[205][206] However, it is unclear how much of this increased risk is due to the underlying cause of infertility or other associated parental factors. In one population-based cohort study in Australia, infants conceived with ART had an increased risk of major genitourinary abnormalities compared with naturally conceived infants from fertile couples and naturally conceived infants from couples with a history of infertility.[207]
In 1992, a study reported that fertility medications increased the risk of ovarian cancer. This study did not identify a precise "fertility drug" and included numerous drugs used to treat infertility. Its conclusion was met with numerous editorials challenging the validity of its results. Subsequent meta-analyses suggest a possible association between ovarian cancer and fertility treatments in nulliparous women (compared with the general population, treated multiparous women, or untreated nulliparous women), but evidence remains low-quality and uncertain.[208][209]
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The American Society for Reproductive Medicine recommends informing women that there may be an increased risk of ovarian cancer and borderline ovarian tumours associated with fertility treatment, based on weak/moderate evidence.[210] It suggests the overall risk is likely to be small, and some of the risk may be related to underlying factors that are also associated with an increased risk of ovarian cancer, including endometriosis, infertility, or nulliparity.[210]
Characterised by an increase in capillary permeability, which results in shifts of intravascular fluid to third-space compartments, particularly the abdominal cavity. Symptoms range from mild to severe. Mild OHSS manifests as bloating and abdominal discomfort. As the abdominal fluid collection continues it restricts diaphragmatic activity with resultant shortness of breath. Increased abdominal pressure can also restrict the inferior vena cava and reduce pre-load. A reduced intravascular volume decreases glomerular filtration rate and may result in renal failure. As intravascular depletion continues, the rising haematocrit can increase the risk of blood clotting. This risk is further increased by the high level of oestradiol. Third spacing can occur in other tissues including the lungs and the brain.
Women with elevated anti-Müllerian hormone levels, polycystic ovary syndrome, or anticipated high oocyte yields have an increased risk of OHSS, and strategies that reduce the risk during controlled ovarian stimulation should be considered.[134]
Treatment of OHSS is supportive.[197][198] Paracentesis can improve respiratory effort and cardiac output. OHSS occurs in approximately 20% of all IVF cases but is only severe in <5%.[199] Symptoms last approximately 1 week, but will continue longer when conception occurs.
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