Adjuvant treatments

Adjuvant treatments can include:

Aspirin >

Clexane >

Corticosteroids >

Intralipid >

Melatonin >

Platelet-rich plasma >

Testosterone and dehydroepiandrosterone (DHEA) >

Viagra (Sildenafil) >

Aspirin

Adjuvant action and why it might be used in IVF

Aspirin, also known as acetylsalicylic acid, is an anti-thrombotic medication that reduces the clotting action of platelets to prevent small blood clot formation within blood vessels. For this reason, it is widely used to prevent heart attacks and strokes. Small clot formation in placenta blood vessels is one of the mechanisms thought to lead to miscarriage.

Aspirin also has a non-steroidal anti-inflammatory action and is used to reduce pain, fever and swelling. Local uterine inflammatory activity may be a contributing factor to embryo implantation failure. Aspirin’s inflammatory inhibition is thought to improve implantation rates in women experiencing infertility.

Potential benefits and evidence

Many well-designed trials have been performed to evaluate the benefit of aspirin in women undergoing fertility treatment. When summarised, these studies have not found conclusive evidence that aspirin increases live birth or pregnancy rates in the general IVF population. Several studies have also specifically looked at women with recurrent miscarriages. Again, there is no robust benefit from taking low-dose aspirin in these studies. However, due to the varying quality of these studies, higher quality evidence is required to obtain more conclusive results.

Potential side effects

Aspirin can cause nausea, vomiting, diarrhoea, gastrointestinal bleeding, asthma exacerbation, tinnitus, vertigo, confusion, itching, pain, stiffness in joints, tachycardia and increased bleeding time. Patients with a history of a bleeding disorder, severe asthma attack, kidney disease or intestinal bleeding should speak to our fertility specialists before taking aspirin.

Safety in pregnancy

Aspirin is listed as a category C drug, as it may have caused or is suspected to cause harmful effects to the human foetus without producing malformations. There is no difference in the rates of obstetric complications in women taking aspirin during pregnancy, including pregnancy loss, preterm birth or foetal growth restriction. However, avoidance during the later stages of pregnancy is recommended, given that it may cause premature foetal closure of the arterial duct (ductus arteriosus) and/or delay labour.

Risk-benefit analysis

Currently, there is limited good-quality evidence to support the use of aspirin to improve pregnancy rates. Therefore, its benefit in the general IVF population is uncertain.

Clexane

Adjuvant action and why it might be used in IVF

Low molecular weight heparin, also known as Clexane, is an anti-coagulation medication that acts as a blood thinner. Clexane inhibits the action of clotting agents in the bloodstream to reduce clotting risk. For this reason, it is used to prevent and treat blood clots, including conditions such as deep vein thrombosis (a blood clot that forms in a deep vein) and pulmonary embolism (blockage within the artery in the lung). It may also prevent small clot formation in placenta blood vessels, one of the mechanisms that may lead to miscarriage.

Potential benefit and evidence

Women with antiphospholipid syndrome (characterised by elevated anti-cardiolipin and lupus anticoagulant antibodies in the bloodstream) are more likely to suffer from recurrent miscarriages and adverse obstetric outcomes, such as preterm birth, foetal growth restriction and pre-eclampsia. Moderate-quality evidence suggests that the combination of heparin and aspirin can decrease the rate of pregnancy loss by 54% in women with antiphospholipid syndrome. However, there is no proven benefit of using heparin in women with a history of recurrent miscarriages who do not have this condition.

Potential side effects

Side effects may include pain, itching and swelling at the injection site. When used in small doses as part of IVF treatment, serious complications are rare. However, larger doses of Clexane are associated with decreased platelet counts, bleeding risk, bone thinning and abnormal liver enzymes.

Safety in pregnancy

Prolonged use of Clexane/heparin can cause osteoporosis (bone thinning) and a low platelet count. There is no evidence to date of altered risk of congenital malformations. There also doesn’t appear to be an increased risk of bleeding in pregnancy, but this has been poorly assessed so far.

Risk-benefit analysis

Limited evidence supports the routine use of Clexane in the general IVF population. However, the combination of Clexane and aspirin may reduce miscarriage risk in women with antiphospholipid syndrome and a history of miscarriage or pregnancy loss.

Corticosteroids – Dexamethasone, Prednisolone

Adjuvant action and why it might be used in IVF

Corticosteroids are used to treat inflammatory and autoimmune conditions, such as asthma, eczema, dermatitis and rheumatoid arthritis. They have potent immunosuppressive effects that may help to reduce a localised inflammatory response. This is thought to improve the uterine environment and assist with embryo implantation in some patients with poor ovarian response to IVF treatment.

Potential benefit and evidence

A small proportion of patients who experience repeat IVF failure (RIF) or recurrent miscarriage (RM) may have an underlying immune dysfunction. – for example, an elevated presence of natural killer (NK) cells in the uterus or autoantibody levels. Elevated NK cell levels are a possible cause of immune dysfunction, contributing to RIF and RM. However, good-quality evidence to support this is limited.

Because corticosteroids suppress the immune system, fertility specialists may prescribe this medication to ‘suppress’ NK cell numbers, potentially improving pregnancy rates and reducing RM. Good-quality evidence does not currently support this. However, limited evidence shows a possible improvement when women with positive autoantibodies take corticosteroids during their IVF cycle. These studies are low in quality and should be interpreted with caution.

Potential side effects

Corticosteroids are known to cause nausea, vomiting, heartburn, gastric disturbance, acne, skin thinning, bloating, diarrhoea, constipation, mood changes, increased appetite, yeast infection and insomnia.

Safety in pregnancy

Dexamethasone and prednisone are category A drugs that have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other harmful effects on the foetus. Some retrospective data suggests an increased risk of cleft lip or palate, congenital heart defects or incomplete formation of the anus.

Risk-benefit analysis

Routine administration of corticosteroids during IVF treatment is not recommended. This is due to the lack of evidence supporting the benefit of corticosteroids in IVF treatment, along with the potential risk of side effects.

Intralipid

Adjuvant action and why it might be used in IVF

Intravenous (administered into a vein) intralipid is a fat-based emulsion containing essential fatty acids, phospholipids, glycerine and soybean oil. It is used to suppress the maternal immunological response. Although the exact mechanism behind this effect is not fully understood, it is proposed to downregulate the pro-inflammatory state and reduce the cytotoxicity produced by uterine natural killer (NK) cells.

Potential benefit and evidence

Conflicting and low-quality evidence suggests that intralipid treatment may improve implantation and clinical pregnancy rates in women with infertility, particularly in patients with recurrent implantation failure or an altered immune response. This evidence should be interpreted with caution, given the small number of women recruited in these studies. There are no high-quality studies to suggest that intralipid improves live birth rates in infertile women.

Potential side effects

Intralipid can cause nausea, vomiting, gastrointestinal upset, headache, dizziness, flushing, shortness of breath, pressure over the eyes, tissue pigmentation, tiredness, shivering, chills and fever.

Safety in pregnancy

Although no known obstetric complications are associated with intralipid use, there are insufficient studies examining its safety during pregnancy. Routine use during pregnancy is not recommended.

Risk-benefit analysis

Currently, there is limited good-quality evidence to support the use of intralipid to improve pregnancy rates. Therefore, routine use during IVF treatment is not recommended.

Melatonin

Adjuvant action and why it might be used in IVF

A hormone naturally produced by the pineal gland (in the brain), melatonin regulates our circadian rhythm and sleep-wake cycle. Melatonin exhibits antioxidant abilities, scavenging reactive oxygen species (ROS) produced by the body’s metabolic processes, which can cause oxidative stress and intracellular damage to ovarian follicles. Several studies have shown the damaging effects of ROS on oocyte and embryo quantity and quality following retrieval for IVF.

Potential benefit and evidence

There is conflicting evidence regarding the benefits of melatonin supplementation in women undergoing fertility treatment. A 2021 meta-analysis of seven randomised controlled trials showed an increase in total mature oocyte count, with no significant benefit seen in embryo quality, clinical pregnancy rates and live birth rates. Another meta-analysis in 2020 demonstrated a slight improvement in oocyte count, embryo quality and biochemical pregnancy rate. At present, studies have not shown improvements in live birth rates. Given the small number of studies available and the quality of the research, further studies are needed to obtain more conclusive results.

Potential side effects

Melatonin use may cause headaches, joint pain, cough, drowsiness, nightmares, and gastrointestinal upset.

Safety in pregnancy

Melatonin is a category B3 drug taken by a limited number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other harmful effects on the foetus.

Risk-benefit analysis

While some studies show that melatonin may benefit ovarian stimulation outcomes, inadequate evidence on live birth rates from high-quality clinical trials limits its use for routine IVF. The optimal dose and timing of melatonin administration have also yet to be determined. Further research is required to understand the effect of melatonin on fertility outcomes.

Platelet-rich plasma

Adjuvant action and why it might be used in IVF

Platelet-rich plasma (PRP) is produced from your own blood using centrifugation, a technique that separates and concentrates your blood’s platelets, growth factors and immune cells. Before an embryo transfer or intrauterine insemination of sperm (IUI), PRP is instilled into the uterus to promote tissue healing and repair areas with reduced healing potential. PRP is also used in other specialities, including joint injuries, cosmetic procedures and wound care.

Potential benefit and evidence

Studies indicate that PRP may increase endometrial thickness and improve embryo implantation, along with clinical pregnancy rates in women who have a thin endometrial lining and recurrent implantation failure Additional studies and more robust evidence are required to strengthen the association between PRP and live birth rates.

Potential side effects

PRP may cause vaginal discharge, spotting, swelling, pain, fever or infection.

Safety in pregnancy

There are an insufficient number of studies examining the safety of PRP in pregnancy. Therefore, PRP use in pregnancy is not routinely recommended.

Risk-benefit analysis

Women who have a thin endometrial lining or recurrent implantation failure may consider PRP to improve implantation rates and clinical pregnancy rates. However, more extensive research is needed to determine if PRP improves live birth rates in the general IVF population.

Testosterone and dehydroepiandrosterone (DHEA)

Adjuvant action and why it might be used in IVF

Testosterone and dehydroepiandrosterone (DHEA) are androgen hormones produced by the adrenal glands and ovaries. Androgen levels peak in women in their mid to late 20s and slowly decline along with egg numbers. Androgens may help protect follicles from degeneration and enhance their growth during folliculogenesis. Androgen supplementation during the early follicular phase may improve the number of small antral follicles and ovarian sensitivity to follicle-stimulating hormone (FSH) during IVF. For this reason, androgens may be used by fertility specialists in women who are older or have a poorer ovarian reserve.

Potential benefit and evidence

Testosterone is a potent androgen that binds directly to androgen receptors within ovarian follicles. Current research suggests that testosterone supplementation may marginally increase the number of eggs retrieved in women with poor ovarian reserve or poor response to IVF cycles. A 2015 Cochrane review of studies suggests a possible improvement in live birth rate in pre-treatment with testosterone when compared with placebo or no treatment. However, due to the varying quality of these studies, additional evidence is required to obtain more conclusive results.

DHEA is an androgen precursor that converts to testosterone and dihydrotestosterone in target tissues. Several low-quality studies showed an improved response to follicle stimulation after oral DHEA use in women with poor ovarian reserve. The 2015 Cochrane review found mixed-quality evidence that DHEA pre-treatment is associated with higher live birth rates. A 2022 systematic review also reported conflicting results, indicating that DHEA is unlikely to enhance fertility outcomes in women who are poor responders.

Potential side effects

Testosterone or DHEA may cause oily skin, acne, body and facial hair growth, and hair loss. Some patients report increased libido and energy levels. Very rarely, patients may report voice deepening or clitoral enlargement.

Safety in pregnancy

Testosterone and DHEA are category D drugs that have caused or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. These medications pose a teratogenic risk to the unborn baby and should be avoided during pregnancy.

Risk-benefit analysis

There is limited evidence suggesting that androgen use improves fertility outcomes in women who are poor responders to IVF treatment. The optimal dose of testosterone or DHEA has not yet been established. More research is required to understand the effect of testosterone and DHEA on fertility outcomes.

Viagra (Sildenafil)

Adjuvant action and why it might be used in IVF

Sildenafil inhibits the phosphodiesterase 5 (PDE5), an enzyme responsible for regulating blood flow to tissues. This results in enlargement of blood vessels and increased blood flow to target organs. For this reason, sildenafil is used to treat erectile dysfunction and certain heart conditions. Sildenafil is thought to increase uterine blood flow and improve endometrial lining thickness in women with infertility.

Potential benefit and evidence

Conflicting and low-quality evidence suggests that sildenafil may increase the endometrial thickness, implantation rate and clinical pregnancy rates in women with a thin endometrial lining. Existing studies are low-quality, and the dosage used and route of administration vary significantly. Presently, no high-quality studies suggest that sildenafil improves live birth rates when taken by infertile women.

Potential side effects

Sildenafil may cause flushing, headaches, dizziness, nasal congestion, heartburn, abnormal vision, gastrointestinal disturbance, hypotension, tinnitus, rash, and priapism.

Safety in pregnancy

Sildenafil is a category B1 drug, which has been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other harmful effects on the human foetus having been observed.

Risk-benefit analysis

Given the lack of evidence for Sildenafil in improving the live birth rate, routine use in the general IVF population is not recommended. Women with a thin endometrium may choose to speak to their fertility specialist first before using Sildenafil.

Further information about adjuvants

For further information, or to understand if any of these treatments are appropriate for you, please talk to your Newlife IVF fertility specialist.