Table 5.

Overview of all recommendations on clinical management with their level of evidence, benefit versus harm and other considerations that contributed to their formulation.

Intervention		Benefits versus harms (efficacy versus safety)	Level of evidence for efficacy (LBR/CPR)1	Level of evidence for safety1	Considerations	Recommendation
Platelet-rich plasma	Intrauterine PRP administration	Evidence of benefit on CPR, no evidence of an effect on miscarriage rate No evidence of harm	⊕◯◯◯	⊕◯◯◯	Current studies include a small sample size and heterogenous study population in addition to different dosages of PRP	Intrauterine administration of platelet-rich plasma is not recommended.
	Intraovarian PRP administration	Mostly uncontrolled studies, no data on effect on LBR or miscarriage rate No evidence of harm	No data	No data		Intraovarian administration of platelet-rich plasma is not recommended.
Duostim		No data of benefit on LBR or miscarriage rate Harms are expected to be similar to standard OS	No data	No data	An RCT comparing duostim with two conventional stimulations has not been performed to date	Duostim is currently not recommended for routine clinical use.
Adjuncts during ovarian stimulation		Conflicting evidence on LBR Safety concerns	⊕⊕◯◯	⊕⊕◯◯	/	Adjuncts (metformin, growth hormone, testosterone, DHEA, aspirin, indomethacin, and sildenafil) before or during ovarian stimulation are not recommended.
Intravaginal and intrauterine culture device	Intravaginal culture device	No evidence of a benefit on LBR No data on harms	⊕◯◯◯	No data	An embryologist and an IVF lab are still required	Intravaginal or intrauterine culture devices are currently not recommended for routine clinical use.
	Intrauterine culture device	One small study showing no benefit on LBR No data on harms	⊕◯◯◯	No data
Additions to transfer media (HA)		With a high dose of HA, a benefit on LBR and reduced risk of miscarriage was found Complications: increased multiple pregnancy rate	⊕⊕⊕◯	⊕⊕⊕◯	The use of HA should be combined with a single embryo transfer policy	Hyaluronic acid addition to transfer media is recommended. Monitoring of the multiple pregnancy rate is still advisable.
Endometrial scratching		Inconclusive data of benefit on LBR, with no effect on miscarriage rate Complications: moderate pain, bleeding, risk of infection	⊕⊕⊕◯	⊕⊕◯◯	Timing of scratch and methodology of the procedure differed between studies.	Endometrial scratching is currently not recommended for routine clinical use.
Flushing of the uterus	Intrauterine administration of hCG	Some benefit for cleavage stage (not blastocyst) transfer at >500 IU No evidence of harm	⊕⊕⊕◯	⊕◯◯◯	Timing of administration, dosage of hCG and timing of embryo transfer differed between studies.	Intrauterine administration of hCG is not recommended.
	Intrauterine administration of G-CSF	RIF: No evidence of benefit on LBR Thin endometrium: may improve LBR (1 RCT) Very few side effects reported	⊕⊕◯◯	⊕◯◯◯	/	Intrauterine administration of granulocyte colony-stimulating factor is not recommended.
	Endometrial administration of embryo culture supernatant	No evidence of benefit on LBR or miscarriage rate No evidence of harm	⊕◯◯◯	⊕◯◯◯	In several studies, it was unclear how the culture media were administered, by injection or as a uterine infusion.	Endometrial administration of embryo culture supernatant is not recommended.
	Endometrial exposure to seminal plasma	No evidence of a benefit on LBR or miscarriage rate Complications: no evidence of an effect on multiple pregnancy rate, potential risk of allergic reaction	⊕⊕◯◯	⊕⊕◯◯	Available evidence is very heterogenous with regards to the inclusion/exclusion criteria of patients, and the interventions	Endometrial exposure to seminal plasma is not recommended.
Stem cell mobilization	Stem cell therapy for POI or DOR	Available evidence comes from case reports and uncontrolled studies with very little information on the actual procedures and long-term follow-up is lacking	No data	No data	/	Stem cell therapy for premature ovarian insufficiency, diminished/poor ovarian reserve or thin endometrium is not recommended.
	Stem cell therapy for thin endometrium		No data	No data
Steroids		No benefit on LBR/CPR Safety concerns: increased risk of miscarriage, preterm births, gestational hypertension, …	⊕⊕◯◯	⊕◯◯◯	/	Glucocorticoids are not recommended in ART treatment.
Elective freeze-all		No benefit on LBR of freeze-all over fresh transfer Complications: higher risk of hypertensive disorder in pregnancy, large-for-gestational age, and higher mean birth weight	⊕⊕⊕◯	⊕⊕◯◯	With similar LBR and OPR and longer time to pregnancy and the added freezing/thawing procedures the cost with a ‘freeze-all’ for all strategy will exceed the costs in conventional fresh embryo transfer.	Elective freeze-all is currently not recommended for routine clinical use.
ICSI for non-male factor infertility		Conflicting evidence of effect on LBR, even if most studies report no significantly higher LBR with ICSI Safety is similar to IVF	⊕⊕◯◯	⊕⊕◯◯	Mean laboratory time is significantly longer for ICSI compared to conventional IVF, in addition to an increase in cost.	ICSI is not recommended for non-male factor infertility.
Antioxidant therapy		Effect on LBR in females is uncertain, no evidence of effect on LBR in males; no evidence of effect on miscarriage rate. Complications: gastrointestinal discomfort has been reported	⊕◯◯◯	⊕⊕◯◯	Most of the studies showed a small sample size, retrospective design, used various combinations of antioxidants and semen parameters or DFI were used as surrogate success parameters rather than pregnancy rate	Antioxidant therapy is not recommended in ART treatment.
Complementary and alternative medicine	Acupuncture	Conflicting evidence of effect on LBR, no evidence of effect on miscarriage rate Minor adverse effects have been reported	⊕⊕◯◯	⊕◯◯◯	Assessing complementary therapies through RCTs is challenging, especially with respect to a suitable control group and consistent methodology.	Acupuncture, Chinese and herbal medicine and other complementary therapies are not recommended.
	Other complementary therapy	No data	No data	No data
	Alternative medicine	May improve LBR/CPR No data regarding safety	⊕⊕◯◯	No data

¹Quality of Evidence Grades: ⊕⊕⊕⊕, body of evidence is of high quality (at least evidence from RCTs); ⊕⊕⊕◯, body of evidence is of moderate quality (evidence from RCTs or a number of observational studies showing a similar large effect); ⊕⊕◯◯, body of evidence is of low quality (mainly observational data); ⊕◯◯◯, body of evidence is of very low quality (few observational data).

CPR: clinical pregnancy rate; LBR: live birth rate; DFI: DNA fragmentation index; DHEA: dehydroepiandrosterone; DOR: diminished ovarian reserve; G-CSF: granulocyte-colony stimulating factor; HA: hyaluronic acid; IMSI: intracytoplasmic morphologically selected sperm injection; OPR: ongoing pregnancy rate; PRP: platelet-rich plasma; RIF: repeated implantation failure; RCT: randomized controlled trial; POI: premature ovarian insufficiency.