What IVF add-ons work best for older patients? Results of a meta-analysis

A 2025 meta-analysis combined 151 studies on interventions for advanced maternal age (>35) patients. It found no clear advantage to any specific stimulation protocol or FSH type, no benefit from routine ICSI, and decreased live birth with assisted hatching, while more research is needed on blastocyst versus cleavage-stage transfer and on PGT-A with modern methods.

In older patients, egg numbers are usually lower, fertilization may not go as smoothly, and embryos are more likely to be chromosomally abnormal. These factors all make pregnancy harder to achieve.

Because of this, many clinics have introduced different strategies for optimizing success rates for advanced maternal age. These include changing stimulation drugs, adding LH, using ICSI instead of IVF, performing assisted hatching, culturing embryos longer, or testing them with PGT-A.

But do these strategies work? Some studies report benefits from certain approaches, while others found no difference or even potential harm, which makes it hard to draw firm conclusions.

A new systematic review and meta-analysis by Ganer Herman et al. (2025) combined the results of 151 studies (including RCTs and other study types) and assessed whether common add-ons or protocol changes truly improve outcomes for this group.

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Addition of LH or hMG for ovarian stimulation for advanced maternal age

This refers to adding LH activity (as recombinant LH or hMG) to FSH during ovarian stimulation, which is thought to improve follicle development.

• The meta-analysis pooled 5 RCTs and found no difference in pregnancy or live birth rates when LH was added to FSH.
• Clinical pregnancy: relative risk 1.01 [95% CI: 0.81–1.27]; I2= 0%
• Live birth: relative risk 1.24 [95% CI: 0.71–2.19]; I2= 0%

Additionally, a large retrospective study also found no clinical benefit.

The quality of evidence was rated as very low to high (multiple RCTs and retrospective studies).

Assisted hatching for advanced maternal age

Assisted hatching is a technique where the zona is thinned or breached to try to help implantation.

• A meta-analysis of four RCTs found lower live birth rates with assisted hatching vs no hatching (19.6% vs 26.1%, risk ratio [95% CI]: 0.77 [0.60-1.00], I2= 0%). Note that this is borderline statistically significant, since the risk ratio includes 1.00.

Additional retrospective and case-control studies mostly showed no benefit. Two smaller RCTs compared assisted hatching techniques, with one suggesting laser may be better than chemical, but overall results did not support routine use.

In summary, randomized evidence suggests assisted hatching may reduce live birth in older patients, and most nonrandomized studies support no benefit.

The quality of evidence was rated as very low to high (5 RCTs, 1 case-control, 6 retrospective studies).

PGT-A for advanced maternal age

PGT-A screens embryos for chromosomal abnormalities before transfer.

The meta-analysis in this review was based mainly on FISH, an older technique that is rarely used today. Most clinics now use NGS, but randomized trials using NGS and focused specifically on older patients are still lacking. This means that their findings may not reflect how PGT-A is used in clinics today.

• In their meta-analysis of seven RCTs, there was no difference in live birth rates between PGT-A and no testing, although some studies reported fewer transfers or miscarriages with testing. The quality of evidence was rated as very low to high.

One relevant study not included was by Munne et al. (2019), which used NGS. This trial found no overall difference in ongoing pregnancy or miscarriage rates, but a post hoc analysis suggested a possible benefit in women aged 35–40, with higher ongoing pregnancy when a euploid embryo was transferred compared to the best-quality embryo (51% vs 37%). I reviewed this study in my post PGT-A doesn’t improve success rates in good prognosis patients.

Other interventions commonly used for advanced maternal age in IVF

Besides the meta-analyses that were shared above, the authors also did a systematic review of other interventions used in older patients. Many of these strategies are widely practiced, but most have only been studied in small or retrospective studies, so the evidence is often limited and the results are mixed.

ICSI for advanced maternal age. ICSI is often used to inject a single sperm directly into the egg.

• One RCT found no difference in pregnancy or live birth rates between ICSI and IVF, though outcomes may be worse with ICSI in patients with 4 or fewer eggs retrieved. Five retrospective studies mostly showed similar fertilization, pregnancy, and live birth rates, with some reporting higher fertilization with ICSI. One RCT suggested a benefit of IMSI (selecting sperm under higher magnification), and one retrospective study suggested Piezo ICSI may improve fertilization and blastocyst development.
• In summary, limited randomized evidence does not support routine use of ICSI in older patients, and it may even be harmful when egg numbers are low.
• The quality of evidence was rated as low to moderate (1 RCT and 5 retrospective studies, plus small studies of IMSI and Piezo ICSI).

Cleavage stage vs blastocyst stage transfer. This refers to whether embryos should be transferred earlier at the cleavage stage (day 2–3) or grown longer to the blastocyst stage (day 5–6).

• One RCT found higher pregnancy rates with blastocyst transfer compared to cleavage-stage transfer. Eight retrospective studies gave mixed results, though some suggested blastocyst culture may be most beneficial when at least three to four good-quality cleavage embryos are available. I reviewed one of these studies in my post Fewer embryos give better results when transferred on day 3, not day 5.
• In summary, limited randomized evidence supports extending culture to the blastocyst stage in AMA patients, with additional retrospective studies pointing in the same direction but with conflicting findings.
• The quality of evidence was rated as very low to moderate (1 RCT, 8 retrospective studies).

DHEA and CoQ10. These are supplements thought to improve ovarian response and egg quality.

• So far, studies have not shown a clear improvement in pregnancy or live birth rates.
• The quality of evidence was rated as very low to moderate (3 studies including 2 retrospective and 1 RCT for DHEA, 1 small RCT for CoQ10).

Stimulation protocol. Different regimens (long or short GnRH agonist, antagonist, natural cycles, estrogen/progestin priming, clomiphene/letrozole variants).

• Limited RCTs suggest a possible benefit of long GnRH agonist protocols over antagonist or short agonist, but most studies found no clear differences. Estrogen priming, modified natural cycles, and progestin priming did not appear helpful.
• The quality of evidence was rated as low to high (mix of RCTs and retrospective studies).

FSH type. Compares urinary vs recombinant FSH, or long-acting vs daily recombinant FSH.

• Studies did not show any consistent differences in pregnancy or live birth rates between types.
• The quality of evidence was rated as low to high (4 RCTs, 1 retrospective study).

FSH dose. Compares standard vs very low doses, or tailoring dose to AMH or AFC.

• Results were mixed, with some evidence suggesting AMH-based dosing may be more effective, but overall no clear conclusions.
• The quality of evidence was rated as very low to low (2 observational studies).

Growth hormone and dexamethasone. GH is used to enhance follicular development; dexamethasone to sensitize the ovary to stimulation.

• One RCT suggested GH may improve pregnancy and live birth, but larger retrospective studies gave inconsistent results. Dexamethasone showed no benefit.
• The quality of evidence was rated as low to moderate (1 RCT, several retrospective studies).

Triggering for oocyte collection. Used to mature eggs before retrieval (hCG, GnRH agonist, or both as a dual trigger).

• One RCT suggested dual trigger may improve embryo quality and outcomes for frozen transfers (but not fresh), while retrospective studies found no clear advantage.
• The quality of evidence was rated as low to moderate (1 RCT, 2 retrospective studies).

Planned freeze-all. Freezing all embryos for later transfer instead of transferring fresh.

• Retrospective studies did not show a clear live birth advantage, and findings were sometimes conflicting.
• The quality of evidence was rated as very low to low (5 retrospective studies).

FET protocol. Compares natural or modified natural, medicated, or GnRH agonist pretreatment (mild ovarian stimulated FET) cycles.

• No approach was consistently better; GnRH agonist pretreatment sometimes improved ongoing pregnancy, but not live birth.
• The quality of evidence was rated as low (3 retrospective studies).

Dual stimulation. Performing both follicular and luteal stimulations in the same cycle.

• This increased the number of oocytes and embryos, but pregnancy outcomes didn’t improve.
• The quality of evidence was rated as low (1 retrospective study).

Conclusions

These are the conclusions the authors presented based on the add-ons they investigated (they didn’t list all of them).

No benefit

• Routine ICSI is not recommended, as outcomes are similar to IVF.
• Routine assisted hatching, as it may reduce live birth rates, but more research is needed.

No clear evidence

• No clear evidence to recommend a specific stimulation protocol or frozen transfer protocol in advanced maternal age; routine use of long agonist protocols should be deferred until more high-quality data are available.
• No clear evidence to prefer one FSH type over another.
• No evidence to support a freeze-all strategy in advanced maternal age.

May have some benefit, but more evidence is needed

• LH supplementation showed no added value when looking only at advanced maternal age patients, but other meta-analyses (including broader groups) suggest possible benefit in women 35–40. More high-quality studies are needed before recommending routine use.
• For cleavage stage vs blastocyst stage transfer, blastocyst transfer may offer advantages, but more good-quality trials are needed; decisions should be individualized.
• Routine PGT-A is not supported by current evidence, however most RCTs either did not focus on advanced maternal age patients or used outdated FISH technology. Some more recent meta-analyses that included comprehensive chromosomal screening (such as NGS) suggest a possible benefit for patients over 35. The authors note that new data with modern testing methods should be carefully reviewed as it becomes available, and patients should be counseled individually about the potential benefits, costs, and limitations.

While other meta-analyses have reported benefits for some of these add-ons, this review focused only on older patients, a group often underrepresented in studies, and the data here remain limited.

Want to read more about advanced maternal age or IVF add-ons?

Related studies

These additional studies were referenced by the authors of the paper and haven’t been covered on Remembryo. They may be helpful if you’re exploring this topic further (specifically, meta-analyses for LH addition, ICSI for older patients and PGT-A). This section is available for paid subscribers.

Reference

Hadas Ganer Herman, Ido Feferkorn, Michael H Dahan, Shauna Reinblatt, Ezgi Demirtas, William Buckett, A meta-analysis and systematic review of advanced maternal age patients in IVF, Human Reproduction Update, 2025;, dmaf020, https://doi.org/10.1093/humupd/dmaf020

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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