New clues to why some women experience recurrent miscarriage

Analysing blood, plasma, and urine samples from 88 women with and without a history of recurrent miscarriage (two or more consecutive losses), the team found distinct changes in three NAD-related metabolites in those who had experienced repeated losses. These differences occurred regardless of vitamin B3 supplementation, suggesting a deeper metabolic imbalance may be involved.

The findings published in Human Reproduction offer a new window into how NAD metabolism and inflammation might affect pregnancy health and could one day help identify women at risk or point to new avenues for treatment.

“Every miscarriage is heartbreaking,” said Dr Cuny. “Our goal is to understand the biology behind them, so that in time, fewer families have to go through such loss.”

This new research builds on Professor Dunwoodie’s 2017 discovery that low NAD levels cause birth defects and miscarriage, which are prevented by vitamin B3 supplementation in mouse models. This led to the theory that insufficient NAD levels might be linked to some cases of miscarriage.

However, in women, the story appears more complex. Rather than NAD being simply “too low,” this new study shows changes in how vitamin B3 is metabolised may also play a key role - revealing that the pathway’s impact on reproduction might be more varied than previously thought.

Building on these findings, the team has now been awarded a Australian Government Medical Research Future Fund Grant to continue this line of investigation. The new three-year project will commence in February 2026.

Working in partnership with women who have experienced miscarriage and their clinicians, the study will investigate NAD levels and related metabolites among women with and without a history of recurrent miscarriage. It will:

1. Identify NAD-related biomarkers that may indicate elevated miscarriage risk.
2. Examine how timing and number of miscarriages correspond to NAD metabolite levels.
3. Assess the impact of diet and nutritional supplements on NAD metabolism.
4. Explore other clinical factors that may interact with NAD metabolism and recurrent miscarriage risk.

The study will involve women from three groups - those with recurrent miscarriage, those currently experiencing recurrent miscarriage, and those with no history of miscarriage - recruited from the Royal Hospital for Women and Nepean Hospital. Each participant will provide blood and urine samples and complete a detailed health and lifestyle questionnaire.

Researchers hope this work will ultimately lead to a diagnostic test to identify women at risk of recurrent miscarriage and improve understanding of the biological mechanisms involved, so that in time some future losses might be prevented.

Reference:

Hartmut Cuny, Antonia W Shand, Jennifer Goth, Delicia Z Sheng, Tamarah Tossey, Ella M M A Martin, Alena Sipka, Olga Aleshin, Francisco J Schneuer, Natasha Nassar, Sally L Dunwoodie, Identification of potential NAD-related biomarkers of recurrent miscarriage risk, Human Reproduction, 2025;, deaf195, https://doi.org/10.1093/humrep/deaf195.