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Randomised, double blind, placebo controlled trial in men Publication date verified at source

The Effects of Alpha-Lipoic Acid Supplement on Sperm Parameters and DNA Fragmentation in Couples with Recurrent Pregnancy Loss: A Randomized Controlled Trial

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Journal
International Journal of Fertility and Sterility
Authors
Khadem N
Institution
Mashhad University of Medical Sciences
Published
27 July 2026
Source
PMID 42571056 · DOI 10.22074/ijfs.2026.2055979.1855
Design
Randomized, double blind, placebo controlled trial over 12 weeks, both arms receiving folic acid. Couples with recurrent pregnancy loss, men with normal semen analysis but high DNA fragmentation.
Sample
Couples with recurrent pregnancy loss, men with normal semen analysis but high DNA fragmentation

What the DNA fragmentation index is

The DNA fragmentation index is the share of sperm in a sample carrying broken DNA strands. It is a laboratory measure of sperm quality, not a measure of whether a pregnancy happens.

Why they ran it

In more than 40 to 50 percent of recurrent pregnancy loss cases no cause is found even after a thorough workup, and attention has been shifting from female factors toward the male partner, in particular sperm DNA fragmentation.

Alpha lipoic acid had been looked at for fertility before, but almost always in infertile couples, with very few studies in couples whose problem is repeated loss.

Drawn from the paper's introduction.

Couples with two or more consecutive pregnancy losses were recruited at a fertility centre in Mashhad, Iran. The men had normal semen analyses but a DNA fragmentation index above 30 percent, and their partners had been worked up with no cause found. One group took alpha lipoic acid three times daily plus 5 mg of folic acid, the other took a placebo plus the same folic acid, for 12 weeks. Sperm concentration, motility and morphology were assessed by standard methods, and DNA fragmentation by sperm chromatin structure assay.

Forty men finished. DNA fragmentation ended at 30.5 percent in the treated arm and 34.75 percent on placebo, a gap the authors report as significant. Concentration ended at 49.85 against 47.1 million per mL, motility 46.7 against 44.3 percent, and morphology 48.55 against 43.45 percent, none of which separated the two groups. Both arms improved on DNA fragmentation from their own baselines, the treated arm falling 4.9 points and the placebo arm 2.4.

Those two drops are the interesting part. Compared head to head, the difference in change from baseline came to p equals 0.058, so the significant result rests on where the arms landed rather than on how far each moved. The paper's own enrolment figures also wobble: the abstract says 64 couples enrolled, the results section says 52 were randomised. And the authors state plainly that they measured no antioxidant capacity, malondialdehyde or other oxidative stress markers.

The numbers

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Why this might happen

Proposed by the authors This is the explanation the authors offer in their discussion. This study did not test it.

The authors describe reactive oxygen species as necessary in small amounts for capacitation, but say excess production triggers lipid peroxidation and apoptosis inducing factors, damaging sperm DNA.

They propose that alpha lipoic acid works by scavenging reactive oxygen species, chelating pro oxidant metal ions, regenerating oxidised antioxidants and raising the activity of glutathione peroxidase, catalase and superoxide dismutase.

None of this chain was measured in the trial: the authors state they did not determine total antioxidant capacity, malondialdehyde or other oxidative stress markers.

Drawn from the paper's discussion.

What this does not show

  • No pregnancy or birth was measured. The authors list this in their own limitations: they did not assess longer term outcomes such as pregnancy or live birth rates, despite recruiting couples specifically for recurrent pregnancy loss.
  • No oxidative stress marker was measured. The stated rationale is that alpha lipoic acid scavenges reactive oxygen species, but the authors write that they did not determine total antioxidant capacity, malondialdehyde or any oxidative stress marker.
  • Conventional semen measures did not separate the arms. At 12 weeks the between group comparisons came to p equals 0.416 for concentration, 0.587 for motility and 0.342 for morphology, so the improvements the abstract highlights are within arm changes only.
  • The placebo arm improved too. DNA fragmentation fell 2.4 points on placebo plus folic acid, a within arm change the paper itself reports as significant at p equals 0.003.

Where this leaves us

At the end of three months the sperm DNA fragmentation index was lower in the treated group than the control group, while count, motility and shape did not separate them. That extends earlier work into a new population and refines it, because the conventional semen measures earlier studies reported as improving did not differ between groups here.

Forty couples analysed out of sixty four enrolled at a single infertility centre in Mashhad, where the man had a normal semen analysis but a fragmentation index above 30 percent and the woman had no identified cause of loss.

The authors name it themselves: long term follow up of pregnancy and live birth rates, molecular measurement of oxidative stress, and work on dose and duration.

Caveats worth holding

  • Forty men is a small trial, and the target sample size was set with a one tailed test using pilot data from ten men per group.
  • Twelve men who started did not finish, split evenly between the two arms, and were left out of the analysis.
  • Both arms received folic acid, so this compares alpha lipoic acid plus folic acid against folic acid alone rather than against nothing.
  • The data were collected between February 2021 and March 2022 and reported in 2026, a long gap between the trial and its publication.

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