Senior Consultant, Medical Genetics, Artemis Hospitals, Gurgaon, India
Part 9 of 12 in Finding Answers in Recurrent Pregnancy Loss
The Immunological Debate: NK Cells, TNF-Alpha, and IVIG Therapy
June 7, 2026
Immunological causes of recurrent pregnancy loss remain genuinely debated, with current guidelines stating that immunological evaluation and treatment should neither be routinely pursued nor withheld outright. The underlying theory: in a normal pregnancy, the embryo is foreign to the mother's body, and protective immune changes prevent rejection; in some women that protective shift doesn't occur, and a hyperimmune state (marked by elevated TNF-alpha and NK cells) may lead to embryo rejection instead.
On a case-by-case basis (clinical suspicion of autoimmune disease, or an otherwise-normal workup with multiple losses), Dr. Singh tests TNF-alpha, CD19 (B cells) and NK cells (CD16/56) in blood. On treatment: IVIG or intralipid therapy for women with an autoimmune predisposition isn't strongly endorsed by guidelines, but she notes it has helped many of her own patients when no other cause was found. Glucocorticoids, by contrast, are now avoided because of an increased risk of birth defects, particularly cleft lip and palate.
This guide is based on a live Jivo Masterclass — Dr. Kanika Singh taught doctors across Africa on June 7, 2026.
FROM THE LIVE Q&A
Dr. Isaya
My question is about sperm collection. In my clinic I often see couples where the male is over 50 years old. What are the chances of getting good quality sperm, and what are the implications for implantation?
Dr. Kanika Singh
I will not be able to give you details about specific sperm selection procedures, as in our hospital this is a multidisciplinary process involving the IVF specialist and the andrology laboratory. But in terms of the genetic implications: above the age of 50, there is a high chance that sperm quality is reduced, and the sperm DNA fragmentation index is likely to be elevated. Unless we specifically test for it, we do not know the exact level, but even without testing, there is a significant chance that sperm DNA quality is impaired, which can result in recurrent pregnancy loss or implantation failure. Testing the sperm DNA fragmentation index in men above 50 with a history of recurrent pregnancy loss or implantation failure would be worthwhile.
Frequently Asked Questions
For patients with PCOS, how long should metformin be taken before conception and after conception?▼
Metformin should be started at least 2 to 3 months before conception. It is safe to continue in pregnancy and is generally continued through the first trimester and sometimes beyond. It should be monitored with GTT as well as regular HbA1c and blood sugar checks throughout.
My question is about sperm collection. In my clinic I often see couples where the male is over 50 years old. What are the chances of getting good quality sperm, and what are the implications for implantation?▼
I will not be able to give you details about specific sperm selection procedures, as in our hospital this is a multidisciplinary process involving the IVF specialist and the andrology laboratory. But in terms of the genetic implications: above the age of 50, there is a high chance that sperm quality is reduced, and the sperm DNA fragmentation index is likely to be elevated. Unless we specifically test for it, we do not know the exact level, but even without testing, there is a significant chance that sperm DNA quality is impaired, which can result in recurrent pregnancy loss or implantation failure. Testing the sperm DNA fragmentation index in men above 50 with a history of recurrent pregnancy loss or implantation failure would be worthwhile.
Do guidelines recommend routine immunological testing for recurrent pregnancy loss?▼
Current guidelines state that immunological evaluation and treatment should neither be routinely pursued nor withheld outright.
What is the theory behind immune-related pregnancy loss?▼
In a normal pregnancy protective immune changes prevent the mother's body from rejecting the foreign embryo; when that protective shift doesn't occur, a hyperimmune state marked by elevated TNF-alpha and NK cells may lead to embryo rejection instead.
Which immune markers are tested when an immunological cause is suspected?▼
TNF-alpha, CD19 (B cells), and NK cells (CD16/56), tested on a case-by-case basis in blood.
Is IVIG or intralipid therapy recommended for recurrent pregnancy loss?▼
It isn't strongly endorsed by guidelines, though it has helped many patients when no other cause was found.
Why are glucocorticoids now avoided as an immunological treatment?▼
They are avoided because of an increased risk of birth defects, particularly cleft lip and palate.
In This Series: Finding Answers in Recurrent Pregnancy Loss
- 1.Finding Answers in Recurrent Pregnancy Loss
- 2.Fetal Chromosomal Abnormalities: The Leading Cause of First-Trimester Loss
- 3.Balanced Translocation: When a Genetically Normal Parent Passes on Recurrent Loss
- 4.Single-Gene Causes: Why Second-Trimester Losses Need a Different Genetic Workup
- 5.Anatomical Causes: Uterine Septum, Fibroids, and Cervical Incompetence
- 6.Antiphospholipid Antibody Syndrome: Diagnosis and Treatment
- 7.Endocrine Causes: Thyroid, PCOS, and Diabetes in Recurrent Pregnancy Loss
- 8.Sperm DNA Fragmentation: The Male Factor in Recurrent Pregnancy Loss
- 9.The Immunological Debate: NK Cells, TNF-Alpha, and IVIG Therapy
- 10.What to Test For: A Practical Investigation Framework by Trimester
- 11.Pre-Implantation Genetic Testing: PGT-A, PGT-M, PGT-SR and PGT-HLA Explained
- 12.Prognosis After Recurrent Pregnancy Loss: Why the Outlook Is Better Than Most Couples Expect