IVIG and Reproductive Immunology

If you do indeed have activated NK cells (NKa) , you wont need IVIG. It has been supplanted by Intralipid which is much less expensive. We should talk online. Call my assistant, Patti at 702-281-7437 and set up an online consultation with me.

Geoff Sher

• Understanding Recurrent Pregnancy Loss(RPL): Looking Beyond “Bad Luck”

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Recurrent Pregnancy Loss (RPL), often called Recurrent Miscarriages (two or more consecutive early pregnancy losses) , is one of the most painful and frustrating problems in reproductive medicine. It is generally defined as two or more consecutive pregnancy losses, and it affects about 5% of pregnancies. Three or more consecutive losses occur in about 1% of pregnancies. Evaluation is encouraged after the second loss rather than waiting for further repeated heartbreak.

Yet despite how common miscarriage is, recurrent miscarriage remains, in many ways, an enigma.

It is poorly understood by many, and because of that, approaches to evaluation and treatment vary widely. Some physicians focus almost entirely on genetics. Others focus on the uterus. Some emphasize blood clotting disorders. Still others, me included, believe that in many patients with RPL, the immune system plays a central and often overlooked role.

I recognize that not everyone in the field agrees with this position. Reproductive immunology remains controversial, and major guidelines still regard many immune tests and immune therapies as insufficiently proven for routine use.

However, my position is based not only on the medical literature, but also on nearly 40 years of experience in IVF, implantation failure, recurrent miscarriage, and clinical reproductive immunology. I have seen too many patients repeatedly told to “try again” when, in fact, there was a potentially treatable reason for their losses. This article reflects the way I personally evaluate and manage such cases, and the approach I believe offers many couples the best chance of success.

Human Reproduction Is Inefficient

Human reproduction is remarkably inefficient compared with that of many other mammals. A large percentage of fertilized eggs never become babies. Many embryos fail before a pregnancy test is ever positive. Others are lost very early in the first trimester.

Most isolated miscarriages are caused by embryo aneuploidy, meaning the embryo has an abnormal number of chromosomes. Instead of the normal 46 chromosomes, there may be too many or too few. These chromosomal errors are strongly influenced by maternal age and are usually random rather than repetitive. Most miscarriages are sporadic and commonly genetic in origin.  That is why one miscarriage, although devastating, does not always indicate an underlying disease.

But recurrent miscarriages are different.

When losses repeat, especially when they occur after transfer of chromosomally normal embryos, the focus must shift. We must ask: Is the problem truly the embryo, or is the problem the environment into which the embryo is trying to implant and grow?

In my opinion, this is the central question in RPL.

The Two Broad Categories of Pregnancy Loss

Pregnancy loss can occur at different stages, and timing often gives important clues.

 

Early Pregnancy Loss

Early pregnancy loss usually occurs in the first trimester. Most isolated early losses are due to embryo chromosomal abnormalities. These are often not preventable and usually do not repeat in a predictable pattern.

However, repeated early losses may suggest a recurring problem with regard to embryo implantation”  such as:

• uterine cavity anatomical  abnormalities (scar tissue; polyps; fibroid tumors; adenomyosis)
• Endometrial insufficiency (a “thin uterine lining of <8mm)
• immunologic implantation dysfunction (IID)

 

Later Pregnancy Loss

Pregnancy losses after the first trimester are less common and often point toward different causes. These may include:

• cervical incompetence (weakness of the cervical neck)
• uterine septum or congenital uterine abnormality
• fibroids distorting the uterine cavity
• intrauterine adhesions
• placental problems
• premature rupture of membranes
• fetal growth restriction
• maternal medical disorders
• congenital clotting disorders (thrombophilia)

 

In these cases, careful evaluation of the uterus, cervix, placenta, and maternal health is essential.

 

Why Products of Conception Testing Matters

One of the most important advances in RPL management is genetic testing of miscarriage tissue, often called products of conception testing.

If the pregnancy tissue shows aneuploidy, then the loss may have been caused by an embryo chromosomal error. If the tissue is chromosomally normal, then the physician must look harder for a uterine, immune, clotting, hormonal, or other maternal factor.

This information can prevent years of guessing.

In my view, early genetic testing of miscarriage tissue is one of the most practical and valuable steps in RPL evaluation.

 

The Uterine Environment Matters

A normal embryo still needs a receptive uterus!

Even the best embryo cannot implant successfully if the uterine cavity is abnormal, the lining is too thin, blood flow is poor, or the local immune environment is hostile.

The uterine evaluation should usually include one or more of the following:

• saline ultrasound, also called sonohysterogram
• hysteroscopy
• ultrasound assessment for submucous fibroids, polyps, or endo-uterine scarring /adhesions
• assessment of endometrial thickness and response to estrogen
• Pelvic MRI (selectively)

 

Small polyps, submucous fibroids, and scar tissue, can interfere with implantation. These lesions may act almost like an intrauterine irritant. When present, they should usually be corrected before further attempts at pregnancy or embryo transfer.

 

The Thin Endometrium

Endometrial thickness is another important factor.

In my experience, an endometrial lining of 9 mm or more around ovulation, egg retrieval, or progesterone initiation is generally favorable. A lining below 8 mm is concerning and may be associated with poor implantation or early loss. A lining between 8 and 9 mm is intermediate.

A thin endometrial lining can result from:

• Endo-uterine adhesions/scaring (due to damage done to the basal endometrium:
  • Endometritis (usually post miscarriage, post-abortal or post childbirth).
  • uterine tuberculosis (very rare)
• Impaired uterine blood flow
  • Multiple uterine fibroids
  • Disseminated  adenomyosis (rare)
• poor endometrial responsiveness to estrogen
  • Following several months of estrogen deprivation that can occur following menopause/ovarian failure;
  • Following prolonged endometrial suppression with GnRH agonists such as Lupron/Buserelin/Superfact/Decapeptyl etc.
  •  following >2 back-to- back (consecutive) clomiphene stimulation cycles
  •  following prolonged and excessive exposure to male hormones such as testosterone
•  In some cases where women with severely diminished ovarian reserve (DOR) are treated using “inappropriate” stimulation protocols

 

In selected cases, improving blood flow to the endometrium may help. I introduced vaginal sildenafil (Viagra) therapy many years ago as one such approach for selected women with thin endometrium and impaired uterine blood flow. It is not effective for every patient, especially when there is permanent basal endometrial damage, but in properly selected cases it can improve lining development.

 

Immunologic Implantation Dymay sfunction (IID): The Often Overlooked Factor

This is where my personal view differ from many conventional approaches.

I believe that Immunologic Implantation Dysfunction (IID) is one of the most overlooked causes of recurrent pregnancy loss and failed implantation of chromosomally normal (euploid) embryos.

Pregnancy is immunologically unusual. The embryo is not genetically identical to the mother. It carries paternal genetic material and is, in a sense, a semi-allograft. The maternal immune system must recognize the embryo but not reject it. Successful implantation requires a carefully balanced immune dialogue between embryo and endometrium.

The balance particularly between TH-1 and TH-2 cytokine activity

is influenced by immune cells in the uterine lining, especially:

• natural killer (NK) cells
• T lymphocytes

 

When functioning properly, these cells help with implantation and placental development. But when overactivated, they may produce excessive inflammatory cytokines such as TNF-alpha, interferon gamma and IL4. These can damage the trophoblast, the embryo’s early “root system,” leading to failed implantation, chemical pregnancy, or miscarriage.

The key point is this:

It is not simply the number of NK cells that matters. It is their activation and cytotoxic behavior.

This is why I consider NK cell activity (Nka) testing, particularly functional assays such as the K-562 target cell assay and evaluation of the cytokine balance more meaningful than merely counting NK cells.

I acknowledge that this position is somewhat controversial. But in my clinical experience over >3 decades, properly selected patients with evidence of immune activation can benefit significantly from targeted therapy.

 

Autoimmune and Alloimmune IID

I divide immunologic implantation dysfunction into two broad categories.

 

Autoimmune IID

Autoimmune IID occurs when a woman’s immune system shows abnormal reactivity against her own tissues or immune markers. It may be associated with:

• Hashimoto’s disease
• antithyroid antibodies
• lupus erythematosus
• rheumatoid arthritis
• scleroderma
• dermatomyositis
• endometriosis
• antiphospholipid antibody syndromes
• positive ANA testing

 

The antibodies may not always be the direct cause of reproductive failure. In many cases, they are markers of a broader immune disturbance. The real reproductive damage may occur when they are associated with activated NK cells (Nka)  and cytotoxic T cells.

In my experience, autoimmune IID is far more responsive to selective immunotherapy than is alloimmune IID.

Alloimmune IID

Alloimmune IID is more complex.

It relates to the immune interaction between the male and female partners. In a normal pregnancy, the embryo must be sufficiently different from the mother for the immune system to recognize it properly and develop tolerance.

In some couples, there may be excessive immunogenetic similarities, especially involving DQ alpha/HLA-related patterns. When this occurs, the maternal immune system may fail to generate normal tolerance. NK and T-cell activation can then develop over time.

Clinically, this may present as:

• one or more live births followed by repeated miscarriages
• recurrent early losses (chemical pregnancies and miscarriages)
• failed implantation of normal looking embryos
• secondary unexplained infertility
• failed transfer of euploid embryos

 

Partial matching  may sometimes be managed with selective immunotherapy. Complete matching is more difficult, and in rare severe cases, donor sperm or gestational surrogacy may need to be considered.

This is a specialized and controversial area, but I believe it is central in a subset of couples with otherwise unexplained RPL or euploid embryo failure.

 

Antiphospholipid Syndrome and Thrombophilia

Antiphospholipid syndrome, or APS, is one of the best-established immune-related causes of recurrent pregnancy loss. It is widely accepted as clinically important in RPL evaluation.

Testing may include:

• measurement of all IgA, IgG and IgM-antiphospholipid antibody panels

 

When APS or specific clinically relevant antiphospholipid antibodies are present, treatment may include  low molecular weight heparin (Lovenox; Clexane), depending on the patient’s history and test results.

Inherited thrombophilias are more controversial as a cause of early RPL, but in selected patients, especially with later losses or placental complications, they may be relevant.

 

Failed Euploid Embryo Transfer: A Major Clue

Modern IVF has transformed our ability to understand reproductive failure.

With PGT-A using next generation gene sequencing, we can identify chromosomally normal embryos. When such embryos repeatedly fail to implant or result in miscarriage, the explanation “bad embryo” becomes less convincing.

In these cases, I believe one should presume that the cause is implantation dysfunction until proven otherwise.

The main categories to evaluate are:

• endometrial thickness (ultrasound)
• uterine cavity integrity (saline sonogram/hysteroscopy/MRI)
• chronic endometritis
• hormonal environment
• autoimmune, IID
• alloimmune, IID
• embryo transfer technique
• male genomic contribution

 

Repeatedly transferring euploid embryos without investigating the implantation environment can cause patients to spin their wheels emotionally, physically, and financially.

 

Treatment Must Be Targeted

The treatment of RPL should not be random. It should follow the diagnosis.

 

Uterine abnormalities

Polyps, fibroids, adhesions, or septa should be corrected when they distort or disturb the cavity.

 

Thin Endometrial lining

Treatment may include correcting inflammation, avoiding harmful stimulation patterns, optimizing estrogen response, improving blood flow, and in selected cases using vaginal sildenafil.

 

APS or Thrombophilia

Treatment may include low-dose aspirin and/or low molecular weight heparin where appropriate.

 

Immune activation

In selected patients with evidence of IID, I use selective immunotherapy. This may include:

• intralipid therapy
• corticosteroids such as prednisone or dexamethasone
• IVIg in selected cases
• Heparinoids (e.g., Clexane and Lovenox) if  antiphospholipid antibodies are present

The timing is critical. In my experience, immune therapy must begin 10–14 days before embryo transfer. Starting treatment too late may fail because the relevant immune cells may already be activated.

This timing principle is often missed.

 

IVF as a Tool in RPL

IVF is not necessary for every patient with recurrent pregnancy loss. But in selected cases, it offers major advantages.

IVF allows us to:

• test embryos for aneuploidy
• transfer one euploid embryo at a time
• control timing of immunotherapy
• control hormonal preparation
• evaluate implantation failure more precisely
• reduce repeated exposure to ineffective cycles

 

When immunotherapy is needed, IVF can be especially useful because treatment can be timed precisely before embryo transfer.

 

The Psychological Burden Must Not Be Ignored

RPL is not simply a medical diagnosis. It is an emotional trauma.

Patients often experience grief, guilt, anxiety, depression, relationship stress, and PTSD-like symptoms. ACOG emphasizes the importance of emotional support after miscarriage and pregnancy loss.

Patients with RPL need more than lab tests and procedures. They need continuity of care, compassion, clear explanations, and a plan. Dedicated RPL programs can be invaluable because they provide both medical structure and emotional support.

One of the most damaging things we can say to these patients is: “Just try again.”

A better message is:

“Let us look carefully, logically, and thoroughly for a reason.”

 

Prognosis: There Is Real Hope

Despite the pain of recurrent miscarriage, many couples ultimately succeed.

Depending on maternal age, embryo quality, prior live birth history, uterine findings, immune factors, and treatment options, the chance of eventual live birth can often exceed 50–70%. In my own experience, when couples are willing to undergo thorough evaluation and individualized treatment, the overall chance of success can be even higher in properly selected cases.

This does not mean every case can be solved. Some patients will face severe uterine damage, advanced reproductive age, profound embryo aneuploidy, severe alloimmune issues, or other limiting factors.

But many patients who have been told their losses are unexplained are not truly unexplained. They are incompletely investigated.

 

Final Takeaway

Recurrent pregnancy loss remains one of the most difficult problems in reproductive medicine. It is emotionally devastating, biologically complex, and still not fully understood.

The strongest established causes include:

• Anatomical uterine factors such as endometrial insufficiency and surface lesions of the uterine cavity.
• IID (often alloimmune, rather than autoimmune)
• uterine abnormalities (septum; fibroids; Asherman’s syndrome; adenomyosis; post -surgical trauma);
• parental chromosomal translocations

 

Emerging areas include:

• chronic endometritis
• microbiome disturbances
• sperm DNA and male genomic factors
• endometrial receptivity

 

After nearly 40 years in IVF and reproductive immunology, I believe that recurrent pregnancy loss is rarely just “bad luck.” It is often a signal. A signal that the embryo, the uterus, the immune system, or the interaction between them needs deeper evaluation.

The goal is not to treat every patient the same way. The goal is to identify the reason for failure and treat that reason.

 

For patients, the message should be hopeful:

• You are not alone.
• You are not imagining the pattern.
• Your losses deserve a serious explanation.
• And with proper investigation, compassionate care, and individualized treatment, many couples can still achieve the healthy birth they have been hoping for.