Do You Have a History of Stillbirth?

Stillbirth: Identifying the Real Issue

Stillbirth is distinct from miscarriage in that it occurs after the twentieth week of pregnancy. The death may occur before labor or during childbirth. Although it is a personal decision, it is advisable that couples who have lost a baby in this way arrange to have a pathologist conduct an examination to attempt to determine the cause of the loss. The more information that you can provide as to what occurred; the better your chances of obtaining successful treatment to better achieve your goal of expanding your family.

At our clinic, we are sensitive to the fact that undergoing a stillbirth, let alone multiple stillbirths, can be a heart-wrenching experience. It is important to remember that it is very rarely as a result of something the parents did or didn't do. Our team will work with you and use our advanced diagnostic testing to identify the factor or factors requiring adjustment. This applies whether or not you have information available regarding previous losses. The factors we discover may involve immunologic causes or non-immune causes and either way, we are committed to finding not only the issue but also an effective treatment.


Placental Inflammation and Stillbirth: Insight into Immune Conflicts Between the Mother and the Fetus

Stillbirths are a devastating experience that appear to be increasing in frequency in this country. They are very rarely due to something the parents did wrong, as most are dictated from the implantation process at the beginning of the pregnancy. It is still however commonly believed that stillbirths are random accidents provoked by the umbilical cord being wrapped around the body or the neck of the baby, which actually occurs in 1 in 4 births without causing such a dramatic fate in the majority of cases.

Besides the conventional maternal conditions that can significantly increase the risk of stillbirth such as obesity, diabetes or infections, a significant number of stillbirths still remains unexplained.

Maternal immune dysregulation could have dramatic effect on the pregnancy outcome. Depending on the severity of these immune alterations, the consequences on pregnancy range from miscarriages, intra uterine growth restriction (IUGR), pre-eclampsia to stillbirth.

In this blog, we will introduce you to the effects of an acute maternal immune rejection (with the production of anti-paternal HLA antibodies) and the effects of chronic immune dysregulations on placental inflammation with lesions such as Villitis of unknown etiology (VUE) and chronic histiocytic intervillositis unknown etiology (CIUE), both associated with increased risk of fetal death.

Stillbirth: Definition and statistics

Stillbirth occurs when a baby is lost in the womb at or after 20 weeks of pregnancy.

Depending on the time of occurrence, stillbirths are classified as either early, late or term:

  • An early stillbirth is a fetal death occurring between 20 and 27 weeks of pregnancy.
  • A late stillbirth occurs between 28 and 36 pregnancy weeks.
  • A term stillbirth occurs after 37 pregnancy weeks.

The majority of stillbirths occur in the womb (intrauterine death) but few can occur during labor or birth (intrapartum death).

Stillbirth is one of the most common adverse pregnancy outcome in the United States and affects 1% of all pregnancies which is about 24 000 babies each year (1).

Placenta: Structure and function

Placenta is a vital organ connecting the developing fetus to the uterus. It supports the pregnancy by producing hormones and fight infections. Through maternal bloodstream filling the intervillous space as seen in the figure below, the placenta provides nutrients and oxygen to the fetus, and allows waste elimination. The trophoblast (fetal side) surrounds the villis that are directly in contact with the maternal blood.

Stillbirth Doctor

Figure 1: Schematic view of the placenta.
Illustration from OpenStax College, Anatomy & Physiology. OpenStax College. 25 April 2013.

Signs predictive of a bad pregnancy outcome

Many signs occurring as early as the first trimester could be considered as harbingers of poor pregnancy outcomes:

  • An abnormal implantation: the implantation process is the key step of a pregnancy, if abnormal this will lead to a spectrum of subsequent dramatic effects ranging from early miscarriage to stillbirth.
  • Low levels of amniotic fluid
  • Poor placental vascularization and development: a study showed that patients destined to develop stillbirths have higher level of the pro-angiogenic factor PlGF and a lower level of anti-angiogenic factors sVEGFR-1 and soluble endoline plasma concentrations in the first trimester than do normal pregnancies; this pattern is reversed during the third trimester (2).
  • Small for gestational age (SGA): it has been frequently associated with stillbirth (3).
  • IUGR
  • Pre-eclampsia

Still birth: a biological signature of maternal anti-fetal rejection

Stillbirth could be considered a consequence of immunologic rejection by the mother against the fetus. We can make an analogy between stillbirth and a failure of graft survival in organ transplantation.
Antibodies against paternal components such as HLA can be harmful to pregnancy maintenance by inducing miscarriage, or later complications as preeclampsia, intrauterine growth restriction, or stillbirth. In a study, seropositivity for anti-HLA class II antibodies was found in 10.9% of preterm live birth versus 35.7% in fetal death cases (4) showing their detrimental role in the maintenance of a pregnancy.

In early pregnancy, when detected, anti-paternal HLA antibodies were associated with a reduced likelihood of a live birth (5). In particular, an altered maternal immune response against male-specific minor histocompatibility (HY) antigens (after the birth of a son) has been shown to be responsible for lower live birth rate in the subsequent pregnancies. The presence of one HY-restricting HLA class II allele in women with firstborn boys significantly reduces the chances of a live birth by 50%, when two HY-restricting HLA class II are detected, the chances of having another live birth are reduced by 80% (6).

Another study showed that maternal plasma antibodies against fetal HLA antigens class I or II were identified in all cases of severe placental lesions, namely massive perivillous fibrin deposition or MPFD and was associated with the presence of C4d deposition (marker of complement activation) which is a known factor of antibody-mediated rejection of the allografts (7).

Placental lesions as manifestations of maternal anti-fetal rejection

To assess the likelihood of graft rejection in patients who undergo transplantation, a test named “HLA panel-reactive antibodies (PRA)” is used to determine the HLA

Sensitization status of recipients (8). Studies showed that maternal HLA PRA

Positivity before 16 weeks (9) and at the time of diagnosis (10) are associated with the presence of placental lesions, suggesting that these lesions are potentially caused by maternal anti-fetal rejection.

  1. Villitis of unknown etiology and stillbirth

Villitis are important lesions of the placenta that can be caused by maternal infections such as toxoplasmosis or rubella. But most of Villitis are of unknown etiology (VUE). These lesions are common with a prevalence of 7.6 -10% of third trimester placenta in the United Sates (11) and are characterized by inflammatory cells infiltration in the chorionic villi (fetal side of the placenta).

Immune cells aggregate in VUE

In placentas with VUE, the predominant inflammatory cells are activated macrophages CD68+ expressing class II major histocompatibility complex antigens and helper T cells. Few CD8+ T cells and no B cells were detected in the same lesions (12).

These results were confirmed in another study showing that activated macrophages CD56+ predominate in Villitis while very few CD4+T lymphocytes and abundant levels of CD8+T cells were detected (13).

As a consequence, the invasion of fetal villi by maternal T-cells was shown to be associated with the destruction of syncytiotrophoblast (embryonic part of the placental villi) (14).

Immunologic reaction: maternal rejection of paternal antigens exposed within villi

(VUE) can be seen as a host versus graft reaction. Twenty years ago, very elegant studies showed that immune cells infiltrating placenta villous were of maternal origin (15), they are not only surrounding the chorionic villi but must have crossed the maternal-fetal barrier to respond to endogenous fetal antigens (16).

Interestingly, two studies have shown an increased incidence of (VUE) in placentas of pregnancies with egg donor compared with placentas from pregnancies where own eggs were used (17-18) suggesting that the lack of shared self-antigens in the placenta may increase risks for (VUE) (19).

While extensive literature shows a role of (VUE) in intra uterine growth restriction (IUGR) (20), very few studies focused on stillbirth. Nevertheless, a recent study showed that (VUE) is independently associated with risk for stillbirth at term (21).

  1. Chronic histiocytic intervillositis and stillbirth

Chronic histiocytic intervillositis are rare placental lesions characterized by an intervillous infiltration of mononuclear inflammatory cells of maternal origin and is associated with fibrin deposits leading to placental insufficiency (22). Fibrin deposition interferes with perfusion and gas/nutrient exchange in the intervillous space which results in placental insufficiency thus impacting fetal health.

Furthermore, (CHI) is associated with a high risk of reoccurrence (23).

While (CHI) lesions have been reported in 0.6% of placenta of second and third trimester pregnancies, their prevalence is significantly higher in first trimester miscarriages (4.5%) (24).

(CHI) can co-exist with Villitis and is considered as a more extreme form of the same pathology although the localization of placental lesions are different (maternal or fetal side of the placenta) (25).

Role of Immune cells in (CHI) pathology

As for (VUE), (CHI) could be considered as an expression of fetal rejection by the maternal immune system with CD68+ activated macrophages being the predominant inflammatory immune cells in (CHI) lesions (with over 90% of cells) whereas T lymphocytes were rarely observed (26).

During pregnancy, maternal immune system usually tolerates the presence of paternal allo-antigens present in the fetus. Regulatory T cells (Tregs) are key players in maintaining immune tolerance towards the fetus by accumulating in the decidua during first trimester and regulate fetal rejection by maternal immune cells (27).

In addition to their presence in the decidua, Treg cells were shown to accumulate in the intervillous space of (CHI) placenta while no cells were detected in placenta of healthy pregnancy (28). Their number was shown to increase with the severity of (CHI). It is not yet understood why an increase in Treg cells could induce placenta lesions but it is believed that these Treg cells may have a lack of functional activity.

CHI and stillbirth

The intensity of the lesions are directly linked to the poor pregnancy outcome (29).
Chronic histiocytic intervillositis has a high (80.0%) recurrence risk. The chance of a live birth is 54% in pregnancies reaching 14weeks. Since this appears to have an immune component, the treatment of abnormal immune parameters may help to prevent this outcome.

Indeed, a recent prospective, multicenter study focusing on the pregnancy outcome of patients with previous (CHI) showed an increase in live births (67%) compare to the previous pregnancy (32%) when immune therapies such as prednisone or aspirin were administrated although (CHI) was still present in 50% of placentas (30).

Regardless of the underlying issues (anti-paternal HLA antibodies, autoimmune disorders), these data collectively demonstrated how a dysregulated maternal immune system during pregnancy could impact placenta physiology thus leading to pregnancy complications and ultimately stillbirth. Most of the time, early signs can be detected and the causes could be treated prior to reaching a dangerous point.

We, at Braverman IVF & Reproductive Immunology, perform a thorough workup to detect any immunological alterations, potentially dangerous to the maintenance of a pregnancy. When found, we can treat the patient and attempt to restore a tolerant immunologic state to possibly prevent the occurrence of these dramatic events.


Getting Pregnant After a Stillbirth & Preventing Miscarriage

Dr. Braverman and our team genuinely care about helping our patients and we consistently maintain one of the highest success rates in New York despite the complexity of our cases. In certain circumstances, there is also 100% financing available as we want to do all we can to allow you the opportunities you deserve. Each member of our team has been with our clinic for at least 15 years and is an invaluable part of the dedicated service we offer.

Contact Dr. Jeffery Braverman for thorough testing and treatment if you have a history of stillbirth or visit our forum to learn more.

For the latest studies on stillbirth, please consult our blog “Ending preventable stillbirths by 2030: Recent Lancet article fails to account for immune related issues.


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