Ending preventable stillbirths by 2030: Recent Lancet article fails to account for immune related issues

Posted By Braverman IVF & Reproductive Immunology || 27-Jan-2016

Stillbirth remains a major issue in the public health with 2.6 million reported worldwide.

A recent article published in The Lancet presents stillbirth as a still neglected issue in global health, despite its high rate and the burden it brings to entire families.

This article emphasizes the fact that stillbirth is the result of multiple factors such as nutrition, lifestyle, infection and poor pregnancy care and not limited to problems with the umbilical cord (knot in the umbilical cord), a common explanation given to families that suffer such an outcome. However this world wide study failed to discuss the maternal immune dysregulation as a cause, which I find rather alarming, giving our advancing knowledge of the role the maternal immune system plays in pregnancy complications.
The article presented follow-up studies showing no clear improvement in stillbirth’s rate since 2011, 50% of them occurring during the delivery (intrapartum) and being preventable with early identification of high risk pregnancies (1) and high quality care at birth (2). But they fail to discuss that if problems with the fetus are detected early, and delivery prevents stillbirth, there is still very likely going to be significant fetal compromise since the problems with the pregnancy started withthe immune interaction at the time of implantation.

While stillbirths could be the result of maternal conditions such as diabetes or Systemic lupus erythematosus, it could also result from maternal immune dysregulation with consequences ranging from miscarriages, intra uterine growth restriction (IUGR), and pre-eclampsia to stillbirth. I believe these factors are the most significant contribution to stillbirth and the overall rate worldwide will not decrease significantly at this point until these issues are addressed. This has to start with basic education for all care givers in Reproductive Immunology. I am not referring to those that hang up a shingle and prescribe immune medications, but those that have a true understanding of the maternal immune system and all myriad of ways dysregulation can lead to pregnancy complications.

In the following blog, we will introduce you to the consequences of some maternal pathologies on fetal health and the effects of an acute maternal immune rejection on the placenta and the fetus that could lead to stillbirth.

  1. Stillbirths: Lancet claims low income and limited access to care as a significant contribution. But Stillbirths are not specific to low income countries with limited access to high-quality care

Low income countries such as India, Nigeria or Pakistan have the highest rate of stillbirths (Source).
If “the highest risks are for the poorest families”, stillbirths are one of the most common adverse pregnancy outcome in the United States and affect 1% of all pregnancies which is about 24 000 babies each year (3), outnumbering infant deaths.

The US fetal death rate remains unchanged since 2006 despite minor fluctuations.

  1. Nutrition and lifestyle are not the only causes of stillbirths

While factors such as diet (obesity) and lifestyle (smoking) are important issues that need to be addressed, they could not entirely explain the high prevalence of stillbirths.

An accumulation of evidence tends to show that the ethnicity of pregnant women and specific diseases/disorders that could be more prevalent in certain ethnic groups might explain these predispositions to stillbirths, and not simply the socioeconomic issues that are raised.

Although socio-economic factors could play a role, recent studies have shown that British women from African or Indian/Pakistani descents have higher rate of stillbirths (4) despite having the same access to health care in the UK.

This trend was the same in the U.S population, where African-American were two times more prone to stillbirth that non-Hispanic white population (3).

Altogether these data seem to show that genetic or rather genetic susceptibility to some disorders such as diabetes (5), PCOS (6) and endometriosis (7) differentially affect women based on their ethnicity and could play a role in stillbirths by triggering placental and metabolic issues that lead to intra uterine growth retardation (IUGR) among other problems (8-9).

A large portion of stillbirths remain unexplained in the world literature and again I feel many have a basis in immune dysfunction with multiple underlying causes.

But there are many “currently identifiable” maternal medical conditions that significantly increase the risk of fetal death as well and these will be described below.

  1. Obesity

Obesity is one of the leading causes contributing to the overall burden of diseases worldwide.
Obesity as defined by a BMI greater than 30 is a major contributor to increased risks for hypertension and diabetes but also fetal death. A meta-analysis study showed that risks associated with fetal death were two times higher in overweight and obese pregnant women (10) compared to lean women. Interestingly, another cohort study led in Sweden on over 200 000 women suggest that even a modest increase in BMI between two consecutive pregnancies could result in increased risks for perinatal complications including stillbirth, even if a woman does not become overweight (11).

Multiple mechanisms appear to link obesity to stillbirth including placenta pathologies (12) or maternal hypertension (13).

Because obesity is the highest ranking modifiable risk factor (13), it is crucial to normalize pre-pregnancy weight to reduce risks associated with a high BMI.

  1. Advanced maternal age

After accounting for medical conditions that are more likely to occur in older women, such as multiple gestation, hypertension, diabetes (all of which associated with higher rates of stillbirth), an advanced maternal age (>35 years old) is an independent risk factor for still birth that multiply the risks by 3.7 compared to younger women (14).

  1. Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting joints, skin, brain, heart and several other organs in women of childbearing age with a prevalence of less than 1%.

Stillbirths were reported to be 5 times more frequent in the lupus group compared with the control group (15) and greatly depends on the activity of the disease.

Autoantibodies directed against Ro/SSA and La/SSB autoantigens are identified in patients with SLE and can passively diffuse through the placenta to attack fetal heart and cause permanent damages by destructing the atrioventricular system (congenital atrioventricular block) (16). In addition, congenital AV block has been associated with the development of hydrops (accumulation of fluids in at least 2 fetal compartments) in 40% of cases, with a third resulting in stillbirth (17).

Antiphospholipid antibodies (such as anti-cardiolipin and anti-b2 glycoprotein I antibodies) are found in about one-third of SLE patients.

By increasing risk of thrombosis, they can severely alter placenta function and impact fetal health.

A large study including over 2000 pregnant women showed that patients with high levels of IgG anti-cardiolipin and IgG anti-β2-glycoprotein-I antibodies were 3 times more likely to have a stillbirth (18).

  1. Diabetes Mellitus

With the obesity rising, diabetes affects 7% of the population in the United States. Affecting 2 to 5% of all pregnancies, it is responsible for 3% of stillbirths (19).

In a prospective study comparing 5000 type 1 diabetes patients with non-diabetic controls, stillbirth rate was found to be 5 times more prevalent than that of the nondiabetic population, with the majority occurring between 34 and 40 gestational weeks (20).

Interestingly, in women with a history of a prior stillbirth, there was a 4-fold increase in glucose intolerance or gestational diabetes in a subsequent pregnancy, suggesting that causes of the stillbirth could have been an undetected maternal diabetes (21).

In stillbirth occurring in diabetic patients, asphyxia and congenital abnormalities were shown to be the two leading causes of mortality. It is interesting to note that hyperglycemia during pregnancy alters placental function (placental angiopathy) which can lead to antenatal asphyxia (19) while hyperglycemia around the conception period is a cause of congenital abnormalities (22).

Moreover, a study comparing placenta weight after stillbirth between non-diabetics versus diabetic women showed a significant lower placenta weight in diabetic women in addition to a very specific histology of the fetal thymus, this results in a metabolic disorder causing the stillbirth (23).
Altogether, these studies pinpoint the recommendations that diabetes should be controlled prior and closely monitor during pregnancy.

  1. High blood pressure and pre-eclampsia

Severe hypertension and pre-eclampsia are predictive of poor obstetrical outcome with stillbirth rate reaching 52/1000 which is more than 5 times than that found in the general population (24).

In pregnancies complicated with hypertension, the fetus is not growing properly (intra uterine growth restriction or IUGR) which is a sign of placental insufficiency that can lead to fetal hypoxia and stillbirth. We now understand that preeclampsia is a result of immune dysregulation and prevention of this syndrome and therefore the prevention of a stillbirth that is a result, must be treated not at the end of the pregnancy but at the start to avoid the syndrome in the first place.

  1. Maternal Immune dysregulation: Is this the last issue that will finally result in decreased Stillbirths worldwide?

Maternal inflammation during pregnancy has devastating consequences for the placenta and fetus, with stillbirth being the ultimate consequence of immunologic rejection by the mother against the fetus.

Multiple causes could induce maternal inflammation during pregnancy: PCOS, endometriosis, autoimmune disorders, alloimmune (HLA similarities between parents, a problem that I believe is inherent in the high risk populations mentioned in the Lancet article) which could lead to placental inflammation and lesions associated with increased risk of fetal death. For more information, read our page “Do you have a history of stillbirth?

In the same way, anti-paternal antibody production by the mother during pregnancy (anti-paternal HLA antibodies) could be harmful to the fetal health. This may be one of the etiologies in Chronic Histiocytic Intervilositis, a common finding in stillbirths that may be treatable and preventable.
When detected early during pregnancy and not treated, anti-paternal HLA antibodies were associated with reduced rate of live birth (25).

More specifically, 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% (26).

We, of course, do agree that a patient’s risk for stillbirth is related to her underlying health issues and lifestyle. However, besides the obvious lifestyle modifications such as quitting smoking or losing weight, a complete immune screening panel before pregnancy and a tight monitoring of patients for immune dysregulation should be provided to any patient that has suffered a stillbirth with a category of “unexplained”. We should also address this type of monitoring for those patients that have any of the high risk factors mentioned above, in order to try and prevent a “first” Stillbirth.

In addition, timely therapeutic interventions may finally begin the process of alleviating this worldwide epidemic and making a significant dent in the “unexplained” stillbirth population.


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