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.
- 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.
- 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.
- 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.
- 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).
- 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).
- 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.
- 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.
- 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.
​References