Preventable Stillbirth. Recent major publication hoping for answers, BRI has the answers.

Posted By Braverman IVF & Reproductive Immunology || 08-Feb-2018

Stillbirth occurs when a woman suffers a fetal demise after 20 weeks of pregnancy.

Stillbirth occurs when a woman suffers a fetal demise after 20 weeks of pregnancy. Most stillbirths occur in the womb (intrauterine demise) but few can occur during labor or birth (intrapartum demise). 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). Stillbirths are mistakenly attributed to umbilical cord accidents such as a cord around the neck, but cord malposition occurs in 1 out of 4 pregnancies which is why it is so unlikely to be the cause of stillbirth otherwise the rate would be much higher. The remainder of the causes of Stillbirth are felt to be unexplained.

In this blog, we will explain you how our knowledge of maternal immune mechanisms to generate tolerance to the pregnancy and its beneficial consequences on pregnancy help lower pregnancy complications  (ranging from early loss to obstetrical complications including pre-eclampsia, preterm labor and ultimately stillbirth) and have allowed us to develop early detection/monitoring tools leading to appropriate therapy  thus restoring a more tolerant immunologic state and likely lowering the risk of stillbirths.

 1. Braverman Reproductive Immunology: Appropriate screening to detect maternal immune dysregulation and implement appropriate therapies interventions.

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, the ultimate consequence of immunologic rejection by the mother against the fetus. The problems with a pregnancy start very early with the immune interactions at the time of implantation.

We have discovered multiple causes of maternal inflammation during pregnancy that can lead to placental inflammation that is associated with increased risk of fetal demise. 


- Endometriosis

- autoimmune disorders

- alloimmune (HLA similarities between parents) 

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 placental lesion commonly found 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 (2).
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 lowerlive birth rate in the subsequent pregnancies (3). The presence of one HY-restricting HLA class II allele in women with firstborn boys significantly reduces the chances of a live birth. Patients with no copy of HY restricting alleles have a subsequent live birth rate of 73%, which dropped to 58% with 1 allele copy and 49% with two allele copies (4).
Most of the time, early signs can be detected, and the causes could be treated prior to reaching a dangerous point.
2. Stillbirth and its prevention: what is known in the scientific literature about?
There is little information on Stillbirth and its prevention in the scientific literature. While recent articles don’t limit its occurrence to problems with the umbilical cord anymore, they mostly focus on factors such as nutrition, lifestyle, infection and poor pregnancy care. However, they largely failed to discuss the maternal immune dysregulation as a cause.
A recent article, published in the journal Obstetrics and Gynecology (5), claimed that up to 25% of the stillbirths included in their study may potentially be preventable. 
They cited several maternal conditions that could be targeted to prevent stillbirths including:
- Placental insufficiency or placental abnormality
- Maternal medical disorder including diabetes, systemic lupus erythematosus
- Hypertensive conditions
- Spontaneous preterm birth
Some of these parameters are currently included in the prenatal care offered in the USA. 
So clearly, looking at maternal medical disorders or hypertensive conditions may not be enough to detect the women at risk as discussed in a previous blog commenting a worldwide study (6).  
For more information, read our blog “Ending preventable stillbirths by 2030: Recent Lancet article fails to account for immune related issues” Further, looking at placental insufficiency could potentially help reduce stillbirths, but the study failed to propose concrete strategies for its early detection (what are the markers of a placental distress? What factors could alter the placental function?) and failed to determine the possible causes leading to placenta injuries and potentially inducing stillbirth.
We, at Braverman Reproductive Immunology, have for years, been offering a  complete immune screening panel before pregnancy and a tight monitoring during pregnancy to detect any immune dysregulation potentially dangerous to the pregnancy maintenance. 
When detected, our timely therapeutic interventions attempt to restore a tolerant immunologic state to likely minimize the occurrence of obstetrical complications including stillbirth.



1- Macdorman MF, Gregory ECW. Fetal and perinatal mortality, United States, 2013. National vital statistics reports; vol 64 no 8. Hyattsville, MD: National Center for Health Statistics. 2015. 

2- Nielsen HS, Wu F, Aghai Z, Steffensen R, van Halteren AG, Spierings E, Christiansen OB, Miklos D, Goulmy E. H-Y antibody titers are increased in unexplained secondary recurrent miscarriage patients and associated with low male: female ratio in subsequent live births. Hum Reprod. 2010 Nov; 25(11): 2745-52.

3- Nielsen HS, Steffensen R, Varming K, Van Halteren AG, Spierings E, Ryder LP, Goulmy E, Christiansen OB. Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy. Hum Mol Genet. 2009 May 1; 18(9): 1684-91.

4- Kolte AM, Steffensen R, Christiansen OB, Nielsen HS. Maternal HY-restricting

HLA class II alleles are associated with poor long-term outcome in recurrent

pregnancy loss after a boy. Am J Reprod Immunol. 2016 Nov;76(5):400-405.

5- Page JM, Thorsten V, Reddy UM, Dudley DJ, Hogue CJR, Saade GR, Pinar H, Parker CB, Conway D, Stoll BJ, Coustan D, Bukowski R, Varner MW, Goldenberg RL, Gibbins K, Silver RM. Potentially Preventable Stillbirth in a Diverse U.S. Cohort. Obstet Gynecol. 2018 Jan 9.

6- de Bernis L, Kinney MV, Stones W, Ten Hoope-Bender P, Vivio D, Leisher SH, Bhutta ZA, Gülmezoglu M, Mathai M, Belizán JM, Franco L, McDougall L, Zeitlin J, Malata A, Dickson KE, Lawn JE; Lancet Ending Preventable Stillbirths Series study group; Lancet Ending Preventable Stillbirths Series Advisory Group. Stillbirths: ending preventable deaths by 2030. Lancet. 2016 Feb 13;387(10019):703-16.



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