The use of surgery (laparoscopy with excision of endometriotic lesions and the destruction of the peritoneum) and assisted reproductive technologies (IVF-ET) has been able to counteract the reduced fertility existing in women with endometriosis thus leading to successful pregnancy.
Nevertheless, many recent published articles pointed the increased risks of obstetrical complications associated with pregnancies in patient with endometriosis including but not limited to:
Endometriosis: a possible root for obstetrical complications
- Placenta previa
- Premature rupture of membranes
- Obstetrical bleeding
- Small for gestational age
- Preterm birth
Our blog on the topic entitled “Endometriosis increases your risk for pregnancy complications” (http://www.preventmiscarriage.com/endometriosis-increases-your-risk-for-pregnancy-.html) explains you how the very nature of endometriosis, an inflammatory disease (1) could play a key role in triggering preterm birth and other obstetrical complications while the increased risk for hypertension and pre-eclampsia is still debated as recently reviewed (2).
Indeed, a recent published study (3) confirmed the strong association between pro-inflammatory factors such as IL-1β and the risk of endometriosis being 4.5 times higher in patients with IL-1β levels in the fourth quintile (highest concentration) as compared to ENDO-free controls.
The peritoneal fluid of women with endometriosis is also characterized by proinflammatory changes, with increased levels of cytokines such as IL-6 and angiogenic factors (1), which could be a possible explanation for the higher risk of preterm birth (4). Further, in ENDO patients, there is an overexpression of two prostaglandins in the endometrium namely PGE2 and PGF2α that could trigger uterine contraction thus leading to premature labor (5).
Endometriosis has also been described as a condition inducing a defective placentation (6).
During pregnancy, spiral arteries undergo a deep transformation in a specific zone of the uterus, named the junctional zone which is the site of placentation. Pre-eclampsia has been characterized by a defective transformation of the spiral arteries at this specific zone (7) and imaging studies have found an association between endometriosis and a thickening of this zone (8) that could explain its disrupted activity thus leading to poor placentation.
Placental inflammation and Stillbirth
Stillbirth is a devastating experience commonly believed to result from 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.
While stillbirths could be the result of maternal conditions such as diabetes or Systemic lupus erythematosus, it could also result from maternal immune dysregulation triggered by conditions such as endometriosis with dramatic consequences on the implantation and the placentation process. This could translate into a large range of obstetrical issues from miscarriages, intra uterine growth restriction (IUGR), preterm birth to stillbirth.
Besides, an increased rate of obstetrical complications associated with endometriosis (2), the increased risk of stillbirths, recently described in a large cohort published study, appeared to be even more concerning.
In a published Danish study (9), the comparison between Danish women with a diagnosis of endometriosis (11 739 patients) and women between 15-49 years old with no endometriosis diagnosis (615 533 women) showed an increased risk for stillbirths (+20%) and neonatal deaths (+80%) in pregnant women affected by endometriosis.
A higher incidence of stillbirths in women with endometriosis was previously shown on a smaller scale in the Canadian population (10). In this study, pregnant women affected by endometriosis were suffering from stillbirth more than two times compared to pregnant control counterparts (ENDO-free patients).
The Stillbirth Collaborative Research Network recently published their data (11) showing that the most useful tests to determine the causes of stillbirths were:
- placental pathology
- fetal autopsy
- genetic testing
- testing for antiphospholipid antibodies.
But, besides APS syndrome, they failed to determine the possible causes leading to placenta injuries potentially inducing stillbirth and they failed to account for other immune related causes of stillbirths.
Indeed, multiple conditions could induce maternal inflammation during pregnancy: PCOS, endometriosis, autoimmune disorders, alloimmune causes (HLA similarities between parents) and lead to placental inflammation with lesions such as Villitis of unknown etiology (VUE) and chronic histiocytic Intervilositis unknown etiology (CIUE) that are strongly associated with an increased risk of fetal death.
For more information, read our blog “Do you have a history of stillbirth?” (http://www.preventmiscarriage.com/stillbirth.html)
The increasing rate of pregnancy complications calls for a better detection and monitoring, of women with endometriosis during pregnancy.
We, at Braverman IVF & Reproductive Immunology, perform a thorough workup to detect any immunological alterations, potentially dangerous to the maintenance of a pregnancy and to the fetal health.
When found, our timely therapeutic interventions attempt to restore a more tolerant immunologic state to possibly reduce the occurrence of these obstetrical complications.
1. Petraglia F, Arcuri F, de Ziegler D, Chapron C. Inflammation: a link between endometriosis and preterm birth. Fertil Steril 2012; 98:36–40.
2. Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M, Berghella V. Endometriosis and obstetrics complications: a systematic review and meta-analysis. Fertil Steril. 2017 Oct;108(4):667-672.e5.
3. Mu F, Harris HR, Rich-Edwards JW, Hankinson SE, Rimm EB, Spiegelman D, Missmer SA. A Prospective Study of Inflammatory Markers and Risk of Endometriosis. Am J Epidemiol. 2017 Jul 13.
4. Pizzo A, Salmeri FM, Ardita FV, Sofo V, Tripepi M, Marsico S. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest 2002; 54:82–7.
5. Jabbour, H.N., Sales, K.J., Smith, O.P., Battersby, S., Boddy, S.C., 2006. Prostaglandin receptors are mediators of vascular function in endometrial pathologies. Mol. Cell. Endocrinol. 252, 191–200.
6. Brosens I, Derwig I, Brosens J, Fusi L, Benagiano G, Pijnenborg R. The enigmatic uterine junctional zone: the missing link between reproductive disorders and major obstetrical disorders? Hum Reprod. 2010;25(3):569-74.
7. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The ‘‘Great Obstetrical Syndromes’’ are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204:193–201.
8. Kunz G, Beil D, Huppert P, Leyendecker G. Structural abnormalities of the uterine wall in women with endometriosis and infertility visualized by vaginal sonography and magnetic resonance imaging. Hum Reprod 2000; 15:76–82.
9. Berlac JF, Hartwell D, Skovlund CW, Langhoff-Roos J, Lidegaard Ø. Endometriosis increases the risk of obstetrical and neonatal complications. Acta Obstet Gynecol Scand. 2017 Feb 9.
10. Aris A. A 12-year cohort study on adverse pregnancy outcomes in Eastern Townships of Canada: impact of endometriosis. Gynecol Endocrinol 2014;30: 34-7.
11. Page JM, Christiansen-Lindquist L, Thorsten V, Parker CB, Reddy UM, Dudley DJ, Saade GR, Coustan D, Rowland Hogue CJ, Conway D, Bukowski R, Pinar H, Heuser CC, Gibbins KJ, Goldenberg RL, Silver RM. Diagnostic Tests for Evaluation of Stillbirth: Results from the Stillbirth Collaborative Research Network. Obstet Gynecol. 2017 Apr;129(4):699-706.