Endometriosis and pregnancy outcome


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Volume 110, Issue 3, Pages 406–407


Philippe R. Koninckx, M.D., Ph.D., Errico Zupi, M.D., Ph.D., Dan C. Martin, M.D.


Reflections on "Obstetric complications after laparoscopic excision of posterior deep infiltrating endometriosis: a case–control study" by Nirgianakis et al.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.


Go to the profile of Konstantinos Nirgianakis
Konstantinos Nirgianakis almost 2 years ago

A Reply to Koninckx „Endometriosis and pregnancy outcome“
Konstantinos Nirgianakis1 MD, Brett McKinnon MD1, PhD, Michael D. Mueller1 MD

1 Department of Gynecology and Gynecological Oncology, University Hospital of Bern and University of Bern, Effingerstrasse 102, 3010, Bern, Switzerland

We thank Dr. Koninckx and colleagues for their comments and interest in our work and for offering explanations for our findings on pregnancy and delivery outcomes in patients with endometriosis (1,2). On this occasion, we would be glad to contribute to the discussion addressing some points raised from the authors.

Regarding the risk of postpartum bleeding, with 10/62 (16.1%) and 16/186 (8.6%) incidence in the case and control group respectively the difference was not statistically significant (p= .0995). The verified higher risk of placenta previa in the case group could be enough to explain alone the higher risk of postpartum bleeding, but may have not reached significance due to insufficient power. On the other hand, the quantity of postpartum blood loss (ml) with 500 (200-2000) in the case vs 400 (200-1500) in the control group, was significantly higher. This difference is, nevertheless, marginal and we interpret it mainly as a result of the increased incidence of cesarean delivery in the case group, known to have higher blood loss (58.1% vs. 43.6%). A higher risk of postpartum bleeding in patients without placenta previa accomplishing a vaginal delivery seems unlikely but further studies with higher number of patients are needed to clear it up.

The difficulty of interpreting studies suffering from a lack of documented stage, severity, type of endometriosis and surgical treatment method is presented very clearly by Koninckx et al. (1). New studies will have to consider these issues as well as accurate stratification for important confounders including adenomyosis that should also be documented with a clear classification system (3).

Koninckx et al. (1) commented that other endometriosis-associated complications during pregnancy (bowel or bladder perforation, spontaneous intra-peritoneal bleeding etc) were not discussed in our article. Indeed, as shown in Table 3 of our article (2) spontaneous intra-abdominal bleeding caused by endometriosis was the reason for c-section in one of the patients in the endometriosis group meaning this rare complication cannot be excluded even if previous complete excision of endometriosis has been performed. This complication took place almost five years after the endometriosis surgery during which time endometriosis recurrence may have occurred. This is in line with the article of Maggiore et al. (4) presenting cases with intra-abdominal bleeding in the pregnancy even if surgery had been previously performed. Which patients with endometriosis are in danger of this complication is currently unknown and considering its rarity it seems very difficult to identify in future.  Thus, obstetricians should always remain alert for this rare but life threatening complication.

We respectfully disagree with Koninckx et al. (1) both that the case group in our study (2) was heterogeneous with variable endometriosis severity and that the number of previous pregnancies was not taken into account. Indeed, all patients in the case group suffered from posterior DIE affecting the bowel and/or the vagina; thus disc or segmental bowel resection, bowel shaving and partial resection of the posterior vaginal fornix was performed in the vast majority of the patients as shown in Table 1. Certainly, the size of the endometriotic nodule was not always the same but no cases of small peritoneal lesions were included in the study. Moreover, the number of previous pregnancies was taken into account since parity was a matching factor of the study. Consequently, as shown in Table 1 there is no difference in the number of previous deliveries between the two groups.
We agree that although no increased risks of vaginal delivery after previous DIE surgery were identified in our study, this needs validation with a much larger series of vaginal deliveries so that stratification for possible risk factors, such as nodule size, degree of bowel anastomosis and length of bowel resection is possible.

Finally, it is indeed very important to recognize endometriosis as a systematic disease resulting from currently unknown genetic and epigenetic incidents. This includes many symptoms or differently said comorbidities above the typical ones (endometriosis-associated pain, infertility) such as migraine, autoimmune and endocrine disorders, chronic fatigue, gastrointestinal-related abdominal pain, bloating and constipation which are associated with endometriosis (5). Surgical treatment of endometriosis can treat endometriosis-associated pain and/or infertility but is highly unlikely to treat all these other symptoms/comorbidities. Obviously the same seems to apply for the pregnancy and obstetrical complications associated with endometriosis. Surgical treatment of endometriosis is unlikely to prevent these complications in future pregnancies, similarly, however, it also unlikely to increase their risk.

Reference list

1. Koninckx PR, Zupi E, Martin DC.Endometriosis and pregnancy outcome. Fertil Steril. 2018;110(3):406-407.

2. Nirgianakis K, Gasparri ML, Radan AP, Villiger A, McKinnon B, Mueller MD. Obstetrical complications after laparoscopic excision of posterior deep infiltrating endometriosis: a case-control study. Fertil Steril 2018; 110: 136-143

3. Gordts S, Grimbizis G, Campo R. Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis. Fertil Steril. 2018;109(3):380-388.e1

4. Leone Roberti Maggiore U, Inversetti A, Schimberni M, Viganò P, Giorgione V, Candiani M. Obstetrical complications of endometriosis, particularly deep endometriosis. Fertil Steril. 2017;108(6):895-912.
5. Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017;107(3):523-532.

Go to the profile of Koninckx Philippe
Koninckx Philippe almost 2 years ago

Dear Dr Konstantinos Nirgianakis,

The relationship between endometriosis and pregnancy outcome is an important topic. The reduction of our text to 1500 words and 5 references [1] might have caused some loss of clarity. In addition, our hypothesis that the pathophysiology of endometriosis can be explained by a series of genetic-epigenetic incidents [2]had to be formulated prudently since not yet accepted for publication.
This hypothesis, postulates that a series of genetic and epigenetic incidents are transmitted at birth, increasing the risk of developing the disease endometriosis after a series of additional incidents.  These genetic and epigenetic incidents transmitted at birth may explain the changes in the endometrium, in the junctional zone and in placentation and pregnancy related problems as pre-eclampsia and small for gestational age babies. These and many other morbidities associated with endometriosis thus are no longer viewed as a consequence of endometriosis but as the consequence of a common causal factor.  This view also is fully compatible with your observation that previous surgery of deep endometriosis does not affect pregnancy outcome[3].

Another consequence  is that each endometriosis lesion  has a specific set of genetic and epigenetic abnormalities and that individual lesions  are heterogeneous and may react differently during a pregnancy. A lesion with an absolute progesterone resistance indeed would be stimulated by the high estrogen concentrations of a pregnancy. The same holds true for a treatment with combined oral contraceptives.  For this reason we formulated that the endometriosis lesions in your study were probably heterogeneous. Unfortunately ‘genetically –epigenetically’ was omitted. In addition, we would not be surprised that the effect upon a pregnancy would vary with the severity  or size of the deep endometriosis and with the number of previous pregnancies. Unfortunately the number of women did not permit to evaluate these variables in a multivariate model.
We were intrigued by the risk of postpartum bleeding and blood loss. This might be an important observation although not or marginally statistically significant. First as you explained ‘not statistically significant‘ does not permit a conclusion if the groups are small. More important is that a statistical tests which compares two groups of women, does not permit to detect a smaller subgroup, with a different behaviour. Considering the genetic and epigenetic incidents transmitted at birth, we would not be surprised that the women with postpartum bleeding constitute a specific subgroup.

Philippe R. koninckx, Errico Zupi, Dan C Martin, Anastasia Ussia and  Victor Gomel


Reference List


1.           Koninckx PR, Zupi E, Martin DC (2018) Endometriosis and pregnancy outcome. Fertil Steril 110:406-407


2.           Koninckx PR, Ussia A, Adamyan L, Wattiez A, Gomel V, Martin D (2018) Pathogenesis of endometriosis: the genetic-epigenetic theory. Fertil Steril in press


3.           Nirgianakis K, Gasparri ML, Radan AP, Villiger A, McKinnon B, Mosimann B, Papadia A, Mueller MD (2018) Obstetric complications after laparoscopic excision of posterior deep infiltrating endometriosis: a case-control study. Fertil Steril 110:459-466