Henrik Falconer

Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome

BACKGROUND Endometriosis, a common gynaecological disease, is characterized by local and systemic inflammation, which may cause infertility and consequently, increased utilization of assisted reproduction technology (ART). We aimed to estimate the risk for preterm birth, small-for-gestational-age (SGA) birth, stillbirth, Caesarean section, pre-eclampsia and antepartal haemorrhage among women with a previous diagnosis of endometriosis compared with women with no previous diagnosis of endometriosis. METHODS In a nationwide Swedish study including 1,442,675 singleton births we assessed the association between adverse pregnancy outcome, ART and a previous diagnosis of endometriosis. Information was obtained by linkage of data between 1992 and 2006 in the Medical Birth Register with the Patient Register between 1964 and 2006. RESULTS There were 13,090 singleton births among 8922 women diagnosed with endometriosis. Compared with women without endometriosis, women with endometriosis had higher risks of preterm birth [adjusted odds ratio 1.33, 95% confidence interval (CI), 1.23-1.44]. Among women with endometriosis 11.9% conceived after ART compared with 1.4% of women without endometriosis. The risk of preterm birth associated with endometriosis among women with ART was 1.24 (95% CI, 0.99-1.57), and among women without ART 1.37 (95% CI, 1.25-1.50). Women with endometriosis had higher risks of antepartal bleeding/placental complications, pre-eclampsia and Caesarean section. There was no association between endometriosis and risk of SGA-birth or stillbirth. CONCLUSIONS Endometriosis appears to be a risk factor for preterm birth, irrespective of ART. Women with endometriosis may be more likely to be delivered by Caesarean section and to suffer from antepartal haemorrhage/placental complications and pre-eclampsia.

Ovarian Cancer Risk After Salpingectomy: A Nationwide Population-Based Study

BACKGROUND Recent genetic and morphologic studies have challenged the traditional view on the pathogenesis of ovarian cancer; suggesting that ovarian cancer predominantly arises within the fallopian tubes or the uterus. We hypothesize that surgical removal of the fallopian tubes is associated with a reduced risk for ovarian cancer. METHODS In this population-based cohort study, we used data on women with previous surgery on benign indication (sterilization, salpingectomy, hysterectomy, and bilateral salpingo-oophorectomy [BSO], hysterectomy; n = 251465) compared with the unexposed population (n = 5449119) between 1973 and 2009 and analyzed with Cox regression models. The effects of one- and two-sided salpingectomy were considered in a subanalysis. All statistical tests were two-sided. RESULTS There was a statistically significantly lower risk for ovarian cancer among women with previous salpingectomy (HR = 0.65, 95% CI = 0.52 to 0.81) when compared with the unexposed population. In addition, statistically significant risk reductions were observed among women with previous hysterectomy (HR = 0.79, 95% CI = 0.70 to 0.88), sterilization (HR = 0.72, 95% CI = 0.64 to 0.81), and hysterectomy with BSO (HR = 0.06, 95% CI = 0.03 to 0.12). Bilateral salpingectomy was associated with a 50% decrease in risk of ovarian cancer compared with the unilateral procedure (HR = 0.35, 95% CI = 0.17 to 0.73, and 0.71, 95% CI = 0.56 to 0.91, respectively). CONCLUSION Salpingectomy on benign indication is associated with reduced risk of ovarian cancer. These data support the hypothesis that a substantial fraction of ovarian cancer arises in the fallopian tube. Our results suggest that removal of the fallopian tubes by itself, or concomitantly with other benign surgery, is an effective measure to reduce ovarian cancer risk in the general population.

Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study

Objective To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome, taking into account maternal characteristics and assisted reproductive technology. Design Population based cohort study. Setting Singleton births registered in the Swedish medical birth register between 1995 and 2007. Participants By linkage with the Swedish patient register, 3787 births among women with a diagnosis of polycystic ovary syndrome and 1 191 336 births among women without such a diagnosis. Main outcome measures Risk of adverse pregnancy outcomes (gestational diabetes, pre-eclampsia, preterm birth, stillbirth, neonatal death, low Apgar score (<7 at five minutes), meconium aspiration, large for gestational age, macrosomia, small for gestational age), adjusted for maternal characteristics (body mass index, age), socioeconomic factors (educational level, and cohabitating with infant’s father), and assisted reproductive technology. Results Women with polycystic ovary syndrome were more often obese and more commonly used assisted reproductive technology than women without such a diagnosis (60.6% v 34.8% and 13.7% v 1.5%). Polycystic ovary syndrome was strongly associated with pre-eclampsia (adjusted odds ratio 1.45, 95% confidence interval 1.24 to 1.69) and very preterm birth (2.21, 1.69 to 2.90) and the risk of gestational diabetes was more than doubled (2.32, 1.88 to 2.88). Infants born to mothers with polycystic ovary syndrome were more prone to be large for gestational age (1.39, 1.19 to 1.62) and were at increased risk of meconium aspiration (2.02, 1.13 to 3.61) and having a low Apgar score (<7) at five minutes (1.41, 1.09 to 1.83). Conclusions Women with polycystic ovary syndrome are at increased risk of adverse pregnancy and birth outcomes that cannot be explained by assisted reproductive technology. These women may need increased surveillance during pregnancy and parturition.

Endometriosis and genetic polymorphisms

Endometriosis is a benign gynecological disease with an unclear pathophysiology characterized by ectopic endometrium causing endometrium-like inflammatory lesions outside the uterine cavity. Recently, a number of studies have investigated genetic polymorphisms as a possible factor contributing to the development of endometriosis. In this review, we have summarized current data regarding genes with nucleotide polymorphisms investigated with regard to endometriosis. We searched PubMed for publications on endometriosis and polymorphism and found 108 publications between January 1979 and September 2005. These were classified according to the type of genetic polymorphism investigated and whether the result favored or did not favor association with endometriosis. We found a strikingly large amount of conflicting results. About 50% of the reviewed studies demonstrated positive correlations between different polymorphisms and endometriosis. This relation is most clearly seen in groups 1 (cytokines and inflammation), 2 (steroid-synthesizing enzymes and detoxifying enzymes and receptors), 4 (estradiol metabolism), 5 (other enzymes and metabolic systems), and 7 (adhesion molecules and matrix enzymes). Group 8 (apoptosis, cell-cycle regulation, and oncogenes) seemed to be negatively correlated with the disease, whereas group 3 (hormone receptors), 6 (growth factor systems), and especially 9 (human leukocyte antigen system components) showed a relatively strong correlation. The review indicates that polymorphisms may have a limited value in assessing possible development of endometriosis. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall the complexity of attempting to link endometriosis to single nucleotide polymorphisms (SNPs), explain that the literature is varied on results and recommendations and is population specific, and state that there are some SNP relationships that are clinically stronger than others.

Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden

Background: Studies of women with ulcerative colitis (UC) during pregnancy have reported increased risks of preterm delivery, growth restriction, and congenital malformation. However, the results are inconsistent due to inadequate study design and limitations in sample size. Methods: We performed a population‐based prevalence study on 2637 primiparous women with a UC hospital diagnosis prior to delivery and 868,942 primiparous women with no UC diagnosis in Denmark and Sweden, 1994–2006. Logistic regression analysis was used to estimate relative risks for moderately (32–36 weeks) and very (before 32 weeks) preterm birth, 5‐minute Apgar score <7, small‐for‐gestational‐age (SGA) birth, stillbirth, neonatal death, and congenital abnormalities. Results: Maternal UC was associated with increased risk of moderately preterm birth (prevalence odds ratio [POR] 1.77, 95% confidence interval [CI]: 1.54–2.05), very preterm birth (POR 1.41, 95% CI: 1.02–1.96), cesarean section (POR 2.01, 95% CI: 1.84–2.19), and neonatal death (POR 1.93, 95% CI: 1.04–3.60). The strongest associations were observed for prelabor cesarean section (POR = 2.78, 95% CI: 2.38–3.25) and induced preterm delivery (POR 2.55, 95% CI: 1.95–3.33). There was a slightly increased risk of SGA birth (POR 1.27, 95% CI: 1.05–1.54). We found no association between UC and overall risk of congenital abnormalities (POR 1.05, 95% CI: 0.84–1.31) or specific congenital abnormalities. Risks for adverse birth outcomes were higher in women with previous UC‐related surgery and hospital admissions. Conclusions: Women with UC have increased risks of preterm delivery, SGA‐birth, neonatal death, and cesarean section but not congenital abnormalities. Adverse birth outcomes appeared correlated with UC disease severity. (Inflamm Bowel Dis 2011;)

Crohn's Disease Is a Risk Factor for Preterm Birth

BACKGROUND & AIMS Women with Crohns disease (CD) are considered to be at increased risk for adverse outcomes of pregnancy. However, the few studies assessing this risk have had small sample sizes and limitations. We examined outcomes of pregnancy among a large cohort of primiparous women with CD. METHODS Our population-based prevalence study utilized data from medical birth registries in Sweden and Denmark between 1994 and 2006. Linking birth registry data with national patient registries, we identified 2377 women with a hospital diagnosis of CD prior to delivery and 869,202 women with no diagnosis of CD. Using logistic regression analysis, we estimated relative risks with 95% confidence intervals (CI) for pre-eclampsia, preterm birth, 5-minute Apgar scores below 7, cesarean section, small for gestational age (SGA), stillbirth, and congenital malformations. RESULTS Maternal CD was associated with increased risk of moderately and very preterm birth (prevalence odds ratio [POR], 1.76; 95% CI, 1.51-2.05; and POR, 1.86; 95% CI, 1.38-2.52, respectively). Maternal CD was also associated with increased risk for cesarean section (POR, 1.93; 95% CI, 1.76-2.12). The strongest associations with CD were observed for prelabor cesarean section and induced preterm delivery. Risk of small size for gestational age birth was slightly increased among women with CD, especially during the time period of 2002-2006 (POR, 1.43; 95% CI, 1.09-1.89). We found no increased risks for pre-eclampsia, low 5-minute Apgar score, stillbirth, or congenital malformations. CONCLUSIONS Maternal CD is a risk factor for preterm birth, but not birth defects.

Follicle-stimulating hormone receptor polymorphisms in a population of infertile women

Background.  There are two known polymorphisms of clinical relevance in the follicle‐stimulating hormone (FSH) receptor exon 10, alanine or threonine at position 307, and asparagine or serine at position 680, giving rise to two discrete allelic variants: Thr307/Asn680 and Ala307/Ser680. At position 680, three FSH receptor variants are possible: Asn/Asn, Asn/Ser, and Ser/Ser. We hypothesized an association between FSH receptor polymorphisms and ovarian reserve.

Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis.

A clear picture of the dynamic relationship between the endometrium and peritoneum is emerging as both tissues may participate in the spontaneous development of endometriosis. Various adhesion molecules, pro-inflammatory cytokines and chemoattractants cytokines have emerged as central coordinators of endometrial-peritoneal interactions. The peritoneal microenvironment which consists of the peritoneal fluid, normal peritoneum and peritoneal endometriotic lesions may play an active role in the pathogenesis of endometriosis, by harbouring most inflammatory responses that are triggered by the presence of endometrial cells, leading to recruitment of activated macrophages and leukocytes locally. Menstrual endometrium has the ability to bond and invade the peritoneal tissue. In baboons intrapelvic injection of menstrual endometrium permits the study of early endometrial-peritoneal interaction in an in vivo culture microenvironment and can lead to important insight in the early development of endometriotic lesions. In this review, we discuss the roles of the endometrial-peritoneal interactions, not only in disease development but also in the broader process of aetiopathogenesis.

IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone.

This study reports on anti-Müllerian hormone (AMH) in serum and follicular fluid (FF) in relation to inflammatory parameters in women with and without endometriosis undergoing IVF. Serum and FF samples were obtained from 72 women, with (n = 34) and without (n = 38) endometriosis, undergoing IVF. The concentrations of AMH, FSH, tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF) and several interleukins were analysed. Women with endometriosis had significantly lower AMH in serum and FF (serum: 6.38 versus 12.8 pM; P < 0.01, FF: 14.0 versus 19.6 pM; P < 0.05). TNF was increased in FF (40.0 versus 30.8 pg/ml, P < 0.05) from women with endometriosis and significantly higher concentrations of IL-15 and GM-CSF were detected in FF (both P < 0.05). During IVF, women with endometriosis responded well to FSH but had lower fertilization rates. Women with endometriosis have elevated concentrations of several cytokines in FF. They respond adequately to exogenous FSH but may have impaired oocyte quality, reflected in lower fertilization rates, presumably resulting from an inflammatory process in the ovaries. Further studies are needed to elucidate the role of AMH in predicting ovarian reserve in women with endometriosis.

Endometriosis and autoimmune disease: association of susceptibility to moderate/severe endometriosis with CCL21 and HLA-DRB1.

This study investigates the association of rheumatoid arthritis-associated single nucleotide polymorphisms in endometriosis. We found an association of CCL21 (rs2812378) and HLA-DRB1 (rs660895) with moderate to severe endometriosis.