Risk factors for inadequate and excessive gestational weight gain in 25 low- and middle-income countries: An individual-level participant meta-analysis.

BACKGROUND: Many women experience suboptimal gestational weight gain (GWG) in low- and middle-income countries (LMICs), but our understanding of risk factors associated with GWG in these settings is limited. We investigated the relationships between demographic, anthropometric, lifestyle, and clinical factors and GWG in prospectively collected data from LMICs. METHODS AND FINDINGS: We conducted an individual participant-level meta-analysis of risk factors for GWG outcomes among 138,286 pregnant women with singleton pregnancies in 55 studies (27 randomized controlled trials and 28 prospective cohorts from 25 LMICs). Data sources were identified through PubMed, Embase, and Web of Science searches for articles published from January 2000 to March 2019. Titles and abstracts of articles identified in all databases were independently screened by 2 team members according to the following eligibility criteria: following inclusion criteria: (1) GWG data collection took place in an LMIC; (2) the study was a prospective cohort or randomized trial; (3) study participants were pregnant; and (4) the study was not conducted exclusively among human immunodeficiency virus (HIV)-infected women or women with other health conditions that could limit the generalizability of the results. The Institute of Medicine (IOM) body mass index (BMI)-specific guidelines were used to determine the adequacy of GWG, which we calculated as the ratio of the total observed weight gain over the mean recommended weight gain. Study outcomes included severely inadequate GWG (percent adequacy of GWG <70), inadequate GWG (percent adequacy of GWG <90, inclusive of severely inadequate), and excessive GWG (percent adequacy of GWG >125). Multivariable estimates from each study were pooled using fixed-effects meta-analysis. Study-specific regression models for each risk factor included all other demographic risk factors measured in a particular study as potential confounders, as well as BMI, maternal height, pre-pregnancy smoking, and chronic hypertension. Risk factors occurring during pregnancy were further adjusted for receipt of study intervention (if any) and 3-month calendar period. The INTERGROWTH-21st standard was used to define high and low GWG among normal weight women in a sensitivity analysis. The prevalence of inadequate GWG was 54%, while the prevalence of excessive weight gain was 22%. In multivariable models, factors that were associated with a higher risk of inadequate GWG included short maternal stature (<145 cm), tobacco smoking, and HIV infection. A mid-upper arm circumference (MUAC) of ≥28.1 cm was associated with the largest increase in risk for excessive GWG (risk ratio (RR) 3.02, 95% confidence interval (CI) [2.86, 3.19]). The estimated pooled difference in absolute risk between those with MUAC of ≥28.1 cm compared to those with a MUAC of 24 to 28.09 cm was 5.8% (95% CI 3.1% to 8.4%). Higher levels of education and age <20 years were also associated with an increased risk of excessive GWG. Results using the INTERGROWTH-21st standard among normal weight women were similar but attenuated compared to the results using the IOM guidelines among normal weight women. Limitations of the study's methodology include differences in the availability of risk factors and potential confounders measured in each individual dataset; not all risk factors or potential confounders of interest were available across datasets and data on potential confounders collected across studies. CONCLUSIONS: Inadequate GWG is a significant public health concern in LMICs. We identified diverse nutritional, behavioral, and clinical risk factors for inadequate GWG, highlighting the need for integrated approaches to optimizing GWG in LMICs. The prevalence of excessive GWG suggests that attention to the emerging burden of excessive GWG in LMICs is also warranted.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Hormonal regulation of mammary gland development and lactation.

Lactation is critical to infant short-term and long-term health and protects mothers from breast cancer, ovarian cancer and type 2 diabetes mellitus. The mammary gland is a dynamic organ, regulated by the coordinated actions of reproductive and metabolic hormones. These hormones promote gland development from puberty onwards and induce the formation of a branched, epithelial, milk-secreting organ by the end of pregnancy. Progesterone withdrawal following placental delivery initiates lactation, which is maintained by increased pituitary secretion of prolactin and oxytocin, and stimulated by infant suckling. After weaning, local cytokine production and decreased prolactin secretion trigger large-scale mammary cell loss, leading to gland involution. Here, we review advances in the molecular endocrinology of mammary gland development and milk synthesis. We discuss the hormonal functions of the mammary gland, including parathyroid hormone-related peptide secretion that stimulates maternal calcium mobilization for milk synthesis. We also consider the hormonal composition of human milk and its associated effects on infant health and development. Finally, we highlight endocrine and metabolic diseases that cause lactation insufficiency, for example, monogenic disorders of prolactin and prolactin receptor mutations, maternal obesity and diabetes mellitus, interventions during labour and delivery, and exposure to endocrine-disrupting chemicals such as polyfluoroalkyl substances in consumer products and other oestrogenic compounds.

Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study.

INTRODUCTION: Lactation is a hormonally controlled process that promotes infant growth and neurodevelopment and reduces the long-term maternal risk of diabetes, cardiovascular disease and breast cancer. Hormones, such as prolactin and progesterone, mediate mammary development during pregnancy and are critical for initiating copious milk secretion within 24-72 hours post partum. However, the hormone concentrations mediating lactation onset are ill defined. METHODS AND ANALYSIS: The primary objective of the investigating hormones triggering the onset of sustained lactation study is to establish reference intervals for the circulating hormone concentrations initiating postpartum milk secretion. The study will also assess how maternal factors such as parity, pregnancy comorbidities and complications during labour and delivery, which are known to delay lactation, may affect hormone concentrations. This single-centre observational study will recruit up to 1068 pregnant women over a 3-year period. A baseline blood sample will be obtained at 36 weeks' gestation. Participants will be monitored during postpartum days 1-4. Lactation onset will be reported using a validated breast fullness scale. Blood samples will be collected before and after a breastfeed on up to two occasions per day during postpartum days 1-4. Colostrum, milk and spot urine samples will be obtained on a single occasion. Serum hormone reference intervals will be calculated as mean±1.96 SD, with 90% CIs determined for the upper and lower reference limits. Differences in hormone values between healthy breastfeeding women and those at risk of delayed onset of lactation will be assessed by repeated measures two-way analysis of variance or a mixed linear model. Correlations between serum hormone concentrations and milk composition and volume will provide insights into the endocrine regulation of milk synthesis. ETHICS AND DISSEMINATION: Approval for this study had been granted by the East of England-Cambridgeshire and Hertfordshire Research Ethics Committee (REC No. 20/EE/0172), by the Health Research Authority (HRA), and by the Oxford University Hospitals National Health Service Foundation Trust. The findings will be published in high-ranking journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN12667795.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Bone turnover in pregnancy, measured by urinary CTX, is influenced by vitamin D supplementation and is associated with maternal bone health: findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial.

BACKGROUND: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized. OBJECTIVES: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices. METHODS: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and ß-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes. RESULTS: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P < 0.0001). Median CTX increased from 14 to 34 weeks of gestation in both groups (n = 372 total) [placebo (n = 188): from 223.6 to 449.7 µg/mmol creatinine; cholecalciferol (n = 184): from 222.3 to 419.3 µg/mmol creatinine; P = 0.03 for placebo compared with cholecalciferol difference in CTX at 34 weeks of gestation]. The conditional mean ± SD increase in CTX [z-score (SD)] from early to late pregnancy was greater in the placebo group (n = 188) than in the cholecalciferol group (n = 184) (placebo: 0.16 ± 0.92; cholecalciferol: -0.16 ± 1.06; P-difference < 0.01). Higher CTX at 34 weeks of gestation was associated, similarly in both groups, with lower maternal total hip and lumbar spine bone mineral content and bone mineral density (BMD) (e.g., lumbar spine BMD: ß = -0.02 g · cm-2 · SD-1 increase in CTX; 95% CI: -0.027, -0.002 g · cm-2 · SD-1; P = 0.02, n = 283). CONCLUSIONS: Maternal urinary CTX, a bone resorption marker, rises through pregnancy, although to a lesser degree with gestational cholecalciferol supplementation, and is inversely associated with maternal bone mass postpartum.This trial was registered at www.isrctn.com as ISRCTN 82927713 and eudract.ema.europa.eu as EudraCT 2007-001716-23.

Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies.

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

Anthropometric Characterization of Impaired Fetal Growth: Risk Factors for and Prognosis of Newborns With Stunting or Wasting.

IMPORTANCE: Stunting (short length for age) and wasting (low body mass index [BMI] for age) are widely used to assess child nutrition. In contrast, newborns tend to be assessed solely based on their weight. OBJECTIVE: To use recent international standards for newborn size by gestational age to assess how stunted and wasted newborns differ in terms of risk factors and prognoses. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study with follow-up until hospital discharge was conducted at urban sites in Brazil, China, India, Italy, Kenya, Oman, England, and the United States that are participating in the INTERGROWTH-21st Project. The study was conducted from April 27, 2009, to March 2, 2014, and the final dataset for analyses was locked on March 19, 2014. EXPOSURES: Sociodemographic and behavioral maternal risk factors, previous pregnancy history, and maternal and fetal conditions during pregnancy were investigated as risk factors for stunting and wasting. Anthropometry at birth was used to predict for neonatal prognosis. MAIN OUTCOMES AND MEASURES: Newborn stunting and wasting were defined as birth length and BMI for gestational age below the third centiles of the INTERGROWTH-21st standards. Prognosis was assessed through mortality before hospital discharge, admission to neonatal intensive care units, and newborn complications. RESULTS: From the 60 206 singleton live births during the study period, we selected all newborns between 33 weeks' and 42 weeks 6 days' gestation at birth (51 200 [85%]) with reliable ultrasound dating. Stunting affected 3.8% and wasting 3.4% of all newborns; both conditions were present in 0.7% of the sample. Of the 26 conditions studied, five were more strongly associated with stunting than with wasting (reported as odds ratios [OR]; 95% CI): short maternal height (6.7; 5.1-9.0), younger maternal age (0.7; 0.5-0.9), smoking (2.8; 2.3-3.3), illicit drug use (2.3; 1.5-3.6), and clinically suspected intrauterine growth restriction (5.2; 4.5-6.0). Wasting was more strongly related than stunting with 4 newborn outcomes (neonatal intensive care stay, 6.7 [5.5-8.1]; respiratory distress syndrome, 4.0 [3.3-4.9]; transient tachypnea, 2.1 [1.5-2.9]; and no oral feeding for >24 hours, 5.0 [3.9-6.5]). Maternal gestational diabetes mellitus was protective against wasting (0.6; 0.5-0.8) but not against stunting (0.9; 0.7-1.1). CONCLUSIONS AND RELEVANCE: Although newborn stunting and wasting share some common determinants, they are distinct phenotypes with their own risk factors and neonatal prognoses. To be consistent with the literature on infant and child nutrition, newborns should be classified using the 2 phenotypes of stunting and wasting. The distinction will help to prioritize preventive interventions and focus the management of fetal undernutrition.

Genome-wide association meta-analysis identifies new endometriosis risk loci.

We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10(-3)), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10(-8) in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10(-11)), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.

Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.

OBJECTIVE: To generate and validate symptom-based models to predict endometriosis among symptomatic women prior to undergoing their first laparoscopy. DESIGN: Prospective, observational, two-phase study, in which women completed a 25-item questionnaire prior to surgery. SETTING: Nineteen hospitals in 13 countries. PATIENT(S): Symptomatic women (n = 1,396) scheduled for laparoscopy without a previous surgical diagnosis of endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sensitivity and specificity of endometriosis diagnosis predicted by symptoms and patient characteristics from optimal models developed using multiple logistic regression analyses in one data set (phase I), and independently validated in a second data set (phase II) by receiver operating characteristic (ROC) curve analysis. RESULT(S): Three hundred sixty (46.7%) women in phase I and 364 (58.2%) in phase II were diagnosed with endometriosis at laparoscopy. Menstrual dyschezia (pain on opening bowels) and a history of benign ovarian cysts most strongly predicted both any and stage III and IV endometriosis in both phases. Prediction of any-stage endometriosis, although improved by ultrasound scan evidence of cyst/nodules, was relatively poor (area under the curve [AUC] = 68.3). Stage III and IV disease was predicted with good accuracy (AUC = 84.9, sensitivity of 82.3% and specificity 75.8% at an optimal cut-off of 0.24). CONCLUSION(S): Our symptom-based models predict any-stage endometriosis relatively poorly and stage III and IV disease with good accuracy. Predictive tools based on such models could help to prioritize women for surgical investigation in clinical practice and thus contribute to reducing time to diagnosis. We invite other researchers to validate the key models in additional populations.

High-quality genomic DNA extraction from formalin-fixed and paraffin-embedded samples deparaffinized using mineral oil.

Extracting DNA from formalin-fixed and paraffin-embedded (FFPE) tissue remains a challenge, despite numerous attempts to develop a more effective method. Polymerase chain reaction (PCR) success rates with DNA extracted using current methods remain low. We extracted DNA from 140 long-term archived FFPE samples using a simple but effective deparaffinization method, removing the wax with mineral oil, and a commercially available DNA extraction kit. DNA quality was subsequently tested in a genotyping experiment with 14 microsatellite markers. High-quality DNA was obtained with a mean PCR success rate of 97% (range: 88-100%) across markers. The results suggested that DNA extracted using this novel method is likely to be suitable for genetic studies involving DNA fragments <200 bp.

A monitoring programme for 1,3-dichloropropene and metabolites in groundwater in five EU countries.

BACKGROUND: 1,3 Dichloropropene (1,3-D) is a preplanting soil fumigant for the control of cyst and free-living nematodes and is currently undergoing a resubmission under Annex 1 listing of Directive 91/414/EEC. The characteristics of 1,3-D are such that the risk of it or its soil metabolites leaching through the soil profile cannot be excluded. As such, groundwater monitoring programmes were established in five EU countries representing a wide range of agricultural, climatic and hydrogeological situations, covering a range of groundwater vulnerability scenarios. All monitoring was conducted in areas where there has been historical use of 1,3-D. RESULTS: Over 5000 groundwater samples were analysed for the presence of 1,3-D and its metabolites over a 2 year period. Almost all analyses (for parent and metabolites) yielded concentrations of <0.1 microg L(-1). There were just two detections of >0.1 microg L(-1) (0.12 microg L(-1) and 0.4 microg L(-1)) for the 3-chloroacrylic acid metabolite in shallow groundwater samples of the alluvial gravels of the River Tiétar in the Caceres region of Spain. CONCLUSION: Groundwater monitoring programmes have been conducted in the EU in five countries. These have demonstrated that there is negligible contamination of groundwater with 1,3-D or its metabolites across a range of agroclimatic regions where 1,3-D is known to have been used for a number of years. Local scientific knowledge of geological features, hydrology, agricultural practice and specific local issues was essential to the conduct of the study.

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.

Histopathology and epidemiology studies have consistently demonstrated a strong link between endometriosis and endometriosis-associated ovarian cancers (EAOCs)--in particular, the endometrioid and clear cell subtypes. However, it is still unclear whether endometriosis is a precursor to EAOCs, or whether there is an indirect link because similar factors predispose to both diseases. In order to search for evidence of clonal progression, we analyzed 10 EAOCs (endometrioid=4; clear cell=6) with coexisting endometriosis for common molecular genetic alterations in both the carcinoma and corresponding endometriosis. We used 82 microsatellite markers spanning the genome to examine loss of heterozygosity (LOH) in the coexisting carcinoma and endometriosis samples. A total of 63 LOH events were detected in the carcinoma samples; twenty two of these were also detected in the corresponding endometriosis samples. In each case, the same allele was lost in the endometriosis and cancer samples. Interestingly, no marker showed LOH in the endometriosis alone. These data provide evidence that endometriosis is a precursor to EAOCs.

Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity.

OBJECTIVE: To evaluate the phenotype, proliferative, and differentiation capacities in vitro of stromal cells derived from peritoneal, ovarian, and deeply infiltrating endometriosis. DESIGN: Experimental study using phase contrast microscopy, immunocytochemistry, and functional bioassays. SETTING: University-based laboratory. PATIENT(S): Women with and without endometriosis undergoing surgery for benign indications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The stability in vitro of stromal cells derived from peritoneal (n = 18), ovarian (n = 29), and deeply infiltrating (n = 14) endometriotic lesions, as well as endometrium from women with (n = 5) and without endometriosis (n = 5) was evaluated by detection of endometrial markers. The proliferative and differentiation capacity of the cells was assessed by the use of cell doubling estimation and in vitro decidualization assays. RESULT(S): The expression of the progesterone receptor and CD10 in stromal cells derived from the three types of endometriotic lesions is retained in culture up to passage 10. The doubling time of stromal cells from deeply infiltrating lesions is lower than that of endometrial stromal cells. Levels of prolactin and insulin-like growth factor binding protein-1 (IGFBP-1) are reduced in supernatants from stromal cells derived from the three types of lesions and from the endometrium of women with endometriosis. CONCLUSION(S): The peritoneal, ovarian, and deeply infiltrating endometriotic stromal cell lines we describe retain in vivo tissue markers. Loss of differentiation capacity of the endometriotic cell lines and endometrial cells from women with endometriosis may influence the capacity for proliferation and survival of these cells in the ectopic environment.

The impact of treatment for gynecological cancer on health-related quality of life (HRQoL): a systematic review.

Gynecologic cancers are major sources of mortality and morbidity. Although many review articles have reported on the impact of these diseases on health-related quality of life (HRQoL), none have reviewed the evidence in specific relation to the effect of treatment on HRQoL. Consequently, we systematically searched 4 electronic databases and hand-searched relevant reference lists and bibliographies to identify literature on this subject. Only 47 studies used a validated questionnaire to measure HRQoL. Although a meta-analysis was not possible, we found HRQoL rarely included as a treatment outcome, and when included assessment was often methodologically flawed. Seldom were pretreatment and posttreatment data collected or treatment regimes documented. Except for a few studies, analysis of HRQoL was conducted on small samples, excluding the cancer site and stage. Consequently, no definitive conclusions could be drawn and therefore we conclude with recommendations for the future reporting of HRQoL in gynecologic oncology studies.

Multivariate genetic analysis of chronic pelvic pain and associated phenotypes.

Chronic pelvic pain (CPP) is a common condition in women that is difficult to diagnose. Although heritability estimates have been published for some conditions potentially underlying pelvic pain, the heritability of CPP itself has never been investigated. Using data from 623 MZ and 377 DZ female twin pairs aged 29-50 from an Australian twin cohort, we found an increased CPP concordance among MZs compared to DZs, with tetrachoric correlations of 0.43 (95% CI: 0.26-0.58) and 0.11 (95% CI: -0.16-0.38), respectively. This corresponded to a heritability of 0.41 (95% CI: 0.25-0.56). Lack of correlations with environmental indicators suggested that violation of the equal environments assumption was not responsible for this effect. Multivariate Cholesky decomposition models incorporating CPP and significantly correlated phenotypes showed that the entire CPP heritability could be explained by genetic variance underlying endometriosis (38%), dysmenorrhoea (23%), fibroids (24%), and somatic distress (15%), the latter a possible indicator of increased nociception. CPP itself is unlikely to be a useful independent phenotype to conduct genetic aetiological studies; contributing conditions such as endometriosis and variation in nociception are likely to provide more useful phenotypes.

Polymorphism at codon 72 of the p53 gene is not associated with endometriosis in a Japanese population.

OBJECTIVE: Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and the environment to produce the phenotype. Previous studies have implicated p53, a tumor suppressor gene, as a factor in the development of the disease. In a Japanese population, we investigated the frequency of the p53 polymorphism in women affected with endometriosis. METHODS: We compared the distribution of the p53 codon 72 polymorphism in endometriosis cases (n = 111) and population controls consisting of female neonates (n = 180) by using polymerase chain reaction restriction fragment-length polymorphism analysis in a Japanese population. RESULTS: The frequencies of the three p53 genotypes, Arginine (Arg)/Arg, Arg/Proline (Pro), and Pro/Pro in controls were 39.4%, 41.7%, and 18.9 %, respectively. The crude genotype frequencies in the endometriosis cases were similar to those of the controls (35.2%, 48.6%, and 16.2%, respectively). Using the Arg/Arg genotype as the reference, the odds ratios of the Arg/Pro and Pro/Pro genotypes were 1.30 (95% confidence interval [CI] 0.72-1.86, P =.33) and 0.96 (95% CI 0.47-1.94, P =.91), respectively. Thus, there were no significant differences in the frequency of the p53 codon 72 polymorphism between endometriosis cases and controls in this population. The endometriosis cases with severe disease only were also evaluated, but no significant difference was observed in the frequency of the polymorphism between this subgroup and the controls. CONCLUSION: Our findings suggest that the p53 codon 72 polymorphism is unlikely to be associated with endometriosis in Japanese women.

Familial aggregation of endometriosis in a large pedigree of rhesus macaques.

BACKGROUND: Endometriosis occurs in several non-human primate species that have menstrual cycles. This study investigated the prevalence and familial aggregation of endometriosis in one of those species, the rhesus macaque. METHODS: Between 1978 and 2001, 142 animals with endometriosis were identified from necropsy and surgical records and through the use of magnetic resonance imaging (MRI) at the Wisconsin National Primate Research Center, Madison, USA. All cases were used to build one large multigenerational pedigree and nine nuclear families comprising 1602 females in total. By 2002, the pedigrees contained 124 cases diagnosed at necropsy; 17 at surgery and three at MRI. Female animals that had died aged > or = 10 years without endometriosis, had both ovaries until at least 1 year prior to death, and had a full necropsy, were considered unaffected. RESULTS: The prevalence of endometriosis among necropsied animals aged > or = 10 years in the colony was 31.4% [95% confidence interval (CI) 26.9-35.9%]; prevalence increased with rising age and calendar age at death. Familial aggregation of endometriosis was strongly suggested by a significantly higher average kinship coefficient among affecteds compared with unaffecteds (P < 0.001) and a higher recurrence risk for full sibs (0.75; 95% CI 0.45-1.0) compared with maternal half sibs (0.26; 95% CI 0.10-0.41) and paternal half sibs (0.18; 95% CI 0.02-0.34). The segregation ratio among affected mothers (44.2%) was not significantly higher compared with unaffected mothers (36.6%). CONCLUSIONS: The results support familial aggregation of endometriosis in the rhesus macaque, and indicate that this is a promising animal model for the investigation of mode of inheritance, the location of potential genetic susceptibility loci and the influence of environmental factors.

Characteristics of patients with endometriosis in the United States and the United Kingdom.

OBJECTIVE: To investigate differences in characteristics of patients with endometriosis in the United States and the United Kingdom. DESIGN: Patient questionnaire. SETTING: Two university-based endometriosis referral centers. PATIENT(S): Women with surgically diagnosed endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patient demographics, menstrual and obstetric history, contraceptive use, medical history, risk factors, family history, endometriosis diagnosis, and current pain status and treatment. RESULT(S): Most demographic characteristics were similar between groups. However, patients in the United States were diagnosed at a younger age than were patients in the United Kingdom (25.6 +/- 6.7 years vs. 28.0 +/- 7.1 years) and more commonly presented with an ovarian mass. More U.K. women used oral contraceptives before diagnosis and were younger at first use. U.K. patients underwent fewer additional surgeries than U.S. patients but reported that surgery alone provided the best relief of symptoms, whereas most U.S. patients reported that surgical and medical therapy together provided the best relief of symptoms. CONCLUSION(S): The many similarities in demographics and symptoms among women with endometriosis in the U.S. and the U.K. support the universality of the disease process. Despite a variety of treatments, most patients from both groups still experienced pain from their endometriosis at the time of the survey.

Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review.

Endometriosis, menorrhagia, chronic pelvic pain, and polycystic ovary syndrome are major sources of psychologic morbidity and can negatively affect quality of life. Although comparative studies have been published on the measurement of health-related quality of life for gynecologic malignancies, a similar review for these benign gynecologic conditions has not been conducted. Consequently, we searched the literature systematically to identify the impact of symptoms and treatments for these conditions on health status and to report on the types and psychometric properties of the instruments used. Papers were retrieved by systematically searching 6 electronic databases and hand-searching relevant reference lists and bibliographies. Forty-six studies used a questionnaire to measure health status: 34 studies (74%) used standardized instruments; of these, 23 studies (68%) used generic tools. Although a meta analysis was not possible, it appears that women with chronic pelvic pain and conditions that are associated with pelvic pain (such as endometriosis) report worse health-related quality of life. Despite the development of disease-specific questionnaires, only 2 questionnaires were generated from interviews of patients with the condition of interest, and few questionnaires are being used to evaluate the outcomes of treatment on subjective health status.