Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology.

BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.

In Vitro Maturation of Oocytes in Women at Risk of Ovarian Hyperstimulation Syndrome-A Prospective Multicenter Cohort Study.

BACKGROUND: In vitro maturation (IVM) is an artificial reproductive technology in which immature oocytes are harvested from the ovaries and subsequently will be matured in vitro. IVM does not require ovarian hyperstimulation (OH) and thus the risk of ovarian hyperstimulation syndrome (OHSS) is avoided. In this study, we assessed the live birth rate per initiated IVM cycle in women eligible for in vitro fertilization/intracytoplasmic sperm injection (IVF/ ICSI) and at risk for OHSS. Furthermore, we followed women who were not pregnant after IVM and committed to a conventional IVF/ICSI procedure. MATERIALS AND METHODS: In this multicenter prospective cohort study, we started 76 IVM cycles using recombinant follicle stimulating hormone (rFSH) priming in 68 patients. There were 66 oocyte retrievals, in which a total of 628 oocytes were collected. We incubated the immature oocytes for 24-48 hours and fertilized those that reached metaphase II by ICSI. RESULTS: Three hundred eighty six (61% oocytes) achieved metaphase II. The fertilization rate was 55%. We performed 59 embryo transfers (1.9 embryos per transfer) in 56 women, including 3 frozen embryo transfers. There were four ongoing pregnancies (5.3% per initiated cycle) leading to the birth of a healthy child at term. None of the patients developed OHSS. The ongoing pregnancy rate of the first conventional IVF/ICSI cycle after an unsuccessful IVM cycle was 44%, which was unexpectedly high. CONCLUSION: We concluded that IVM led to live births but with low effectiveness in our study. Earlier reported IVM success rates are higher which can be caused by a more extended experience in these centers with the intricate laboratory process. However, a possible selection bias in these studies cannot be ruled out. Furthermore, IVM might have a beneficial effect on further IVF/ICSI treatments due to its "ovarian drilling" effect.

Clinical practice guidelines for fertility preservation in young women undergoing gonadotoxic treatment: an overview and critical appraisal of methodological quality and content.

RESEARCH QUESTION: What is the methodological quality and content of internationally available clinical practice guidelines (CPGs) on fertility preservation (FP) care in adult women? DESIGN: Internationally available CPGs on FP care in adult women were identified after conducting an extensive literature search and consulting (inter)national key experts. The methodological quality of the CPGs was appraised by an (inter)national panel of experts using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The content of the best CPGs, scoring ≥60% for the domain 'Rigour of development' of the AGREE II instrument, was extracted and categorized according to their topic. RESULTS: Thirty of the 1808 documents found were included. After consulting (inter)national key experts, 30 CPGs were included, six of which scored ≥60% for their 'Rigour of development'. The number of FP-related topics discussed by these six CPGs ranged from 4 to 12. The number of recommendations provided by the CPGs on these topics varied. The number of topics to which ≥5 recommendations were dedicated ranged from 0 to 4 between CPGs. CONCLUSION: CPGs on the subject of FP care are available, but there is room for improvement in quality and content. Although written for use in daily practice, the CPGs can also be used to develop quality indicators to monitor the quality of current FP care or to evaluate future improvement initiatives.

Treatment strategies and cumulative live birth rates in WHO-II ovulation disorders.

OBJECTIVE: To assess the live birth rate in women with WHO II anovulation and the proportion of women that need second or third line treatments if the initial therapy fails. STUDY DESIGN: In this multicenter cohort study we included couples with unfulfilled child wish who were referred to three fertility clinics in the Netherlands and selected women with a WHO II ovulation disorder as the only final infertility diagnosis (n = 468). RESULTS: The cumulative live birth rate of the total group was 82% (383/468). The majority started with clomiphene-citrate as first-line treatment (n = 378) resulting in 180 (48%) live births. There were 153 couples (40%) who underwent a second-line treatment (recombinant-FSH or laparoscopic electrocoagulation of the ovaries, LEO) and 52 couples (14%) a third-line treatment (IVF/ICSI), resulting in 44% and 63% treatment dependent live births rates, respectively. Of all couples, 92 (20%) conceived naturally, 186 (40%) after clomiphene-citrate, 60 (13%) after recombinant-FSH, nine (2%) after LEO and 36 (8%) after IVF. CONCLUSION: Subfertile women with a WHO II ovulation disorder have a good prognosis on live birth, and most did so after ovulation induction with clomiphene-citrate. If first-line ovulation induction has failed ovulation induction with gonadotrophins or IVF still result in a live birth in about half of the cases.

Long-term ongoing pregnancy rate and mode of conception after a positive and negative post-coital test.

OBJECTIVE: Many fertility clinics have decided to abolish the post-coital test. Yet, it is a significant factor in prognostic models that predict the spontaneous pregnancy rate within one year. The aim of this study was to evaluate (1) the long-term outcome of infertile couples with a positive or a negative post-coital test during their fertility work-up and (2) the contribution of the different modes of conception. DESIGN: Retrospective cohort study. SETTING: Three fertility clinics in the Netherlands, of which two are secondary care training hospitals and is a one tertiary care academic training hospital. POPULATION: 2476 newly referred infertile couples, where a post-coital test was performed in 1624 couples. METHODS: After basic fertility work-up, couples were treated according to the national treatment protocols. MAIN OUTCOME MEASURES: Spontaneous and overall ongoing pregnancy rate. RESULTS: The spontaneous and overall ongoing pregnancy rates after three years were 37.7 and 77.5% after a positive post-coital test compared with 26.9 and 68.8% after a negative test (p < 0.001). Even in couples with severe male factor infertility (total motile sperm count <3) (p = 0.005) and mild male factor infertility (total motile sperm count 3-20) (p < 0.001), there was a significantly higher spontaneous ongoing pregnancy rate, justifying expectant management. CONCLUSION: After a follow-up of three years a positive post-coital test is still associated with a higher spontaneous and a higher overall ongoing pregnancy rate, even in couples with severe male factor infertility.

[Chronic Q fever during pregnancy]. / Chronische Q-koorts tijdens de zwangerschap.

A 42-year-old woman visited the pulmonologist for follow-up after a pneumonia. In retrospect the pneumonia appeared to be a manifestation of an acute Q fever infection. A few weeks later the patient was found to be unexpectedly pregnant. At the normal serological follow-up six months after the primary infection chronic Q fever infection was diagnosed. Doxycycline and hydroxychloroquine are contraindicated in pregnancy and the patient was found to be allergic to co-trimoxazole. Therefore treatment with erythromycin was chosen on empirical grounds. The patient had many symptoms during pregnancy. After 38 weeks and 2 days amenorrhea labour was induced on maternal indication. Finally a healthy boy of 3850 grams was born by caesarean section. In view of the increased risk of chronic Q fever infection during pregnancy we advise intensified serological monitoring of patients with acute Q fever who subsequently become pregnant.

Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial.

BACKGROUND: In The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands. METHODS/DESIGN: We will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group. DISCUSSION: With this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov, protocol record NL30340.042.09.

Origin of multiple pregnancies in a subfertile population.

OBJECTIVE: To evaluate the contribution of different subfertility treatments to the number of multiple pregnancies in a subfertile population. DESIGN: A prospective cohort study between January 2002 and December 2006. SETTING: A subfertility clinic in a large regional training hospital in the Netherlands. POPULATION: A total of 1,001 continuing pregnancies, of which 63 (6.3%) were multiple. METHODS: Of all pregnancies, mode of conception, outcome and type of pregnancy (singleton or multiple) were documented. MAIN OUTCOME MEASURES: Proportions of continuing and multiple pregnancies caused by the different modes of conception. RESULTS: Of all subfertility related continuing pregnancies, 46% were conceived spontaneously, 16% were induced by clomiphene citrate (CC), 2.4% by follicle stimulating hormone (FSH) and 14% by intra-uterine insemination combined with controlled hyperstimulation (IUI/(COH)). In vitro fertilization (IVF) and its related techniques resulted in about a fifth of all continuing pregnancies (n = 212), but were responsible for more than half (n = 36) of the multiple pregnancies. Furthermore, 18% of the multiple pregnancies were induced by IUI/(COH), 3% by FSH, 11% by CC, whereas about 11% were conceived spontaneously. CONCLUSIONS: IVF and intra-cytoplasmic sperm injection (ICSI) were responsible for the majority of the multiple pregnancies in a subfertile population. Therefore, twin prevention should be focused on further promoting elective single embryo transfer (eSET). Fertility treatment and particular IVF should not be started as long as the spontaneous pregnancy prognosis is good.

Prediction of pelvic pathology in subfertile women with combined Chlamydia antibody and CA-125 tests.

OBJECTIVES: Chlamydia antibody test (CAT) has been proposed to predict tubal disease. A correlation between CA-125 and the extent of endometriosis has been found by others. In this study we explored whether a combination of the two tests adds to the predictive value of the individual tests for predicting tubal disease or endometriosis. We also used the combination of tests as a new index test to screen for severe pelvic pathology. STUDY DESIGN: This retrospective study compares the findings of 240 laparoscopies with the serological test results. Findings were classified according to the existing ASRM scoring systems for adnexal adhesions, distal tubal occlusion and endometriosis. Severe pelvic pathology was defined as the presence of ASRM classes III and IV tubal disease or ASRM classes III and IV endometriosis. The predictive value was calculated for both tests separately and for the combined test. The combined test was positive if at least one test result was abnormal (CAT positive and/or CA-125 > or =35 IU/ml). RESULTS: 67/240 women had tubal disease, 81/240 had some degree of endometriosis. The odds ratios (ORs) of the CAT and the combined test to diagnose severe tubal disease were 6.6 (2.6-17.0) and 7.3 (2.9-19.3), respectively. The ORs of the CA-125 and the combined test to diagnose severe endometriosis were 15.6 (6.2-40.2) and 3.0 (1.2-8.0), respectively. Severe pelvic pathology was present in 65/240 women (27%). The ORs for severe pelvic pathology of the CAT, CA-125 and the combined test were 2.5 (1.4-5.3), 4.9 (1.9-9.6) and 6.6 (3.3-13.4), respectively. If the combined test was normal 15 out 131 women (11%) were shown to have severe pelvic pathology. CONCLUSIONS: The combined test adds hardly anything to the predictive value of CAT alone to diagnose severe tubal disease. The combined test is better than the CAT to predict severe pelvic pathology, but is not significantly better than the CA-125. If both the CAT and CA-125 are normal one could consider not performing a laparoscopy.