Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis.

STUDY QUESTION: What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6-12 months for infertile women of age ≥35 years? SUMMARY ANSWER: Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY: In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION: A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms 'fertility service', 'waiting list', 'treatment-independent' and 'spontaneous conception'. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle-Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE: We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5-8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35-42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11-0.19) after 6 months and 0.24 (95% CI 0.17-0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04-0.11) after 6 months and 0.13 (95% CI 0.07-0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION: In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS: Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility. STUDY FUNDING/COMPETING INTEREST(S): S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet. PROSPERO REGISTRATION NUMBER: CRD42018096552.

The prevalence and potential determinants of dysmenorrhoea and other pelvic pain in women: a prospective study.

OBJECTIVE: To estimate the prevalence of pelvic pain and model associations with potential demographic, obstetric, gynaecological and psychosocial determinants. DESIGN, SETTING AND SAMPLE: A cohort study of women born between 1972 and 1973 in Dunedin, New Zealand, most recently assessed when aged 38 years (95% of survivors retained); 429 women were eligible for analysis. METHODS: Women self-completed reproductive health questionnaires at ages 21, 26, 32 and 38 years, with questions on dysmenorrhoea at ages 13 and 15, and on all pelvic pain at age 38. Prevalence and 95% confidence intervals (CI) were calculated and Poisson regression used to model associations. MAIN OUTCOME MEASURES: The prevalence of pain and adjusted relative risks (ARR) for potential explanatory factors. RESULTS: Over half (54.5%, 95% CI 49.7-59.3%) of women experienced pelvic pain in the past 12 months at age 38. Dysmenorrhoea was reported by 46.2% (41.3-51.3%), dyspareunia by 11.6% (8.7-15.2%) and other pelvic pain (OPP) by 17.3% (13.8-21.2%). After adjusting for multiple factors, pregnancy (ARR 0.60, 95% CI 0.32-1.13) and childbirth (ARR 0.52, 95% CI 0.25-1.09) were borderline protective for dyspareunia and OPP, respectively. However, childbirth was not associated with dysmenorrhoea (ARR 0.97, 95% CI 0.74-1.28). Dysmenorrhoea and dyspareunia were strongly associated, and both were associated with endometriosis. CONCLUSIONS: Our data confirm that female pelvic pain is common, and suggest common gynaecological and obstetric causal pathways, but there was no strong evidence supporting a benefit of childbirth for dysmenorrhoea. Further research on obstetric events and pelvic pain is needed, with both being common experiences. TWEETABLE ABSTRACT: Pelvic pain was common at age 38, especially dysmenorrhoea (46.2%), and no improvement was detected following childbirth.

Resolution of infertility and number of children: 1386 couples followed for a median of 13 years.

STUDY QUESTION: How common were children among infertile couples? SUMMARY ANSWER: A total of 61.7% of infertile couples presenting for care subsequently had live born children 13.1 years after first being clinically assessed, with a mean of 1.7 children among those who had at least one. WHAT IS KNOWN ALREADY: While the prognoses for infertile couples undertaking specific treatments have been well described, less is known about those not undergoing these treatments or the total number of children. This information is necessary for decision-making in many individual cases; not knowing this has been cited by patients and clinicians as impeding implementation of care. STUDY DESIGN, SIZE, DURATION: The sole provider of specialist fertility care for the two southern-most regions in New Zealand enroled 1386 infertile couples from 1998 to 2005 in a longitudinal study with follow-up on all births until the end of 2014. Couples were followed in care for a median of 1.1 years and median follow-up for births was 13.1 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinic-collected data were linked to national maternity data to extend follow-up past the end of clinical contact. The primary outcome was the total number of live born children. Hurdle regression was used to investigate factors associated with resolving infertility and the total number of children. MAIN RESULTS AND THE ROLE OF CHANCE: Infertility was resolved with a live birth by 61.7% (95% CI 59.1-64.2%) of couples; just over half of all first births were treatment-dependent. Among couples who resolved their infertility, 55.6% (52.2-58.9%) had at least one additional child and the mean number of children was 1.7. While female age strongly influenced outcomes, one-third of women aged 40-41 years had a child, not significantly less than those in their late 30s. The lowest levels of resolution occurred in women aged ≥42 years, couples who were infertile for >4 years and women with a BMI ≥ 35 kg/m2. Moderate obesity did not affect outcomes. LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study was insufficient data to investigate male factor infertility outcomes. It is also possible that treatment-dependent resolution could be higher in more recent cohorts with the increased use of ART. WIDER IMPLICATIONS OF THE FINDINGS: Outcomes in these couples are comparable to those seen in other studies in high-income countries despite the relatively low contribution of ART. The prognosis for most infertile couples is positive and suggests many will not require treatment. Further research is needed to inform best practice for women in their early forties or with moderate obesity, and to develop prediction models that are more relevant for the initial management of infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was co-funded by a University of Otago PhD Scholarship and the Department of Women's and Children's Health, University of Otago. There were no competing interests to declare.

Factors associated with parents' decisions to tell their adult offspring about the offspring's donor conception.

BACKGROUND: Tensions and anxieties surround secrecy within families in the context of gamete donation and family building. This paper presents the views of parents who had kept their use of donor insemination a secret from their offspring. A sub-set of these parents said that they wished to tell their now-adult offspring, and discussed the questions and issues this secrecy raised to them. METHODS: In-depth interviews were undertaken with heterosexual parents (of 44 families) who had given birth to children conceived via donor insemination between 1983 and 1987. These interviews comprised a follow-up study, with the first interviews being undertaken when the children were aged up to seven. In this paper, qualitative data relating to a sub-set of 12 parents (from seven families) who now wished to tell their offspring are presented. RESULTS: The parents describe the pressures that the secret-keeping had created for them as well as the impact of those pressures. They report on the reasons they now want to share the family building history and the associated fears and anxieties about doing so. The parents all say that they wish they had told their offspring much earlier. In five of the seven families, parents describe how the offspring had raised questions concerning a perceived genetic disconnection between them and their parents. CONCLUSIONS: Keeping the use of donor insemination a secret from offspring created considerable pressure for these parents. Despite the secrecy, offspring can become aware of the genetic disconnection.

Prioritising for fertility treatments--the effect of excluding women with a high body mass index.

The effect of clinical priority access criteria for access to infertility treatment was examined for women outside the body mass index (BMI) range of 18-32 kg/m2. Treatments and outcomes were analysed from 1280 cases referred from 1998 to May 2005. Sixteen percent of women had a BMI of >32 kg/m2. Overall, 38% of these women had a birth from conceiving a treatment-related pregnancy or spontaneous pregnancy, compared with 52% of women with BMI < 32 kg/m2. Weight loss allowed women in the BMI group >32<35 kg/m2 to access treatment, but women in higher BMI groups were less successful.

In vitro fertilisation versus tubal reanastomosis (sterilisation reversal) for subfertility after tubal sterilisation.

BACKGROUND: Tubal sterilisation is the most popular contraceptive method in the world. Approximately 138 million women of reproductive age have had tubal sterilisation and there is evidence that increasingly younger women are being sterilized. With such large numbers of women choosing this option of birth control, it is clear that even if a small percentage of women later regret the decision, large numbers of women will seek counselling regarding reversal from their physicians. OBJECTIVES: To compare the efficacy of surgical tubal reanastomosis and in vitro fertilisation in terms of live birth rates. The morbidity and cost-effectiveness of both techniques were also to be compared. SEARCH STRATEGY: The following databases were searched: Cochrane Menstrual Disorders and Subfertility Review Group Specialised Register, MEDLINE (1966 to 2005), EMBASE (1980 to 2005), and other electronic databases. We handsearched the reference lists of trials, reviews and relevant textbooks; searched abstracts from relevant conferences, and personally communicated with experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing surgical reversal of tubal sterilisation with in vitro fertilisation (IVF). The method of allocation will be assessed and results subgrouped according to whether the trials were randomised or quasi-randomised. DATA COLLECTION AND ANALYSIS: No trials were found that met the selection criteria. MAIN RESULTS: No data exist on which to report. AUTHORS' CONCLUSIONS: There is a need for well-designed controlled clinical trials to compare the efficacy and safety of surgical reversal of tubal sterilisation and IVF in restoring fertility in women seeking pregnancy following tubal sterilisation.

Purification of granulosa cells from human ovarian follicular fluid using granulosa cell aggregates.

Human follicular fluid can provide a source of human granulosa cells for scientific study. However, removing potentially contaminating cells, such as white and red blood cells, is important for molecular and in vitro studies. We have developed a purification technique for human granulosa cells based on the selection of cellular aggregates. Human granulosa cells from 21 IVF patients were collected. A 50% Percoll gradient was used to remove red blood cells, and granulosa cell aggregates were collected, washed and processed for histology, electron microscopy, flow cytometry analysis, cell culture and RNA extraction. Granulosa cell aggregates were found to be homogeneous and free of white blood cells after histological and electron microscopic analysis. White blood cell contamination, measured by flow cytometry, was found to be between 2 and 4%. Polymerase chain reaction analysis revealed expression of known human granulosa cell genes and a white blood cell marker. Human granulosa cells grown in vitro showed flattened fibroblast-like morphology with lipid droplets consistent with previous reports. Cultured cells expressed the FSH receptor. Selection of human granulosa cell aggregates following centrifugation through a Percoll gradient provides an efficient method of selecting granulosa cells, suitable for both molecular and in vitro studies.

Complete genome sequence of the genetically tractable hydrogenotrophic methanogen Methanococcus maripaludis.

The genome sequence of the genetically tractable, mesophilic, hydrogenotrophic methanogen Methanococcus maripaludis contains 1,722 protein-coding genes in a single circular chromosome of 1,661,137 bp. Of the protein-coding genes (open reading frames [ORFs]), 44% were assigned a function, 48% were conserved but had unknown or uncertain functions, and 7.5% (129 ORFs) were unique to M. maripaludis. Of the unique ORFs, 27 were confirmed to encode proteins by the mass spectrometric identification of unique peptides. Genes for most known functions and pathways were identified. For example, a full complement of hydrogenases and methanogenesis enzymes was identified, including eight selenocysteine-containing proteins, with each being paralogous to a cysteine-containing counterpart. At least 59 proteins were predicted to contain iron-sulfur centers, including ferredoxins, polyferredoxins, and subunits of enzymes with various redox functions. Unusual features included the absence of a Cdc6 homolog, implying a variation in replication initiation, and the presence of a bacterial-like RNase HI as well as an RNase HII typical of the Archaea. The presence of alanine dehydrogenase and alanine racemase, which are uniquely present among the Archaea, explained the ability of the organism to use L- and D-alanine as nitrogen sources. Features that contrasted with the related organism Methanocaldococcus jannaschii included the absence of inteins, even though close homologs of most intein-containing proteins were encoded. Although two-thirds of the ORFs had their highest Blastp hits in Methanocaldococcus jannaschii, lateral gene transfer or gene loss has apparently resulted in genes, which are often clustered, with top Blastp hits in more distantly related groups.

The retained twin/triplet following a preterm delivery--an analysis of the literature.

We summarized the overall experience of the management and outcome of the retained twin/triplet and statistically analyzed the effects of the different variables such as cervical cerclage, tocolysis, use of antibiotics etc. on the retained fetal survival; 45 case reports in English were analyzed. The survival rate of the first born was very poor in contrast to the second and third-born infants. Spontaneous rupture of the membranes was the most common cause of the loss of the first born, whereas for the second born, premature labour was the commonest cause. Despite substantial obstetric events leading to delivery of the first-born infant, interval problems were uncommon. The mean period of retention of the surviving retained twin/triplet was 48.9 +/- 37.9 days compared to 25.7 +/- 31.6 days for the dead retained twins/triplets (p=0.08). The female retained twins/triplets were retained much longer than the males (p=0.008). The pregnancies lasted 45.9 days in the tocolytic group and 37 days in the nontocolytic group (p=0.51). The delivery interval of the second born in the cerclage group was 52 +/- 42 days compared to 34 +/- 30 days in the noncerclage group (p=0.1). The longer the twins/triplets were retained the better was their survival. Tocolysis, cervical cerclage and prophylactic use of antibiotics failed to make a statistically significant difference in the fetal outcome. The birth-weights, gestations and sex of the retained twins/triplets affected their survival significantly.

First and subsequent pregnancies after tubal microsurgery: evaluation of the fertility index.

OBJECTIVE: To determine the number of children born after a tubal microsurgical operation and to evaluate the fertility index, a long-term measure of reproductive potential. DESIGN: A case series involving a follow-up questionnaire. SETTING: A tertiary care university hospital. PATIENT(S): Three hundred twelve women undergoing microsurgery for tubal disease. INTERVENTIONS: A range of open microsurgical procedures including reversal of sterilizations. MAIN OUTCOME MEASURE(S): Cumulative pregnancy rates to the first and second normal pregnancies and calculation of the fertility index. RESULT(S): The 2-year cumulative pregnancy rates (probability +/- SE) for a first normal pregnancy for proximal disease, distal disease, tubal reanastomoses, and tubal adhesions were 0.51 +/- 0.05, 0.29 +/- 0.06, 0.47 +/- 0.06, and 0.30 +/- 0.07, respectively. Of the 288 (92%) women responding to the questionnaire, 142 women had at least one child. Of the 100 women who wanted a second child, 68 succeeded, the proportions being similar in each surgery category. The fertility index described restoration of normal fertility in 30%, 12%, 34%, and 23% for women with proximal disease, distal disease, anastomotic procedures, and adhesion disease, respectively. CONCLUSION(S): The fertility index is a useful measure of long-term reproductive potential. The high recurrent pregnancy rate emphasizes the value of microsurgery in restoring normal fertility to some women.

Successful donor insemination and its impact on recipients.

Male and female partners of couples who conceived a child by donor insemination (DI) independently completed a questionnaire. Fifty-seven women and 53 men representing 58 couples taking part. Fifty-one were in a continuing relationship and seven were separated. A likert scale (0-7) of "happiness' before, during and after treatment and their perception of their partner's feelings were used as measures. These feelings were evaluated in relation to demographic and clinical factors. Fifty-one women and 49 men who were in a continuing relationship answered questions about their feelings about DI, compared to six and three, respectively, who had separated. Feelings about DI were consistently low before treatment began. For both continuing and separated couples there was an improvement of their feelings about having DI during treatment, and then again after treatment was complete. For the male partner, factors that were associated with greater unhappiness included difficulties with the relationship prior to treatment, waiting time for treatment and subsequent separation. The women, however, had more positive experiences with no measured factors adversely affecting their feelings about DI. The arrival of the DI child had a significant effect in improving the relation-ship. Our findings suggest that for many couples acceptance of the DI program was less than ideal and only improved with having the treatment and then conceiving. The data highlight the need for psychosocial assistance to be made available to couples prior to the commencement of treatment.

Feelings of couples who have had a child by donor insemination: the degree of congruence.

The study aimed to assess the congruence of feelings about donor insemination (DI) in couples who have had a child by this means. Male and female partners of 50 couples (in continuing relationships) who had had a child by DI individually completed a questionnaire. A Likert scale (0, very unhappy to 7, very happy) was used to assess feelings before, during and after treatment, and the perception of their partner's feelings. Individual partner's responses were also compared for views about the donor and assessment of their relationship. For both males and females, their feelings about DI before, during and after treatment did not correlate with their perceived view of their partner's feelings. This difference was much more striking before treatment started with male feelings (mean +/- SD) being 4.1 +/- 1.8 compared to the females' perception of the males' feelings of 3.5 +/- 1.9 (t test, p = 0.004) and females' feelings of 3.7 +/- 2.0 compared to the males' perception of female feelings of 4.3 +/- 2.0 (p = 0.05). In comparing attitudes about the donor, individual couples' views did not correlate well, the exceptions being their views on whether or not to have another child and whether they wanted the same donor. All but one couple agreed that the DI child had brought them closer together as well as agreeing that they confided in each other. The marital interaction assessment showed close compatibility in most issues. The impact of DI on couples affected by male factor infertility raises many issues, the views of which may not be shared between partners. This is especially the case of attitudes about the donor and is of some concern when viewed in the wider context of marital and parent-child relationships. It is not known whether these opposing views have an impact on the later development of these relationships but they should be considered as part of the preparation for beginning treatment.

Assembly of high-resolution restriction maps based on multiple complete digests of a redundant set of overlapping clones.

An approach to restriction-site mapping and contig building that uses fragment-size data from multiple complete digests of a set of clones that oversample a genomic region is presented. Maps containing both fragment-length data and clone-end data are maintained for each restriction enzyme. Synchronization between the maps for the different enzymes is achieved by requiring the clone-end maps for all enzymes to be compatible. Basic concepts that underlie multiple-complete-digest mapping--including the match/merge approach to map incorporation, extension vs assimilation, ambiguity, and clone-end compatibility--are presented. An initial application of multiple-complete-digest mapping to real data on a set of cosmid clones suggests that this mapping method has exceptional power to produce accurate maps that are well suited to the needs of large-scale DNA-sequencing projects.

Telling donor insemination offspring about their conception: the nature of couples' decision-making.

The issue of openness and secrecy in the use of donor gametes is the subject of considerable disagreement and debate, not only for social scientists and health professionals, but also for the recipients of donor gametes. This paper has its origins in a study of 58 couples who had a child/children as a result of donor insemination (DI) at the Dunedin Infertility Clinic. Respondents completed questionnaires and took part in an interview during which they were asked whether they intended to tell their offspring about their DI conception. The nature of agreement/disagreement between partners on this issue, the dynamics operating between couples that may affect decision-making, and the views of couples in a time-frame perspective are the focus of this paper. Transcripts from some of the interviews are presented to illustrate the points made and commentary and discussion is provided.

Assessment of the laparoscopic treatment of ectopic pregnancy.

AIMS: To assess the first 2 years experience of the laparoscopic surgical treatment of ectopic pregnancy in a regional referral centre. METHODS: All cases of ectopic pregnancy in a 2 year period from August 1991 were evaluated to assess the impact on the routine management of this condition. RESULTS: In the first year 14 cases were managed by laparoscopic means and took an average operating time of mean 73.8 (SD 17.2) minutes compared to mean 69.1 (17.9) minutes in the 26 cases managed this way in the second year. The 40 patients were hospitalised for an average of 1.4 days and 24 stayed one night only. There was no difference in operating time between registrars and consultants. The only major complication was a patient who required an emergency laparotomy because of continued bleeding. When all cases of ectopic surgery were evaluated in the second year, six of the 32 cases required laparotomy to complete the operation. CONCLUSION: The benefits of laparoscopic surgical treatment of ectopic pregnancy dictate that this should be employed as first line treatment for all cases of tubal ectopic gestation. Our experience suggests that achieving such a service, whilst not without pitfalls, should be possible in all gynaecology units provided that staff are motivated and that laparoscopic equipment is available.

Fragment collapsing and splitting while assembling high-resolution restriction maps.

In the process of constructing high-resolution restriction maps via greedy algorithms, a classical anomaly, known as fragment collapsing, introduces errors into the maps that impedes further map assembly. Fragment collapsing occurs when two different genomic fragments of approximately the same length and occurring in the digestion of two different overlapping clones are incorrectly identified as representative of a single genomic fragment. This introduces a single fragment of commensurate length into an incorrect position in the map. The present work describes techniques for detecting and correcting such anomalies.

Removal of the ovarian surface epithelium from the rabbit ovary--a cause of adhesions following a standard injury.

To assess the effect of the removal of ovarian surface epithelium on repair, a standard injury was induced in the ovaries of 10 rabbits. In one ovary the surface cells were denuded, and in the other they were left intact. The effect on adhesion formation was assessed at 12 days. Adhesions were assessed by visual inspection at laparotomy and histological examination of adhesion formation, including a stereological assessment of scar volume. On visual assessment the overall adhesion scores for the denuded ovaries were greater than for the intact ovaries. Histology showed the adhesions were attached only to the site of injury. The Fallopian tube was adherent to 35 and 4% of the denuded and intact ovarian segments respectively (P = 0.003). The scar volumes for each side were similar. After 12 days there was only partial re-epithelialization on the denuded ovaries. Electron microscopy confirmed the slow healing, with much of the surface still covered by a fibrinous-like exudate. The findings of this small study lend further weight to the importance of the surface epithelium in the control of adhesion formation. Standard surgical procedures may generate adhesions by the inadvertent denuding of surface epithelium from adjacent healthy tissues, possibly by the loss of plasminogen activator activity that is found in the mesothelium of the peritoneum. This study highlights the importance of controlling for inadvertent cell loss whilst investigating methods for adhesion prevention.

Withdrawal from a donor insemination programme.

The aim of this study was to examine the factors that influenced the withdrawal of couples from a regional donor insemination programme. Demographic, medical, treatment and outcome data were prospectively recorded on 375 referrals. One hundred and eight women had conceived at least 1 normal pregnancy. Withdrawals from the programme, without pregnancy, accounted for 165 couples, whilst 47 had begun treatment, and a further 29 were on the waiting list. Thirty nine (24%) of those withdrawing did so without notice or reason. Most of these (33) were in couples waiting to begin treatment. Natural conception, adoption, identifiable medical or social reasons (including separation) and moving to another region were the predominant causes for withdrawing. Women who had entered the programme because of their partner's oligospermia had a high natural conception rate. Age, socioeconomic status, geographic location and length of infertility did not affect the withdrawal rate.