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.

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.

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.

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.

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.

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.

Reversal of female sterilisation: outcome of 210 referrals.

AIMS: To determine the outcome of request for reversal of sterilisation and to compare demographic and social factors of women who subsequently withdrew their request with those who proceeded with the reversal assessment and operation. METHODS: Information relating to the sterilisation and regret intervals were sought from 210 women. Demographic and social factors were recorded and the outcome of the reversal request determined. Patients who withdrew or were deferred/declined were compared on relevant factors with the group who proceeded to, or are still planning, the reversal operation. RESULTS: Ninety-two (44%) withdrew before or during the assessment phase. Another 13 withdrew after laparoscopy identified a poor prognosis. Three declared their intention not to conceive after they underwent the reversal operation. To date, 83 have had surgery with the cumulative intrauterine pregnancy rate at 1, 2 and 3 years being 0.46, 0.62 and 0.78 respectively. In comparing those women who proceeded and withdrew, there were no differences in mean age at referral, age at sterilisation, the number of living children nor marital status. The regret interval prior to referral was significantly longer in the women who proceeded (27.9 and 19.5 months respectively, p = 0.03). Those who were highly motivated in their reversal request were also more likely to proceed (p = 0.003). CONCLUSIONS: There is a large dropout rate of women who seek a reversal of sterilisation. Women who regret sterilisation may have sought sterilisation as a solution to problems that were psychosocial rather than contraceptive in nature. We stress the importance of counselling for both sterilisation and its reversal, since in the latter many developmental personality and relationship problems remain unresolved.

A stereological study of the human ovarian surface epithelium.

The surface of the ovary has been found to be composed of two types of epithelial cells called A and B cells which are found in their own respective zones, the A and B zones. A quantitative study was undertaken to determine the mean cell volumes and cell ultrastructure. Ovarian biopsies were taken from six women and A and B zones, having been identified by scanning electron microscopy, were re-embedded for transmission electron microscopy. Stereological measurements using point sampled intercepts were made on vertical sections and showed that B cells are significantly larger than A cells. The volume weighted mean cell volumes of the A and B cells were 237.3 microns 3 and 676.8 microns 3 respectively. The volume fractions of the nucleus and mitochondria were similar in the two cell types. Although the vesicle content of each type was similar, a large variation between cases made the interpretation difficult. The stereological tools used in this study proved to be easy and efficient estimators of surface cell ultrastructure and give an important direction for ultrastructural research.

A scanning electron microscopic study of the human ovarian surface epithelium: characterization of two cell types.

The surface of the ovary has two types of epithelial cells. We have called these A and B cells and they are found in their own respective zones (A and B). To assess the scanning electron microscopic features of these cell types, 65 ovarian samples were collected from biopsies taken from 35 women with normal ovaries. Biopsies included developing follicles, corpora lutea and ovarian capsules. Type A cells were cuboidal and sometimes tall, with a mean diameter of 6.49 microns, and a mean density of microvilli of 6.48/microns 2. Type B cells, on the other hand, were flat squamous cells with broader and flat apices with mean diameters and microvillus density of 11.71 microns and 3.88/microns 2 respectively. The A and B zones were common to all surfaces including the distending follicle. Type A cells overlying the distended surface of a follicle had a mean diameter of 7.03 microns compared to a mean of 6.05 microns for the capsular surface. Type B cell diameters and the microvillus density of both types were more variable and did not differ significantly over any of the surfaces. We suggest that previous human studies which identified flattening of cells over the distending follicle were probably observing B cells. The relationship of the B zones to papillae and surface bridges on the ovarian surface, and the association of these with ovulation sites, suggests that B cells are probably metaplastic cells derived in response to chronic surface injury with ovulation.

Artefactual loss of human ovarian surface epithelium: potential clinical significance.

To investigate whether the human ovarian surface has an intact epithelial layer, 69 ovarian biopsies from 39 women were taken. When the surface was touched or wiped, there was a widespread loss of cells that were otherwise retained in surface depressions or crypts. By avoiding contact with the surface, the layer was retained. A temporary disruption to the surface following ovulation was followed by complete healing and re-epithelialization. These observations suggest that previous studies describing the loss of surface epithelium may have artifactually generated this loss, possibly by handling the surface during surgical retrieval. The possible clinical significance of these observations is that inadvertent ovarian handling during any ovarian surgery may be implicated in the pathogenesis of adhesion formation, simply by removing the surface that is important in tissue repair.