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.

Chlamydia trachomatis Incidence Using Self-Reports and Serology by Gender, Age Period, and Sexual Behavior in a Birth Cohort.

BACKGROUND: Although understanding chlamydia incidence assists prevention and control, analyses based on diagnosed infections may distort the findings. Therefore, we determined incidence and examined risks in a birth cohort based on self-reports and serology. METHODS: Self-reported chlamydia and behavior data were collected from a cohort born in New Zealand in 1972/3 on several occasions to age 38 years. Sera drawn at ages 26, 32, and 38 years were tested for antibodies to Chlamydia trachomatis Pgp3 antigen using a recently developed assay, more sensitive in women (82.9%) than men (54.4%). Chlamydia incidence by age period (first coitus to age 26, 26-32, and 32-38 years) was calculated combining self-reports and serostatus and risk factors investigated by Poisson regression. RESULTS: By age 38 years, 32.7% of women and 20.9% of men had seroconverted or self-reported a diagnosis. The highest incidence rate was to age 26, 32.7 and 18.4 years per 1000 person-years for women and men, respectively. Incidence rates increased substantially with increasing number of sexual partners. After adjusting age period incidence rates for partner numbers, a relationship with age was not detected until 32 to 38 years, and then only for women. CONCLUSIONS: Chlamydia was common in this cohort by age 38, despite the moderate incidence rates by age period. The strongest risk factor for incident infection was the number of sexual partners. Age, up to 32 years, was not an independent factor after accounting for partner numbers, and then only for women. Behavior is more important than age when considering prevention strategies.

Sero-epidemiological assessment of Chlamydia trachomatis infection and sub-fertility in Samoan women.

BACKGROUND: In our recent village-based cross-sectional study, the prevalence of nucleic acid amplification technique (NAAT) diagnosed Chlamydia trachomatis (CT) in sexually active Samoan women was very high (36 %), and test positivity was associated with sub-fertility. We conducted a serological and epidemiological analysis in these participants to identify if serological data can provide further insight into the potential contribution of CT to sub-fertility in this population. METHODS: Serological prediction of CT associated sub-fertility was conducted using a series of commercial tests. The correlation between fertility or sub-fertility, behavioral factors, and serologically predicted CT associated sub-fertility was determined. RESULTS: A positive antibody reaction against the Chlamydia Major Outer Membrane Protein (MOMP) was significantly associated with sub-fertility, with 50 % of infertile women being positive. Serum IgG and IgA antibodies against MOMP correlated with current infection measured by urine NAAT, suggesting longer term infections are common in this population. Chlamydia pneumoniae antibodies were frequently detected in this population (84 %), and unexpectedly, were significantly associated with sub-fertility. CONCLUSIONS: The high prevalence of chlamydial infection and of positive chlamydial sub-fertility results suggests that CT is an important and frequent contributory factor to sub-fertility in this population.

Syphilis surveillance and epidemiology in the United Kingdom.

The aim of this article is to describe trends in infectious syphilis in the UK, and specifically the epidemiology of the London syphilis outbreak, the largest in the UK to date. Analysis of routine surveillance data from genitourinary medicine (GUM) clinics was performed as well as data collection through enhanced surveillance systems. There have been substantial increases in diagnoses of infectious syphilis between 1998 and 2003, with a 25-fold increase seen in men who have sex with men (MSM) (from 43 to 1028 diagnoses); 6-fold (138 to 860) in heterosexual men and 3-fold (112 to 338) in women. The national rise in syphilis was driven by a series of local outbreaks, the first of which occurred in 1997. To date, 1910 cases have been reported in the London outbreak, first detected in April 2001. High rates of HIV co-infection were seen among MSM, with MSM likely to be of white ethnicity and born in the UK. In contrast, heterosexuals were more likely to be of black ethnicity and born outside the UK. Most syphilis infections were acquired in London. MSM bear the brunt of the national resurgence in infectious syphilis. Substantial rises in male heterosexual cases has resulted in a divergence between male heterosexual and female cases, which now requires further investigation.

Syphilis surveillance and epidemiology in the United Kingdom.

The aim of this article is to describe trends in infectious syphilis in the UK, and specifically the epidemiology of the London syphilis outbreak, the largest in the UK to date. Analysis of routine surveillance data from genitourinary medicine (GUM) clinics was performed as well as data collection through enhanced surveillance systems. There have been substantial increases in diagnoses of infectious syphilis between 1998 and 2003, with a 25-fold increase seen in men who have sex with men (MSM) (from 43 to 1028 diagnoses); 6-fold (138 to 860) in heterosexual men and 3-fold (112 to 338) in women. The national rise in syphilis was driven by a series of local outbreaks, the first of which occurred in 1997. To date, 1910 cases have been reported in the London outbreak, first detected in April 2001. High rates of HIV co-infection were seen among MSM, with MSM likely to be of white ethnicity and born in the UK. In contrast, heterosexuals were more likely to be of black ethnicity and born outside the UK. Most syphilis infections were acquired in London. MSM bear the brunt of the national resurgence in infectious syphilis. Substantial rises in male heterosexual cases has resulted in a divergence between male heterosexual and female cases, which now requires further investigation.

Monitoring the effectiveness of HIV and STI prevention initiatives in England, Wales, and Northern Ireland: where are we now?

Primary and secondary prevention are essential components of the response to HIV and sexually transmitted infections (STIs). We present findings from nationally implemented HIV/STI prevention interventions. In 2003, of those attending STI clinics at least 64% of men who have sex with men (MSM) and 55% of heterosexuals accepted a confidential HIV test; 88% of all HIV infections in women giving birth in England were diagnosed before delivery; 85% of MSM eligible for hepatitis B vaccination received a first dose of vaccine at their first STI clinic attendance; 74% of STI clinic attendees for emergency appointments, and 20% of those for routine appointments were seen within 48 hours of initiating an appointment; the National Chlamydia Screening Programme in England found a positivity of 10% and 13% among young asymptomatic women and men, respectively. Prevention initiatives have seen recent successes in limiting further HIV/STI transmission. However, more work is required if current levels of transmission are to be reduced.

Surveillance of antenatal infections--HIV, hepatitis B, syphilis and rubella susceptibility in London.

London has relatively high rates of HIV, hepatitis B and syphilis, and has the potential for undiagnosed infection in pregnancy. As part of a drive to improve HIV testing in pregnancy, surveillance of a number of antenatal infections has been carried out in London's 30 maternity units since 2000. Infection screening rates rose from 89% in 2000 to 94% in 2002, and HIV screening rates increased from 66% to 86%. During 2002, 115,230 women booked for antenatal care; 998 were HBsAg positive (about ten in 1000), 452 were HIV positive (five in 1,000), 412 tested positive for syphilis (four in 1000), and 3,929 were susceptible to rubella (36 in 1000). The main burden of infection was concentrated in a few geographic areas. Worryingly the majority of women found to be HIV positive were diagnosed by antenatal screening and not before.