Women's reflections on timing of motherhood: a meta-synthesis of qualitative evidence.

INTRODUCTION: Fertility declines with increasing age, especially in women. In recent decades women's age at the birth of their first child has risen markedly in many countries, and an increasing number of women do not establish a family until their late-twenties to mid-thirties. Although there can be various reasons that couples experience fertility problems, advanced maternal age is the most frequent cause for difficulties with achieving pregnancy. OBJECTIVE: In this meta-synthesis, we investigated reflections on timing of motherhood in women who have not yet had children. METHODS: A systematic literature search of six electronic databases and manual searches of reference lists identified eight qualitative studies published between 2011 and 2018 that focused on women's reflections on timing of motherhood. The studies were assessed with the Critical Assessment Skills Programme (CASP) quality appraisal tool. The results were synthesized using Noblit and Hare's meta-ethnographic approach as described by Malterud. FINDINGS: An overall theme of 'Timing of motherhood' and four overlapping subthemes were identified: Making a life-changing decision, The right time, Fear of regret, and Plan B. The dilemmas associated with timing of motherhood leave women of reproductive age balancing their priorities and values against a biological deadline for having children naturally or through assisted reproductive technology. CONCLUSIONS: Women of reproductive age are aware that they must make a life-changing decision as to if or when to have children, but they consider having children at 'the right time' to be important. Simultaneously, while some women are reluctant to have children for various reasons, they express fear that waiting too long could result in their regretting not having children later in life. Although women of reproductive age express concern about their ability to achieve pregnancy, they have limited focus on the medical risks associated with postponing motherhood. There is a need to establish preventive health initiatives to support women of reproductive age in their considerations regarding timing of motherhood. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42020175151.

In many countries, women's age at the birth of their first child has risen markedly, and an increasing number of women do not establish a family until their late-twenties to mid-thirties. This causes risk of couples experiencing fertility problems, as fertility declines with increasing age. Although fertility problems can be caused by various reasons, advanced maternal age is the most frequent cause for women having difficulties achieving pregnancy. In this study, we investigated reflections on timing of motherhood in women who have not yet had children. Through a systematic literature search we identified eight qualitative studies published between 2011 and 2018 that focused on women's reflections on timing of motherhood. The included studies were synthesized using a meta-ethnographic approach. We identified an overall theme 'Timing of motherhood' and four overlapping subthemes: Making a life-changing decision, The right time, Fear of regret, and Plan B. The dilemmas associated with timing of motherhood leave women of reproductive age balancing their priorities and values against a biological deadline for having children naturally or through assisted reproductive technology. Women of reproductive age are aware that they must make a life-changing decision as to if or when to have children, but they consider having children at 'the right time' to be important. Simultaneously, while some women are reluctant to have children for various reasons, they express fear that waiting too long could result in their regretting not having children later in life. Although women of reproductive age express concern about their ability to achieve pregnancy, they have limited focus on the medical risks associated with postponing motherhood, which emphasizes the need for establishing preventive health initiatives to support women of reproductive age in their considerations regarding timing of motherhood.

Probiotic treatment with specific lactobacilli does not improve an unfavorable vaginal microbiota prior to fertility treatment-A randomized, double-blinded, placebo-controlled trial.

Objective: To investigate whether treatment with proprietary lactobacilli-loaded vaginal capsules improves an unfavorable vaginal microbiome diagnosed using a commercially available test and algorithm. Design: A randomized, double-blinded, placebo-controlled study was conducted in 74 women prior to undergoing fertility treatment at a single university fertility clinic between April 2019 and February 2021. The women were randomly assigned in a 1:1 ratio to receive one vaginal capsule per day for 10 days containing either a culture of more than 108 CFU of Lactobacillus gasseri and more than 108 CFU Lactobacillus rhamnosus (lactobacilli group) or no active ingredient (placebo group). Vaginal swabs for microbiota analysis were taken at enrollment, after treatment and in the cycle following treatment. Participants and methods: Women aged 18-40 years who prior to fertility treatment were diagnosed with an unfavorable vaginal microbiota, characterized by either a low relative load of Lactobacillus or a high proportion of disrupting bacteria using the criteria of the IS-pro™ diagnostic system (ARTPred, Amsterdam, the Netherlands), were enrolled in the study. The primary outcome measure was the proportion of women with improvement of the vaginal microbiota after intervention. Results: The vaginal microbiota improved after intervention in 34.2% of all participants (lactobacilli group 28.9%, placebo group 40.0%), with no significant difference in the improvement rate between the lactobacilli and placebo groups, RR = 0.72 (95% CI 0.38-1.38). Conclusion: This study indicates that administering vaginal probiotics may not be an effective means of modulating the vaginal microbiome for clinical purposes in an infertile population. However, a spontaneous improvement rate of 34.2% over a period of one to three months, confirming the dynamic nature of the vaginal microbiota, indicates that a strategy of postponing further IVF treatment to await microbiota improvement may be relevant in some patients, but further research is needed. Clinical trial registration: ClinicalTrials.gov, identifier NCT03843112.

The importance of the 'family clock': women's lived experience of fertility decision-making 6 years after attending the Fertility Assessment and Counselling Clinic.

This study explored women's lived experience of making fertility decisions six years after attending the Fertility Assessment and Counselling (FAC) clinic in Copenhagen, Denmark, which is a personalised fertility awareness intervention. We conducted a qualitative interview study with 24 women who attended the FAC clinic 6 years earlier. Interviews were semi-structured and broadly examined the women's perceptions and experience of the intervention during follow-up. Data was analysed using a phenomenological framework and themes were identified related to women's experience of making fertility decisions after attending the FAC clinic. The overarching theme regarding the women's lived experience of making fertility decisions after attending the FAC clinic was: Fertility decisions were guided by the 'family clock'. There were four themes: (i) Deciding to 'get started' by attending the FAC clinic; (ii) Sense of making informed and empowered decisions; (iii) Influence of partner status on fertility decisions; and (iv) Decisions dictated by circumstance over preference and knowledge. At follow-up, the majority (21 women, 88%) had become parents. More than half of the women said that they had not achieved their desired family size. Consideration of women's 'family clock' is necessary in personalised fertility awareness interventions to enable women to achieve their family goals.

Assessing endometrial receptivity after recurrent implantation failure: a prospective controlled cohort study.

RESEARCH QUESTION: What is the prevalence of disrupted markers of endometrial function among women experiencing recurrent implantation failure (RIF), and does the prevalence differ from a control cohort? DESIGN: Prospective controlled cohort study. In total, 86 women with a history of RIF and 37 women starting their first fertility treatment were recruited for this study. Endometrial and blood profiling were carried out in a hormone-substituted cycle using oestradiol and progesterone. Endometrial biopsies were analysed by histology, immune cell profiling, and the endometrial receptivity array (ERA®) test (Igenomix, Valencia, Spain). The vaginal microbiome was analysed using a NGS-based technology (ArtPRED, Amsterdam, the Netherlands). Blood tests included oestradiol, progesterone, prolactin, thyroid-stimulating hormone, vitamin D and anti-phospholipid antibody levels. RESULTS: Patients who had experienced RIF produced a range of test abnormalities. Compared with controls, women with RIF had a higher prevalence of chronic endometritis (24% versus 6%), a lower vitamin D level and a borderline lower progesterone level. Women who had experienced RIF had a more favourable vaginal microbiome compared with controls. Although the RIF cohort was older than the controls (mean age 33.8 years versus 30.2 years), no differences between the groups were observed in immune cell profiling and the ERA test. CONCLUSION: These data demonstrate that a single test or treatment for the endometrial factor in RIF is unlikely to be clinically effective. Diagnosing the endometrium in women with RIF permits targeted rather than blind interventions. Relative vitamin D deficiency, lower mid-luteal progesterone and chronic endometritis are ready targets for treatment. Understanding the role and treatment of an unfavourable vaginal microbiome in RIF needs further investigation.

[Recommended therapy for psychosocial consequences of infertility and fertility treatment].

Infertility and fertility treatment are both major stressors, which can cause prolonged psychological distress and vulnerability as summarised in this review. There are well-founded initiatives such as screening, patient-centred care and, in a Nordic context, psychosocial interventions with training sessions in e.g. coping in order to improve the well-being of these patients. However, in Denmark, psychosocial care in public fertility clinics is limited, and no mental health professionals are represented at the public clinics. Consequently, a gap remains between the recommendations in this area and the clinical practice.

Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial.

INTRODUCTION: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome. METHODS AND ANALYSIS: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed. ETHICS AND DISSEMINATION: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated. TRIAL REGISTRATION NUMBER: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.

Concerns on future fertility among users and past-users of combined oral contraceptives: a questionnaire survey.

Objective: The combined oral contraceptive pill is the most preferred contraceptive method worldwide. Despite high life-time prevalence of infertility of 16-26%, scarce data about concerns of future fertility among COC users are available. We aimed to study whether COC usage induces concerns about fertility. Methods: Online questionnaire-based survey included 1283 current COC users and 1006 past users. The questionnaire covered knowledge and concerns of various aspects of fertility with respect to COC usage. Results: Significantly, more current users (66%) than past users (52%) had considered whether or not COC usage could affect future fertility (OR = 1.6, 95% CI 1.3-1.9). Nearly 50% of both groups believed COC usage could impair conception rates after discontinuation. Furthermore, 28% current vs. 19% past users believed COC could diminish the ovarian reserve more permanently. Conversely, 14% current and 11% past users believed that lack of ovulation could 'spare' the eggs (OR = 0.9, 95% CI 0.7-1.3). Significantly fewer current users (22%) vs. past users (35%) had heard, primarily by female friends, that a short break of 1-2 months during long-term COC usage was healthy, (OR 0.72, 95%CI = 0.56-0.92). Conclusions: Health care professionals prescribing hormonal contraception should be aware of misapprehensions and concerns of fertility among users of COC.

Investigation of anti-Müllerian hormone concentrations in relation to natural conception rate and time to pregnancy.

The objectives of this study were to investigate whether anti-Müllerian hormone (AMH) concentrations can predict pregnancy rates and time to pregnancy (TTP) in women attempting to conceive naturally/having an unplanned conception, and whether there is a lower AMH threshold compatible with natural conception. This prospective cohort study included 260 women aged 25-42 years in two subcohorts: (A) healthcare workers at Rigshospitalet (2008-2010), and (B) women consulting the Fertility Assessment and Counselling Clinic (2011-2014), Rigshospitalet, Denmark. Pregnancy rates and TTP at 2-year follow-up were stratified into AMH groups: low: < 9.5 pmol/l, intermediate: 9.5-33 pmol/l, high: > 33 pmol/l. Pregnancy rates increased with increasing AMH: 60.1% (low) versus 70.0% (intermediate) versus 78.3% (high) (P = 0.03). The highest pregnancy rate (84.1%) was seen in regular cycling women with high AMH. TTP was reduced in women with high AMH compared with intermediate or low AMH (stepwise trend test P = 0.01). Natural conceptions were observed with AMH concentrations down to 1.2 pmol/l. In conclusion, high AMH, especially in ovulatory women, was associated with higher pregnancy rates. Nonetheless, TTP reflected a large variation in fecundity within similar AMH concentrations and natural conceptions occurred with AMH down to 1.2 pmol/l.

[Fertility screening is a new concept].

The Fertility Assessment and Counselling Clinic was initiated in 2011 as an analogue to the family planning clinics in the 1970s, but with a pro-fertility aim. The idea was to provide individual assessment of fertility risk factors, ovarian reserve and sperm concentration to help women and men to fulfil their reproductive life plan. Fertility screening on an individual level is a new concept, and the Fertility Assessment and Counselling Clinic is the first of its kind. The aim of the clinic is to reduce the need for fertility treatments and to prevent involuntary childlessness.

Individual fertility assessment and counselling in women of reproductive age.

The overall aim of this thesis was to validate the new concept of the Fertility Assessment and Counselling (FAC) Clinic at Rigshospitalet. The intention was to: explore the prognostic value of fertility risk factors by a risk score and provide an estimate of female fecundity, to quantify the impact of oral contraception (OC) on ovarian reserve parameters defined as Anti Müllerian Hormone (AMH), Antral Follicle Count (AFC) and ovarian volume, and to gain knowledge of attitudes and considerations toward family formation in women of advanced age. The thesis is based on the following four manuscripts:   Manuscript I describes the predictive value of individual fertility assessment and counselling in terms of subsequent time to pregnancy within two years after the initial consultation at the FAC Clinic. The follow up study comprised 519 women, of which 352 had tried to conceive. At the time of follow-up, 259/352 had achieved a pregnancy, 74/352 were still trying and 19/352 had given up. The remaining 167 women had no attempts to conceive. The risk assessment provided a score based on the appearance of fertility risk factors: green (low), yellow (low), orange (medium) and red (high). Two-thirds of the women with only low risk scores conceived spontaneously within 12 months (65%), while this figure was only 32% for women with at least one high risk score (n=82). Accordingly, presence of at least one high risk score reduced the odds of achieving a pregnancy within 12 months by 73% (OR 0.27, 95%CI 0.13-0.57). The FAC Clinic concept seems as a usable tool for fertility experts to guide women on how to fulfil their reproductive life-plan, but longer follow-up studies are needed. Manuscript II describes the impact of OC on ovarian reserve parameters in 887 women at the FAC Clinic. Of the 887 women, 244 (27.5%) used OC.  The 244 users of OC were significantly younger than non-users with a mean age of 31.5 (SD 4.3) vs. 34.1 (SD 4.3) years (p < 0.001). Overall, there was no difference between the two groups in relation to bodyweight, BMI, smoking habits, gestational age at birth, prenatal exposure to maternal smoking or maternal age at menopause. In linear regression analyses adjusted for age, ovarian volume was 50% lower, AMH was 19% lower, and AFC was 18% lower in OC-users compared to non-users. Among the OC users there was a significant decrease in antral follicles sized 5-7 and 8-10 mm and an increase in the number of small follicles sized 2-4 mm. Physicians have to be aware of the impact of OC use on ovarian reserve parameters and possible concealment of premature ovarian insufficiency, when assessing the fertility status and estimating the reproductive lifespan in OC users. Manuscript III describes the family intentions and personal considerations on postponing childbearing in 340 childless women of advanced age. The study comprised 140 cohabiting and 200 single women aged 35-43 seeking fertility assessment and counselling at the FAC Clinic. The majority (82%) was well-educated and in employment. Despite their mean age of 37.4 years, the main reasons for attending the FAC Clinic were to gain knowledge on the possibility of postponing pregnancy (63%) and due to a concern about their fecundity (52%). Both the cohabiting and single women expressed a wish for two or more children (60%). The most important benefits were "personal development" (89%) and "to give and receive love" (86%). The main concerns about childbearing were "less time to myself" (82%) and "less time to job and career" (76%). The single women were more positive regarding the use of donor sperm (70%) compared to the cohabiting women (25%). Our results indicated a general overestimation of the women´s own reproductive capacity and an underestimation of their risk of future infertility and childlessness with continuous postponement of pregnancies. Manuscript IV describes attitudes toward family formation in ten single and ten cohabiting childless women of advanced age. The women were interviewed one week before their consultation at the FAC Clinic about their family formation intentions, considerations and concerns. The interviews were analysed and condensed into four categories: ''The biological clock'', ''The difficult choice'', ''The dream of the nuclear family'', and ''Mother without a father''. The categories were condensed into two subthemes; `Fear´ and `Expectations´ and gathered into one main theme 'The conflict of choosing', which reflected the women's attitudes toward family formation prior to individual fertility counselling. The women attended the FAC Clinic due to a concern about their fecundity and a fear for infertility. Overall, the women expressed a dream of the nuclear family and finding "Mr. Right" and many with the wish of buying more time. Both groups would consider solo motherhood due to their advanced age, although it was considered to be Plan B, as it was not "natural".

Individual fertility assessment and pro-fertility counselling; should this be offered to women and men of reproductive age?

During the 1970s new contraceptive options developed and legal abortions became accessible. Family planning clinics targeting young women and men provided advice and assistance on contraception. Today, delayed childbearing, low total fertility rates and increasing use of social oocyte freezing create a need for pro-fertility initiatives. Three years ago we established a new separate unit: The Fertility Assessment and Counselling (FAC) clinic. The FAC clinic offers free individual counselling based on a clinical assessment including measurement of serum anti-Müllerian hormone and ovarian and pelvic sonography in women, sperm analysis in men, and a review of reproductive risk factors in both sexes. The FAC clinic includes a research programme with the goal to improve prediction and protection of fertility. Our first proposition is that clinics for individual assessment and counselling need to be established, as there is a strong unmet demand among women and men to obtain: (i) knowledge of fertility status, (ii) knowledge of reproductive lifespan (women) and (iii) pro-fertility advice. Addressing these issues is often more challenging than treating infertile patients. Therefore, we propose that fertility assessment and counselling should be developed by specialists in reproductive medicine. There are two main areas of concern: As our current knowledge on reproductive risk factors is primarily based on data from infertile patients, the first concern is how precisely we are able to forecast future reproductive problems. Predictive parameters from infertile couples, such as duration of infertility, are not applicable, diagnostic factors like tubal patency are unavailable and other parameters may be unsuitable when applied to the general population. Therefore, strict validation of reproductive forecasting in women and men from the general population is crucial. The second main concern is that we may turn clients into patients. Screening including reproductive forecasting may induce unnecessary anxiety through false positive predictions and may even result in overtreatment in contrast to the intended preventive concept. False negative findings may create false reassurance and result in postponement of conceptions.

Increasing prevalence of group B streptococcal infection among pregnant women.

INTRODUCTION: Group B streptococci (GBS) can cause preterm delivery for women and sepsis and meningitis in infants younger than 90 days of age. The present retrospective cohort study determines the trend over time in the rates of GBS and in demographic risk factors for GBS among pregnant women delivering at Rigshospitalet (RH). MATERIAL AND METHODS: In the period from 2002 to 2010, a total of 33,616 women gave birth at the RH. Our cohort was defined as 16,587 (49%) women examined by 24,724 cultures. All microbiological requisitions from the Department of Obstetrics at RH were extracted from the Clinical Microbiology Database. Maternal data were obtained from a local database at the RH. RESULTS: In our cohort, a total of 638 (3.8%) women were diagnosed with GBS, 517 (81%) from urine, 92 (14%) from vaginal swabs and 29 (5%) from both. The overall rate of women colonised with GBS rose from 3.3% in 2002 to 5.1% in 2010 (p < 0.0001). A total of 48 infants had early-onset group B streptococcus (EOGBS), 1.4 per 1,000 neonates in the general population and 7.8 per 1,000 among women with GBS (p < 0.0001). CONCLUSION: We found a low GBS colonisation rate in our pregnant cohort, but the rate followed an increasing trend over the study period. GBS during pregnancy was associated with a low birth weight and preterm delivery. More research on preventive measures is needed, but updated guidelines, screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of EOGBS disease prevention. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[Pneumomediastinum and subcutaneous emphysema complicating active labour]. / Pneumomediastinum og subkutant emfysem som komplikation i forbindelse med fødsel.

Subcutaneous emphysema and pneumomediastinum were first described by Hamman in 1945. Spontaneous pneumomediastinum is an uncommon, self-limiting condition caused by alveolar rupture and usually results from bronchial hyper-reactivity or barotraumas. We report a case describing a 25 year old patient in her first pregnancy, who during active labour developed subcutaneous emphysema and pneumomediastinum. Pneumomediastinum in labour is a rare complication to Valsalva maneuver, and it is diagnosed with a computed tomography. The most common symptoms are chest pain, dyspnea, neck pain and odynophagia.

[Treatment of placenta percreta requires a multidisciplinary approach]. / Behandling af placenta percreta kræver involvering af flere specialer.

Placenta percreta is a rare life-threatening obstetrical condition, often resulting in severe haemorrhage and hysterectomy. The incidence seems to be increasing, probably secondary to the increase in caesarean section rates. We present a protocol for an elective multidisciplinary approach with proactive management to reduce haemorrhage and allow appropriate surgery, which imply a low maternal and fetal morbidity as well as maintained fertility.

[Pregnancy within the uterine scar of a prior Caesarean section]. / Graviditet i uteruscikatricen efter tidligere sectio.

Rarely, but with increasing frequency, we detect pregnancies within the uterine scar of a prior Caesarean section. These ectopic pregnancies entail a risk of severe bleeding and uterine rupture, and thus constitute a threat to the pregnant woman's life, underlining the necessity of awareness about these complications. Vaginal bleeding and/or mild to moderate lower abdominal pain are symptoms seen in half of the women. The diagnosis is made by sonography and criteria for these are listed. We here present the most recent studies on treatment strategies, follow-up and future fertility.