Perspectives of obstetricians and midwives on the provision of immediate postpartum intrauterine devices: a qualitative service evaluation.

BACKGROUND: Immediate postpartum intrauterine device (PPIUD) insertion is safe and effective but largely unavailable in Europe. Data on maternity staff views on the provision and implementation of PPIUD services are limited. The objective of this qualitative evaluation was to explore the views and experiences of obstetricians and midwives providing PPIUD within a UK maternity setting, in order to identify areas for improvement and inform service provision in other areas. METHODS: Qualitative health services research within two public maternity hospitals in Lothian (Edinburgh and surrounding region), UK. Interviews with 30 maternity staff (obstetricians n=8; midwives n=22) involved in PPIUD provision. Data were analysed thematically. RESULTS: Maternity staff were positive about the benefits of PPIUD for women. Midwives reported initial concerns about PPIUD safety, and the impact on workload; these views shifted following training, and as PPIUD was embedded into practice. Having a large pool of PPIUD-trained staff was identified as an important factor in successful service implementation. Having PPIUD 'champions' was important to address staff concerns, encourage training uptake, and advocate for the service to ensure continued resourcing. CONCLUSIONS: PPIUD in maternity services can help address unmet need for effective contraception in the immediate postpartum period. We emphasise the importance of widespread engagement around PPIUD among all healthcare professionals involved in the care of women, to ensure staff are informed and supported. Clinical champions and leaders play a key role in amplifying the benefits of PPIUD, and advancing organisational learning.

Women's experiences of accessing postpartum intrauterine contraception in a public maternity setting: a qualitative service evaluation.

OBJECTIVES: The aims of the study were to explore women's experiences of an immediate postpartum intrauterine contraception (PPIUC) service recently introduced in a UK maternity setting, to identify areas for improvement and inform service provision. METHODS: Qualitative research was carried out in hospital and community maternity services in Lothian, UK. In-depth interviews were conducted with 35 women who had received PPIUC at vaginal or caesarean delivery. The interview data were analysed thematically to explore the women's experiences of PPIUC service provision. RESULTS: Women's decisions to choose PPIUC were influenced by their perception of intrauterine contraception (IUC) as a suitable and effective method and the convenience of immediate postpartum insertion. Most women were satisfied with their experience of PPIUC. Women delivering vaginally sometimes reported concerns about delays to insertion, particularly where they perceived a lack of communication from staff about when and where insertion would occur. PPIUC information was described as being difficult to absorb in the context of ante/postnatal information overload. Those receiving PPIUC at caesarean delivery sometimes expressed concerns about what post-insertion support might be available in primary care. CONCLUSION: Women typically reported satisfaction with their decision to have PPIUC. For maternity services considering introducing PPIUC, our findings reinforce the importance of anticipating and addressing implementation challenges in order to enhance women's experience of the service. These include ensuring that: clear and appropriate PPIUC information and support are provided antenatally; women are able to access PPIUC immediately after delivery; robust clinical pathways are in place to support post-insertion IUC care; and both staff and women are familiar with the clinical pathways.

Provision of immediate postpartum intrauterine contraception after vaginal birth within a public maternity setting: Health services research evaluation.

INTRODUCTION: Expanding access to postpartum intrauterine contraception (PPIUC) can reduce unintended pregnancies and short inter-pregnancy intervals; however, provision across Europe is limited. Our aim was to determine the feasibility, clinical outcomes and patient satisfaction of providing immediate PPIUC after vaginal birth using a health services research model. MATERIAL AND METHODS: Phased introduction of PPIUC across two Lothian maternity hospitals; all women intending vaginal birth during the study period without a contraindication to use of the method were eligible to receive PPIUC. Midwives and obstetric doctors were trained in vaginal PPIUC insertion using Kelly forceps. Women received information antenatally and had PPIUC insertion of either a levonorgestrel intrauterine system or a copper intrauterine device within 48 hours of vaginal birth. Follow-up was conducted in-person at 6 weeks postpartum and by telephone at 3, 6 and 12 months. Primary outcomes were: uptake, complications (infection, uterine perforation), expulsion and patient satisfaction at 6 weeks; and method of continuation up to 12 months. Secondary outcomes included hazard ratio for expulsion adjusted for demographic and insertion-related variables. RESULTS: Uptake of PPIUC was 4.6% of all vaginal births; 465/447 (96.1%) of those requesting PPIUC successfully received it and most chose a levonorgestrel intrauterine system (73%). At 6 weeks postpartum, the infection rate was 0.8%, there were no perforations and 98.3% of women said they would recommend the service. The complete expulsion rate was 29.8% (n = 113) and most had symptoms (n = 79). Of the additional 121 devices removed, 118 were because of partial expulsion. The rate of complete/partial expulsion was higher for insertions by midwives compared with those by doctors. The re-insertion rate after expulsion/removal was 87.6% and method continuation at 12 months was 79.6%. CONCLUSIONS: Routine PPIUC at vaginal birth is feasible. Complications were extremely rare. High expulsion rates may be observed in early stages of service introduction and with inexperienced providers. Re-insertion and therefore longer-term continuation rates of intrauterine contraception were very high. In settings with low rates of attendance for interval postpartum intrauterine contraception insertion, PPIUC could be a useful intervention to prevent unintended and closely spaced pregnancies.

GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript.

During human fetal ovary development, the process of primordial follicle formation is immediately preceded by a highly dynamic period of germ cell and somatic cell reorganisation. This is regulated by germ-cell specific transcription regulators, by the conserved RNA binding proteins DAZL and BOLL and by secreted growth factors of the TGFß family, including activin ßA: these all show changing patterns of expression preceding follicle formation. In mice, the transcription factor Nobox is essential for follicle formation and oocyte survival, and NOBOX regulates the expression of GDF9 in humans. We have therefore characterised the expression of GDF9 in relation to these known key factors during follicle formation in the human fetal ovary. mRNA levels of GDF9, BMP15 and NOBOX were quantified by qRT-PCR and showed dramatic increases across gestation. GDF9 protein expression was localised by immunohistochemistry to the same population of germ cells as those expressing activin ßA prior to follicle formation but did not co-localise with either BOLL or DAZL. A novel NOBOX isoform was identified in fetal ovary that was shown to be capable of up-regulating the GDF9 promoter in reporter assays. Thus, during oogenesis in humans, oocytes go through a dynamic and very sharply demarcated sequence of changes in expression of these various proteins, even within individual germ cell nests, likely to be of major functional significance in determining selective germ cell survival at this key stage in ovarian development. Transcriptional variation may contribute to the range of age of onset of POI in women with NOBOX mutations.

Activation of the aryl hydrocarbon receptor by a component of cigarette smoke reduces germ cell proliferation in the human fetal ovary.

Fetal life is a critical time for female fertility, when germ cells complete proliferation, initiate meiosis and ultimately form the lifetime stock of primordial follicles. Female fertility may be reduced by in utero exposure to cigarette smoke, which contains ligands for the aryl hydrocarbon receptor (AhR). The AhR is a critical regulator of ovarian germ cell survival in mice; thus activation of this receptor in the ovaries of fetuses exposed to maternal cigarette smoke in utero may provide a mechanism by which female fertility is reduced in later life. We have therefore investigated AhR expression in the human fetal ovary, and examined the effects of an AhR ligand present in cigarette smoke, on germ cells in human fetal ovaries cultured in vitro. The results showed that AHR mRNA expression increased 2-fold between first and late second trimester (P = 0.008). AhR protein was confined to germ cells at all gestations, but varied from expression in most germ cells during the first trimester, to only patchy expression by clusters of germ cells at later gestations. Culture of human fetal ovaries with the AhR ligand 9,10-dimethyl-1,2-benzanthracene-3,4-dihydrodiol (DMBA-DHD; a component of cigarette smoke) did not affect germ cell number in vitro, but significantly reduced the proportion of proliferating germ cells by 29% (as assessed by phospho-histone H3 staining (P = 0.04)). Germ cell apoptosis was not significantly affected. These results reveal that germ cells in the human fetal ovary express AhR from the proliferative stage of development through entry into meiosis and beyond, and demonstrate that AhR ligands found in cigarette smoke have the capacity to impair human fetal ovarian germ cell proliferation.

N- and E-cadherin expression in human ovarian and urogenital duct development.

OBJECTIVE: To investigate expression of N- and E-cadherin in the developing human ovary. DESIGN: The expression of N- and E-cadherin was analyzed in 18 human fetal ovaries between 8 and 20 weeks' gestation using immunohistochemistry. Fetal human male and rat urogenital tracts were used for comparison of expression. SETTING: Academic research institute. PATIENT(S): Women undergoing termination of pregnancy. INTERVENTION(S): Immunofluorescent analysis of cadherin expression. RESULT(S): In fetal ovary, N- and E-cadherins were expressed at all gestations with overlapping but not identical patterns. Expression was associated with germ cells and adjacent somatic cells, including within newly formed primordial follicles, but neither cadherin was expressed in the somatic cell cords. The epithelia of the müllerian and wolffian ducts expressed only N- and E-cadherin, respectively, in a mutually exclusive fashion. This pattern of cadherin expression was found to be conserved between human and rat fetuses of both genders. CONCLUSION(S): The demonstration of N- and E-cadherin expression in the human fetal ovary indicates likely roles in gonadal development from germ cell proliferation to primordial follicle formation, as well as in the development of the urogenital ducts of both genders. This is consistent with animal studies identifying cadherins as key regulators of early germ cell development.

Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression.

Ovarian germ cell survival is dependent upon the formation of primordial follicles, which occurs during fetal life in the human. Activin contributes to germ cell proliferation and survival at this time. SMADs2 and 3 are central elements in the activin signalling pathway and thus indicate sites of activin action. We have investigated the expression and localisation of SMADs2 and 3 in the fetal ovary between 14 and 20 weeks gestation, i.e. preceding and during primordial follicle formation. SMAD3 mRNA expression increased 1.9 fold (P=0.02). SMAD2 and 3 proteins were localised by immunofluorescence to the nuclei of three distinct populations of somatic cells: (a) stromal cells between clusters of germ cells; (b) some somatic cells intermingled with activin beta A-expressing germ cells; (c) pre-granulosa cells surrounding primordial follicles. Germ cells did not express SMAD2 or 3. Activin A increased and follistatin decreased phosphorylation of SMAD2/3 in vitro, and activin increased SMAD2 and decreased KITLG mRNA expression. It therefore appears that somatic cells are the targets for activin signalling in the developing ovary. The effects of activin on germ cells are indirect and include mediation by the kit ligand/c-Kit pathway, rather than being an autocrine germ cell effect.

Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human.

BACKGROUND: Certain phthalates can impair Leydig cell distribution and steroidogenesis in the fetal rat in utero, but it is unknown whether similar effects might occur in the human. OBJECTIVES: Our aim in this study was to investigate the effects of di(n-butyl) phthalate (DBP), or its metabolite monobutyl phthalate (MBP), on testosterone production and Leydig cell aggregation (LCA) in fetal testis explants from the rat and human, and to compare the results with in vivo findings for DBP-exposed rats. We also wanted to determine if DBP/MBP affects testosterone production in vivo in the neonatal male marmoset. METHODS: Fetal testis explants obtained from the rat [gestation day (GD)19.5] and from the human (15-19 weeks of gestation) were cultured for 24-48 hr with or without human chorionic gonadotropin (hCG) or 22R-hydroxycholesterol (22R-OH), and with or without DBP/MBP. Pregnant rats and neonatal male marmosets were dosed with 500 mg/kg/day DBP or MBP. RESULTS: Exposure of rats in utero to DBP (500 mg/kg/day) for 48 hr before GD21.5 induced major suppression of intratesticular testosterone levels and cytochrome P450 side chain cleavage enzyme (P450scc) expression; this short-term treatment induced LCA, but was less marked than longer term (GD13.5-20.5) DBP treatment. In vitro, MBP (10(-3) M) did not affect basal or 22R-OH-stimulated testosterone production by fetal rat testis explants but slightly attenuated hCG-stimulated steroidogenesis; MBP induced minor LCA in vitro. None of these parameters were affected in human fetal testis explants cultured with 10(-3) M MBP for up to 48 hr. Because the in vivo effects of DBP/MBP were not reproduced in vitro in the rat, the absence of MBP effects in vitro on fetal human testes is inconclusive. In newborn (Day 2-7) marmosets, administration of a single dose of 500 mg/kg MBP significantly (p = 0.019) suppressed blood testosterone levels 5 hr later. Similar treatment of newborn co-twin male marmosets for 14 days resulted in increased Leydig cell volume per testis (p = 0.011), compared with co-twin controls; this is consistent with MBP-induced inhibition of steroidogenesis followed by compensatory Leydig cell hyperplasia/hypertrophy. CONCLUSIONS: These findings suggest that MBP/DBP suppresses steroidogenesis by fetal-type Leydig cells in primates as in rodents, but this cannot be studied in vitro.

Gonadotrope and thyrotrope development in the human and mouse anterior pituitary gland.

Genes and orthologous intrinsic and extrinsic factors critical for embryonic pituitary gonadotrope and thyrotrope cell differentiation have been identified mainly in rodents, but data on the human are very limited. In human fetal pituitaries examined between 14 and 19 weeks of gestation using immunofluorescent confocal microscopy, we found that most fetal gonadotropes expressed alpha-GSU, LHbeta, and FSHbeta gonadotropin subunits while almost no cells expressed alpha-GSU and LHbeta alone. Gonadotropes expressing alpha-GSU and FSHbeta only were detected in both male and female pituitaries, increasing in proportion to total gonadotropes in both males and females from 14 (approximately 4.5%) to 19 weeks (approximately 16.5%) with a peak in males of 45.5% compared with females of 16.5% at 17 weeks of gestation. When FSHbeta or LHbeta genes were expressed, gonadotropes were non-dividing. This profile of human fetal gonadotrope development differs from the current mouse model. Furthermore, while expression of alpha-GSU appears to be the lead protein in gonadotropes, in thyrotropes which ultimately express alpha-GSU with TSHbeta, we observed that most if not all thyrotropes were TSHbeta-positive but alpha-GSU-negative until around 19 weeks in human, and e15 in mouse, fetal pituitaries. Furthermore, the TSHbeta-only thyrotropes were dividing, and TSHbeta rather than alpha-GSU was the lead protein in thyrotrope development. Thus, while biologically active dimeric FSH and LH can be produced by the human fetal pituitary by 14 weeks, dimeric biologically active TSH will only be produced from around 17 weeks of gestation. The mechanism(s) responsible for the different molecular regulation of alpha-GSU gene expression in gonadotropes and thyrotropes in the developing human fetal pituitary now requires investigation.