[Show abstract][Hide abstract] ABSTRACT: Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.
In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.
In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).
Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.
BMC Medicine 12/2015; 13(1):18. DOI:10.1186/s12916-014-0251-x · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One in 5 pregnant women is obese but the impact on later health is unknown. We aimed to determine whether maternal obesity during pregnancy associates with increased premature mortality and later life major cardiovascular events. Maternity records of women who gave birth to their first child between 1950 and 1976 (n=18 873) from the Aberdeen Maternity and Neonatal databank were linked to the National Register of Deaths, Scotland and Scottish Morbidity Record. The effect of maternal obesity at first antenatal visit on death and hospital admissions for cardiovascular events was tested using time-to-event analysis with Cox proportional hazard regression to compare outcomes of mothers in underweight, overweight, or obese body mass index (BMI) categories compared with normal BMI. Median follow-up was at 73 years. All-cause mortality was increased in women who were obese during pregnancy (BMI>30 kg/m(2)) versus normal BMI after adjustment for socioeconomic status, smoking, gestation at BMI measurement, preeclampsia, and low birth weight (hazard ratio, 1.35; 95% confidence interval, 1.02-1.77). In adjusted models, overweight and obese mothers had increased risk of hospital admission for a cardiovascular event (1.16; 1.06-1.27 and 1.26; 1.01-1.57) compared with normal BMI mothers. Adjustment for parity largely unchanged the hazard ratios (mortality: 1.43, 1.09-1.88; cardiovascular events overweight: 1.17, 1.07-1.29; and obese: 1.30, 1.04-1.62). In conclusion, maternal obesity is associated with increased risk of premature death and cardiovascular disease. Pregnancy and early postpartum could represent an opportunity for interventions to identify obesity and reduce its adverse consequences.
[Show abstract][Hide abstract] ABSTRACT: The United Kingdom (UK) caesarean section (CS) rate is largely determined by reluctance to augment trial of labour and vaginal birth. Choice between repeat CS and attempting vaginal birth after CS (VBAC) in the next pregnancy is challenging, with neither offering clear safety advantages. Women may access online information during the decision-making process. Such information is known to vary in its support for either mode of birth when assessed quantitatively. Therefore, we sought to explore qualitatively, the content and presentation of web-based health care information on birth after caesarean section (CS) in order to identify the dominant messages being conveyed.
The search engine Google™ was used to conduct an internet search using terms relating to birth after CS. The ten most frequently returned websites meeting relevant purposive sampling criteria were analysed. Sampling criteria were based upon funding source, authorship and intended audience. Images and written textual content together with presence of links to additional media or external web content were analysed using descriptive and thematic analyses respectively.
Ten websites were analysed: five funded by Government bodies or professional membership; one via charitable donations, and four funded commercially. All sites compared the advantages and disadvantages of both repeat CS and VBAC. Commercially funded websites favoured a question and answer format alongside images, 'pop-ups', social media forum links and hyperlinks to third-party sites. The relationship between the parent sites and those being linked to may not be readily apparent to users, risking perception of endorsement of either VBAC or repeat CS whether intended or otherwise. Websites affiliated with Government or health services presented referenced clinical information in a factual manner with podcasts of real life experiences. Many imply greater support for VBAC than repeat CS although this was predominantly conveyed through subtle use of words rather than overt messages, with the exception of the latter being apparent in one site.
Websites providing information on birth after CS appear to vary in nature of content according to their funding source. The most user-friendly, balanced and informative websites appear to be those funded by government agencies.
[Show abstract][Hide abstract] ABSTRACT: Numerous tests and interventions have been proposed for optimizing performance in preparation for in vitro fertilization (IVF) treatment. We critically appraised the available evidence underpinning some of the popular investigations and treatments, including the role of hysteroscopy, laparoscopy, ovarian reserve tests, sperm function tests, as well as the role of lifestyle modifications or surgery for endometriosis, fibroids, and endometrial polyps. We also reviewed the evidence behind novel techniques, such as the use of endometrial injury before IVF. Only a few of the aforementioned modalities are justified based on the available research evidence. Other factors may affect the uptake of a test or intervention before IVF, namely the complexity of the proposed modality, its potential for harm, and its cost-effectiveness.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Seminars in Reproductive Medicine 03/2015; 33(2):65-76. DOI:10.1055/s-0035-1545364 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Repeat caesarean sections make a substantial contribution to the overall caesarean section rate. It is important to understand what influences women to choose this option when the alternative of attempting vaginal birth after caesarean section is available. As many such women use the internet while seeking information on their options, the aim of this study was to assess content of websites on birth after previous caesarean and identify website characteristics which predict content.
An internet survey of the forty eight most frequently encountered websites retrieved from a search using various terms relating to birth after caesarean section via a popular search engine was performed. Websites were assessed for their content supportive of either vaginal birth after caesarean (VBAC) or elective repeat caesarean section (ERCS), using the RCOG patient information document, ‘Birth after previous caesarean; Information for You’ as a ‘gold standard’. A simple scoring method which categorised information into either supportive of VBAC (14 facts available) or ERCS (10 facts available) was employed and mean scores compared. Poisson regression analysis was used to assess the extent to which the score was predicted by website funding source, country of origin, author status and intended audience.
A mean of 42.4% (SD 23.8) of facts supportive of VBAC and 44.8% (SD 25.0) of facts supportive of ERCS were featured across the 48 websites, with corresponding scores in the five most frequently encountered websites being 40.0% (SD 13.9) and 66.0% (SD 20.7). Extent of featured information supportive of ERCS was related to country of origin with the UK having higher scores on average than the US.
Women searching for internet information on birth after previous caesarean are exposed to incomplete information. Origin of website has a significant effect on website content.
[Show abstract][Hide abstract] ABSTRACT: Background
Researchers are being urged to involve patients in the design and conduct of studies in health care with limited insight at present into their needs, abilities or interests. This is particularly true in the field of reproductive health care where many conditions such as pregnancy, menopause and fertility problems involve women who are otherwise healthy.Objective
To ascertain the feasibility of involving patients and members of the public in research on women's reproductive health care (WRH).SettingUniversity and tertiary care hospital in north-east Scotland; 37 women aged 18–57.Method
Four focus groups and one individual interview were audio-recorded and verbatim transcripts analysed thematically by two researchers using a grounded theory approach.Results and discussionMost participants were interested in WRH, but some participated to promote a health issue of special concern to them. Priorities for research reflected women's personal concerns: endometriosis, polycystic ovary syndrome, menopause, fertility risks of delaying parenthood and early post-natal discharge from hospital. Women were initially enthusiastic about getting involved in research on WRH at the design or delivery stage, but after discussion in focus groups, some questioned their ability to do so or the time available to commit to research. None of the respondents expected payment for any involvement, believing that the experience would be rewarding enough in itself.Conclusions
Involving patients and public in research would include different perspectives and priorities; however, recruiting for this purpose would be challenging.
Health expectations: an international journal of public participation in health care and health policy 09/2014; DOI:10.1111/hex.12233 · 3.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels to ensure safe practice by reducing the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the good ovarian response needed for assisted reproduction treatment. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered.
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION What is the impact of different age and BMI groups on total investigation and treatment costs in women attending a secondary/tertiary
care fertility clinic?
Human Reproduction 07/2014; 29(10). DOI:10.1093/humrep/deu184 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND Increasing numbers of children are being conceived by assisted reproductive technology (ART). A number of studies have highlighted
an altered epigenetic status in gametes from infertile couples and the possibility of an increased risk of imprinting defects
and somatic epigenetic changes in ART conceived children, but the results have been heterogeneous. We performed a systematic
review of existing studies to compare the incidence of imprinting disorders and levels of DNA methylation in key imprinted
genes in children conceived through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with those in children conceived spontaneously.
Human Reproduction Update 06/2014; 20(6). DOI:10.1093/humupd/dmu033 · 10.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One in five women in the United Kingdom is obese at antenatal booking. We aimed to determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in later life.
[Show abstract][Hide abstract] ABSTRACT: Is DNA methylation in buccal cell DNA from children born following IVF (in vitro fertilization) and ICSI (intra-cytoplasmic sperm injection) different from that of spontaneously conceived children?
DNA methylation in the imprinted gene, small nuclear ribonucleoprotein polypeptide N (SNRPN), was higher in children conceived by ICSI and in those born to women with the longest duration of infertility regardless of the method of conception.
Fertility treatment is associated with a small but significant increase in the risk of a range of adverse obstetric outcomes, birth defects and longer term sequelae, but the biological basis for this is unknown. A growing evidence base suggests that epigenetics may play a role in subfertility and the link between fertility and health.
In this retrospective cohort study of children born between 2002 and 2008, we measured DNA methylation in paternally expressed gene 3 (PEG3), insulin-like growth factor II (IGF2), SNRPN, long interspersed nuclear element 1 (LINE1) and the insulin gene (INS) in buccal cell DNA from children born following IVF (n = 49) and ICSI (n = 20) and compared them with a matched spontaneous conception group (n = 86).
Participants were identified from the Aberdeen Maternity and Neonatal Databank and IVF and ICSI pregnancies were matched to spontaneous conception pregnancies on year of birth and maternal age at delivery. Only singleton pregnancies following fresh embryo transfer were included. DNA methylation was determined by pyrosequencing. Regression with adjustment for covariates was used to determine the effect of infertility on offspring DNA methylation.
SNRPN methylation in the offspring was linked to fertility treatment in the parents. This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (1.03%; 95% CI 0.10, 1.97; P = 0.031), ICSI versus standard IVF (1.13%; 95% CI 0.04, 2.23; P = 0.043) and ICSI versus standard IVF and spontaneous conception (1.05; 95% CI 0.15, 1.94; P = 0.023). In all comparisons, the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (0.18% per year of infertility; 95% CI 0.02, 0.33; P = 0.026) and after excluding ICSI cases (0.21% per year of infertility; 95% CI 0.04, 0.37; P = 0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (0.77% per year; 95% CI 0.49, 1.05; P < 0.001). Methylation in the INS gene decreased significantly over the same period (-0.46% per year; 95% CI -0.89, -0.03; P = 0.035). There was no evidence from this cross-sectional data that methylation within the imprinted genes changed over the first 7 years of life.
The ICSI sample size was limited but the groups were carefully selected and well matched and the SNRPN findings were consistent across different outcomes.
The results of this study provide support for a role for epigenetics, and imprinting in particular, in fertility. The specific changes point to possible long-term consequences of fertility treatment for the health and fertility of future generations.
The authors report no conflict of interest in relation to this work. Funding was provided by the University of Aberdeen and the Scottish Government.
Human Reproduction 05/2014; 29(7). DOI:10.1093/humrep/deu094 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The expression and regulation of endometrial proteins are crucial for conceptus implantation and development. However, little is known about site-specific proteome profiles of the mammalian endometrium during the peri-implantation period. We utilised a two-dimensional gel electrophoresis/mass spectrometry-based proteomics approach to compare and identify differentially expressed proteins in sheep endometrium. Caruncular and intercaruncular endometrium were collected on days 12 (C12) and 16 (C16) of the oestrous cycle and at three stages of pregnancy corresponding to conceptus pre-attachment (P12), implantation (P16) and post-implantation (P20). Abundance and localisation changes in differentially expressed proteins were determined by western blot and immunohistochemistry. In caruncular endometrium, 45 protein spots (5% of total spots) altered between day 12 of pregnancy (P12) and P16 while 85 protein spots (10% of total spots) were differentially expressed between P16 and C16. In intercaruncular endometrium, 31 protein spots (2% of total spots) were different between P12 and P16 while 44 protein spots (4% of total spots) showed differential expression between C12 and C16. The pattern of protein changes between caruncle and intercaruncle sites was markedly different. Among the protein spots with implantation-related changes in volume, 11 proteins in the caruncular endometrium and six proteins in the intercaruncular endometrium, with different functions such as protein synthesis and degradation, antioxidant defence, cell structural integrity, adhesion and signal transduction, were identified. Our findings highlight the different but important roles of the caruncular and intercaruncular proteins during early pregnancy.
[Show abstract][Hide abstract] ABSTRACT: In-vitro fertilization (IVF) is the treatment of choice for unresolved infertility. It comprises a number of key steps, each of which has to be negotiated before the next is attempted, but the factors which are associated with failure at each stage have not been reported.
We analyzed anonymised national data on women undergoing their first fresh autologous IVF and intracytoplasmic sperm injection (ICSI) cycle in the United Kingdom between 2000 and 2007 to predict factors associated with overall lack of livebirth as well as the chance of non-progress at different stages of an IVF cycle. A total of 121,744 women were included in this analysis. Multivariable models underlined the importance of increased female age and duration of infertility, lack of previous pregnancy, and a diagnosis of tubal or male factor infertility in predicting the risk of not having a live birth in an IVF treatment. At each stage, a woman's chance of proceeding to the next stage of IVF treatment is affected by increased age and duration of infertility. The intention to use intra-cytoplasmic sperm injection (ICSI) is associated with a decreased risk of treatment failure in women starting an IVF cycle (RR 0.93, 99% CI 0.92, 0.94) but this association is reversed at a later stage once fertilisation has been confirmed (RR=1.01, 99%CI 1.00, 1.03).
Female age is a key predictor of failure to have a livebirth following IVF as well as the risk of poor performance at each stage of treatment. While increased duration of infertility is also associated with worse outcomes at every stage, its impact appears to be less influential. Women embarking on ICSI treatment for male factor infertility have a lower chance of treatment failure but this does not appear to be due to increased chances of implantation of ICSI embryos.
PLoS ONE 12/2013; 8(12):e82249. DOI:10.1371/journal.pone.0082249 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple pregnancy, a complication of assisted reproduction technology, is associated with poorer maternal and perinatal outcomes. The primary reason behind this is the strategy of replacing more than one embryo during an assisted reproduction technology cycle to maximise pregnancy rates. The solution to this problem is to reduce the number of embryos transferred during in-vitro fertilisation. The transition from triple- to double-embryo transfer, which decreased the risk of triplets without compromising pregnancy rates, was easily implemented. The adoption of a single embryo transfer policy has been slow because of concerns about impaired pregnancy rates in a fresh assisted reproduction technology cycle. Widespread availability of effective cryopreservation programmes means that elective single embryo transfer, along with subsequent frozen embryo transfers, could provide a way forward. Any such strategy will need to consider couples' preferences and existing funding policies, both of which have a profound influence on decision making around embryo transfer.
Best practice & research. Clinical obstetrics & gynaecology 12/2013; 28(2). DOI:10.1016/j.bpobgyn.2013.11.005 · 1.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To perform a systematic review and meta-analysis of obstetric and perinatal complications in singleton pregnancies after the transfer of blastocyst-stage and cleavage-stage embryos generated through IVF.
Singleton pregnancies resulting from ET at the blastocyst stage versus those at the cleavage stage.
Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE, and CINAHL (1980–2013) were searched. Two independent reviewers extracted data and assessed the methodological quality of the relevant studies using CASP scoring. Risk ratios and risk differences were calculated in Rev Man 5.1.
Main Outcome Measure(s)
Very preterm birth, preterm birth, small for gestational age, low birth weight, very low birth weight, congenital anomalies, perinatal mortality, preeclampsia, and placenta previa.
In vitro fertilization pregnancies occurring as a result of ET at the blastocyst stage were associated with a higher relative risk (RR; 95% confidence interval [CI]) of preterm (RR 1.27; 95% CI 1.22–1.31) and very preterm delivery (RR 1.22; 95% CI 1.10–1.35) in comparison with those resulting from the transfer of cleavage-stage embryos. The risk of growth restriction was lower in babies conceived through blastocyst transfer (RR 0.82; 95% CI 0.77–0.88).
Data from observational studies show that ET at the blastocyst stage is associated with a higher risk of very preterm delivery. However, we were not able to adjust for confounders. Perinatal outcome data from existing randomized trials are needed to determine the safety of ET at the blastocyst stage compared with the cleavage stage.
Fertility and Sterility 12/2013; 100(6):1615–1621.e10. DOI:10.1016/j.fertnstert.2013.08.044 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring.
Record linkage cohort analysis.
Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems.
37 709 people with birth records from 1950 to present day.
Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI.
All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes.
Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required.
[Show abstract][Hide abstract] ABSTRACT: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000-10 000 IU/L METHODS AND ANALYSIS: We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000-10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m(2)) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.
Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.
BMJ Open 07/2013; 3(7). DOI:10.1136/bmjopen-2013-002902 · 2.27 Impact Factor