[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.
[Show abstract][Hide abstract] ABSTRACT: 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.
BMC Pregnancy and Childbirth 10/2014; 14(1):361. · 2.15 Impact Factor
[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; · 1.80 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: 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; · 8.66 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.
[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. · 3.53 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; · 1.87 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. · 4.30 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.
[Show abstract][Hide abstract] ABSTRACT: Guidelines issued by a number of bodies highlight the importance of providing information on fertility for young adults receiving a cancer diagnosis. However, previous research has established that provision is uneven and even when information is available, counselling may not be offered. This paper draws on interviews with 15 professionals and 30 younger adults (17-39 years) following a diagnosis of cancer at one tertiary referral centre. Sociological insights highlight the disruption to biographies, plans, identities and personal values involved in acknowledging and responding to the impact of cancer on fertility. Patients and professionals are involved in making difficult decisions in a rapidly evolving situation, in terms of both progression of cancer and advances in treatments for cancer and fertility preservation. It is argued that the constellation of knowledge and skills required does not readily map onto existing professional roles and we suggest that it may be appropriate to provide further training or even to draw on the services of specialist 'oncofertility' counsellors.
[Show abstract][Hide abstract] ABSTRACT: Various methods of conscious sedation and analgesia have been used for pain relief during oocyte recovery in in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) procedures. The choice of agent has also been influenced by the quality of sedation and analgesia as well as by concerns about possible detrimental effects on reproductive outcomes.
To assess the effectiveness and safety of different methods of conscious sedation and analgesia on pain relief and pregnancy outcomes in women undergoing transvaginal oocyte retrieval.
We searched the Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL (from their inception to present); the National Research Register and Current Controlled Trials. We searched reference lists of included studies for relevant studies and contacted authors for information on unpublished and ongoing trials. There was no language restriction. The search was updated in July 2012.
Only randomised controlled trials comparing different methods of conscious sedation and analgesia for pain relief during oocyte recovery were included.
Quality assessment and data extraction were performed independently by two review authors. Interventions were classified and analysed under broad categories or strategies of sedation and pain relief to compare different methods and administrative protocols of conscious sedation and analgesia. Outcomes were extracted and the data were pooled when appropriate.
With this update, nine new studies were identified resulting in a total of 21 trials including 2974 women undergoing oocyte retrieval. These trials compared five different categories of conscious sedation and analgesia: 1) conscious sedation and analgesia versus placebo; 2) conscious sedation and analgesia versus other active interventions such as general and acupuncture anaesthesia; 3) conscious sedation and analgesia plus paracervical block versus other active interventions such as general, spinal and acupuncture anaesthesia; 4) patient-controlled conscious sedation and analgesia versus physician-administered conscious sedation and analgesia; and 5) conscious sedation and analgesia with different agents or dosage. Evidence was generally of low quality, mainly due to poor reporting of methods, small sample sizes and inconsistency between the trials.Conflicting results were shown for women's experience of pain. Compared to conscious sedation alone, more effective pain relief was reported when conscious sedation was combined with electro-acupuncture: intra-operative pain mean difference (MD) on 1 to 10 visual analogue scale (VAS) of 3.00 (95% CI 2.23 to 3.77); post-operative pain MD in VAS units of 2.10 (95% CI 1.40 to 2.80; N = 61, one trial, low quality evidence); or paracervical block (MD not calculable).The pooled data of four trials showed a significantly lower intra-operative pain score with conscious sedation plus paracervical block than with electro-acupuncture plus paracervical block (MD on 10-point VAS of -0.66; 95% CI -0.93 to -0.39; N = 781, 4 trials, low quality evidence) with significant statistical heterogeneity (I(2) = 76%). Patient-controlled sedation and analgesia was associated with more intra-operative pain than physician-administered sedation and analgesia (MD on 10-point VAS of 0.60; 95% CI 0.16 to 1.03; N = 379, 4 trials, low quality evidence) with high statistical heterogeneity (I(2) = 83%). Post-operative pain was reported in only nine studies. As different types and dosages of sedative and analgesic agents, as well as administrative protocols and assessment tools, were used in these trials the data should be interpreted with caution.There was no evidence of a significant difference in pregnancy rate in the 12 studies which assessed this outcome, and pooled data of four trials comparing electro-acupuncture combined with paracervical block with conscious sedation and analgesia plus paracervical block showed an odds ratio (OR) of 0.96 (95% CI 0.72 to 1.29; N = 783, 4 trials) for pregnancy. High levels of women's satisfaction were reported for all modalities of conscious sedation and analgesia as assessed in 12 studies. Meta-analysis of all the studies was not attempted due to considerable heterogeneity.For the rest of the trials a descriptive summary of the outcomes was presented.
The evidence from this review of 21 randomised controlled trials did not support one particular method or technique over another in providing effective conscious sedation and analgesia for pain relief during and after oocyte recovery. The simultaneous use of more than one method of sedation and pain relief resulted in better pain relief than one modality alone. The various approaches and techniques reviewed appeared to be acceptable and were associated with a high degree of satisfaction in women. As women vary in their experience of pain and in coping strategies, the optimal method may be individualised depending on the preferences of both the women and the clinicians and resource availability.
[Show abstract][Hide abstract] ABSTRACT: The cause of infertility is unexplained in about 22-28% of all infertile couples. The prognosis for spontaneous pregnancy in such couples is better than in those with diagnosed causes of infertility. Traditional treatment options in this group have included expectant management, clomifene citrate, intrauterine insemination with (super ovulation plus intrauterine insemination) or without (intrauterine insemination) super ovulation and in-vitro fertilisation. Despite being more expensive, empirical clomifene and intrauterine insemination in an unstimulated cycle do not improve the chances of live birth compared with expectant management. Although unlikely to be more effective than no treatment in couples with a reasonably good prognosis, super ovulation plus intrauterine insemination has been shown to be more effective than intrauterine insemination. Any potential advantage of super ovulation plus intrauterine insemination has to be balanced against the relatively high risk of iatrogenic multiple pregnancy. In-vitro fertilisation remains the treatment of choice in longstanding unresolved infertility and, when coupled with the use of elective single embryo transfer, can minimise the risk of multiple pregnancies. Data from randomised trials confirming the superiority of in-vitro fertilisation over expectant management is limited.
Best practice & research. Clinical obstetrics & gynaecology 08/2012; 26(6):729-38. · 1.87 Impact Factor