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Assisted reproductive safety

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

Of all aspects of assisted reproductive treatments, in vitro fertilisation (IVF) has the highest profile. Refined over the last 35 years, IVF is now a highly efficient means of conception, with about 40% of young couples achieving success from a single IVF cycle; it is estimated that 5 million children in total have been born using these technologies (Cedars JAMA 2013;310:42–3). Currently the percentage of IVF births in developed countries is 1–4% of all births.

Risks to the offspring conceived via IVF include perinatal problems, such as preterm delivery, raised mortality rates, low birthweight, and congenital abnormalities. These risks may arise from inherent parental factors, multiple pregnancies, or perhaps the procedures used in IVF. In addition, researchers are now looking at the neurodevelopment of children born using these techniques.

Sandin et al. (JAMA 2013;310:75–84) studied the chances of IVF-conceived children having autism or mental retardation, compared with those conceived spontaneously in Sweden between 1982 and 2007. Over 2 million children (1.2% IVF assisted) were included in the study, all of whom had mandatory assessments of their developmental function at 4 years of age, according to national policy. They were therefore able to assess the effects of IVF on autism spectrum disorders and mental retardation across all aspects of IVF-treated infertility, including parental age, laboratory procedures, and multiple pregnancies.

The results were reassuring: there was no effect of IVF on the occurrence of autism disorders, and although there was an increase in mental retardation, this was very small, with absolute numbers being seven extra cases per 100 000 person years. Further analysis showed this to be highest where intracytoplasmic sperm injection from surgically derived sperm and fresh embryos were used.

The authors note the falling rate of multiple embryo transfers, with a concomitant fall in multiple births, which should presumably reduce differences between IVF and natural conceptions even further.

A broadly similar study from Denmark (Bay et al. BMJ 2013;346:f3978) also found that there was a very small increase in mental disorders in the offspring of those using assisted reproductive techniques. This was a large national survey of children well into their teenage years, and showed IVF or intracytoplasmic sperm injection (ICSI) to be associated with fewer disorders than spontaneous conceptions, whereas ovulation induction and intrauterine insemination were linked to slightly more disorders.

Again, the absolute numbers show little variation in the total number of problems encountered, being 3.9% for the entire population, 3.5% for children born after IVF/ICSI, and 4.1% for other assisted reproduction treatments.

These are comprehensive databases, spread over decades, from countries where follow-up is diligent and involves entire populations, so parents and clinicians can be reassured about existing assisted reproductive techniques.

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Source: Drawn from Bay et al. BMJ 2013;346; f3978.

Supplementation in pregnancy

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

There is now unequivocal evidence that antenatal iron supplementation is of benefit to both mother and child. It seems strange that something so apparently ‘self-evident’ has not previously been documented to the satisfaction of the Cochrane Review group.

Anaemia is exceedingly common worldwide, especially in women during their reproductive years, with the WHO estimating that nearly a third of the world's population may be anaemic because of iron deficiency. The body has a limited capacity to absorb iron from the normal diet, and given the extra demands of pregnancy, supplementation seems logical.

A meta-analysis by Haider et al. from Harvard (BMJ 2013;346:f3443) demonstrates that iron, up to 60 mg per day, increases maternal haemoglobin levels in a dose-related fashion. Not only does this reduce the risk of anaemia, it lowers the risk of low-birthweight babies, and improves neonatal haematological profiles.

The question of vitamin D supplementation is a lot less clear. Although vitamin D is an essential component of calcium metabolism and bone mineralisation, it is not easy to measure in pregnancy, with reference levels of 25 hydroxyvitamin D [25(OH)D] being inconsistent, depending on sunlight exposure, race, supplementation, and surrogate downstream outcomes, like childhood health or disease.

A large prospective study by Lawlor et al. (Lancet 2013;381:2176–83) from the UK showed no correlation between maternal 25(OH)D levels in pregnancy and the bone-mineral content in their children at 10 years of age. So it seems the evidence supporting routine antenatal supplementation is flimsy, which is reflected in the less than dogmatic advice given out in the UK and USA. Steer (Lancet 2013;381:2143–5) suggests that women with dark skin or who have limited exposure to sunlight because of their habits or weather, whose diet is low in vitamin D, or who have a high body mass index, should add vitamin D to their diet in pregnancy.

So it seems there is recent evidence to advise folic acid periconceptually, fluoride, iodine, and iron to all pregnant women, vitamin D to some, and most importantly a mixed diet that does not increase obesity – and of course – no alcohol or smoking.

Giving iron as part of a micronutrient package to young children in developing countries does reduce anaemia rates, but is not without unintended consequences (Soofi et al. Lancet 2013;382:29–40). Ensuring optimal maternal iron supplies together with late cord clamping are important obstetric components towards a healthier next generation.

Dual osteoporosis treatment

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

The treatments for osteoporosis fall into two main categories: those that work by stimulating bone formation (anabolic agents); and those that inhibit bone turnover (anticatabolic agents).

Anabolic agents

Parathyroid hormone and its recombinant form, teriparatide, both lead to increased osteoblastic activity, resulting in improved bone-mineral density. This in turn leads to a reduction in fracture risk. Because of costs and the need for daily subcutaneous injections, these anabolic agents are usually reserved for patients with severe osteoporosis or in whom other treatments have failed.

Anticatabolic agents

This category of drugs acts by suppressing bone resorption, which is an osteoclastic activity. There are two classes of drugs in use here that act via different mechanisms:

  • Bisphosphonates, for example alendronic acid orally or zolendronic acid as an annual infusion, work by inhibiting an enzyme that regulates osteoclastic action (called farnesyl pyrophosphate synthetase).
  • Monoclonal antibodies such as denosumab work by blocking osteoclastic formation, activation, and survival [by receptor activator of the NF-inline imageB ligand (RANKL) binding].

Trials combining anabolic agents plus bisphosphonates have not been successful, and strontium ranelate, which does have a dual action, is used in restricted situations because of potentially dangerous side effects.

Tsai et al. now report a study from the USA (Lancet 2013;382:50–6) in which teriparatide and denosumab were used in a comparative trial, on their own and in combination, for osteoporotic postmenopausal women. The subjects had their bone mineral density measured at the start of the trial and three times over the next year, with the critical end-point being spinal density at 12 months. Those receiving combination therapy increased their bone mineral density by 9%, compared with 5–6% for the drugs on their own.

Long-term safety and the effects on fractures are yet to be reported, but the proof of concept looks promising in an affliction that needs effective treatments.

Magnetic resonance imaging (MRI)-assisted versus conventional autopsy

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

Conventional autopsies following a perinatal death are often declined by parents. In the UK fewer autopsies are being performed on fetuses (now less than half) or neonates (less than a quarter), despite considerably more being offered than before, thus losing the opportunity to discover potentially useful information about the cause of death and to guide future advice.

There is evidence that whole-body magnetic resonance image (MRI) scanning is more acceptable to parents, but its precision in delivering accurate findings compared with a conventional autopsy is unknown. Thayyil et al. from the UK (Lancet 2013;382:223–33) carried out MRIs prior to performing a minimally invasive autopsy or full autopsy on 400 fetuses and young children for whom permission for these investigations had been granted.

A minimally invasive autopsy in which the MRI played a crucial role was defined as not making incisions, but with blood sampling by needle puncture, plus genetic studies, radiological imaging, and metabolic tests, as indicated by a review of the notes. It did not include tissue histology. The conventional autopsy included open dissection, macro- and microscopic examinations, plus microbiology testing on organs and fluids. Both forms of autopsy included placental and cord examinations.

Concordance between the two forms of autopsy (minimally invasive and conventional) was high: around 95% for fetuses, 80% for neonates or infants up to 1 year, but only about half of those older than 1 year. Once the MRI had been performed, a full autopsy was considered unnecessary in 40% of cases, and in this trial the forecast was accurate 99% of the time, indicating that for a large proportion of cases a minimally invasive autopsy will provide all of the data required.

The authors’ conclusion is that minimally invasive autopsies have a similar accuracy to conventional autopsies for a cause of death or major pathology detection in fetuses or young children. For those faced with decisions about investigations under difficult circumstances, this is hopeful information. The accuracy provided by this trial is therefore important.

USA health economics

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

The Americans are paying a great deal of attention to the costs of their health care. This is finding expression in the ever-increasing number of financially linked articles in major journals from the USA. The drivers of this raised interest in economics are the Affordable Care Act, the inexorable rise of services, doctors’ fees, imaging (Jha NEJM 2013;369:5–7), screening, hospitalisation, the continuance of pharmaceutical firms as one of the most successful groups of companies, and a population that is both ageing and becoming more overweight.

The result is an industry in which growth is outstripping all others at an unsustainable rate. To quote Fuchs (NEJM 2013;369:107–9), over the last 60 years ‘real GDP per capita grew at an average of 2.0% per year, while the national health care expenditures per capita grew at 4.4% per year. The gap between the two rates of growth – 2.4% per year – resulted in the share of the GDP related to health care spending increasing from 4.4% in 1950 to 17.9% in 2011. Most experts believe that a gap close to this magnitude over many future years would have catastrophic consequences for the federal government and the U.S. economy’.

New reports and guidelines

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

Incidence and complications of unsafe abortion in Kenya: key findings of a national study

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This report, produced by the African Population and Health Research Center (APHRC), the Ministry of Health in the Republic of Kenya, Ipas, and the Guttmacher Institute, provides an overview of the practice of unsafe abortion in Kenya, and the consequences for women's health and wellbeing. The report states that 464 690 abortions took place in Kenya in 2012, and of those 157 762 women had to receive care for related complications. The report provides detailed abortion-related data, including the technology used for uterine evacuation, the severity of abortion complications, and national and regional induced abortion rates. The report concludes that training health professionals to ensure that they have the skills and knowledge to provide abortion-related care to women, and improving access to family planning services and contraception, are key to helping prevent unintended pregnancy and unsafe abortion in Kenya, and ultimately to reducing maternal morbidity and mortality.

Available online at www.guttmacher.org.

Reproductive health in humanitarian settings toolkit

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K4Health have recently launched this new toolkit designed for use by emergency workers, disaster relief teams, and healthcare providers during natural disasters, conflicts, and other humanitarian crises. The toolkit provides links to service-delivery resources and guidance regarding HIV and AIDS, maternal and child health, gender-based violence, reproductive health, and family planning, to help integrate sexual and reproductive health care into emergency management plans. The toolkit includes a section dedicated to guidance and information on providing youth-friendly reproductive health services in humanitarian settings. Information specifically addressing gender considerations in emergency health service delivery is also provided, including links to advice from the World Health Organization (WHO), United Nations Children's Fund (UNICEF), and the Women's Refugee Commission. Links to key international humanitarian organisations are also included.

Available online at www.k4health.org.

Female genital mutilation/cutting: a statistical overview and exploration of the dynamics of change

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This comprehensive report published by the Statistics and Monitoring Section, Division of Policy and Strategy at UNICEF, aims to chart changes in practice, and progress made in eliminating the practice, of female genital mutilation (FGM). The report states that, over the next decade, about 30 million girls around the world are at risk of FGM if the current trends in practice continue. The report provides an overview of FGM in the 29 countries where it is performed most, and aims to provide in-depth information that can inform policies and programmes to help eliminate this practice. The report explores the social dynamics of FGM, how widespread the practice is, when and how it is performed, prevailing attitudes towards FGM, and the relationship between the experience of FGM and attitudes towards the practice of it. Change in attitudes, practice, and prevalence are assessed, and implications for programming and policy-making are discussed. Key findings include: a greater than anticipated decline in the practice of FGM in the Central African Republic; the attitudes of men and women towards FGM are very similar, with more men than women wanting an end to FGM in Guinea, Sierra Leone, and Chad; and that overall support for practicing FGM is declining, even within countries such as Egypt and Sudan, where the practice is almost universal.

Available online at www.unicef.org.

Exploring contraceptive use differentials in sub-Saharan Africa through a health workforce lens

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This policy brief, published by CapacityPlus, aims to investigate supply-side differences within areas of eastern and western Africa, which have been classified as undergoing a health workforce crisis, and to identify factors that contributed to the success of a group of five East African countries (Ethiopia, Madagascar, Malawi, Rwanda, and Zambia) in increasing their contraceptive prevalence rate (CPR), whilst a similar group of countries experiencing a health workforce crisis in West Africa (Benin, Ghana, Mali, Nigeria, and Senegal) did not improve their CPR. The brief states that the overall modern contraceptive prevalence rate in sub-Saharan Africa of 19% masks the diversity in CPR within individual countries, which range from 1% in Somalia to 60% in South Africa. The briefing discusses macro-level trends in the use of services provided by health workers, urban/rural differentials in the use of family planning services, and public versus private provision of contraception. The briefing concludes that health worker access is only one factor in determining levels of contraceptive use, but this ‘exploratory analysis nonetheless raises questions about whether government commitment and certain policy choices vis-à-vis health workforce distribution and qualifications—even when absolute levels of health worker density are low—could make a difference in the provision of family planning services in resource-constrained countries’.

Available online at www.capacityplus.org.

Clinical guidelines updates

The Society of Obstetricians and Gynaecologists of Canada (SOGC)

The following guideline is now available online at www.sogc.org.

The American Congress of Obstetricians and Gynecologists (ACOG)

The following guidelines are now available online at www.acog.org.

Royal College of Obstetricians and Gynaecologists (RCOG)

The following guidance is now available at www.rcog.org.uk.

US Preventive Services Task Force

The following guidelines are now available at http://www.uspreventiveservicestaskforce.org/.

Innovations and Patents

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

Patent applications

The following patents can be found online at http://worldwide.espacenet.com.

Method of assessing influence of herpes virus infection on erythrocyte membrane stability in newborns of mothers suffered aggravated herpes virus infection in third trimester of pregnancy RU2488112 (C1). This patent application relates to a method of assessing the influence of herpes virus infection on erythrocyte membrane stability in newborn babies whose mothers suffered from aggravated herpes. Specifically, blood from the newborn is obtained and examined for malondialdehyde (MDA), and the level of spectrin in the newborn's erythrocyte membrane is determined by disk electrophoresis. The inventors state that when spectrin and MDA levels reach a pre-specified level, this can indicate instability of the newborn's erythrocyte membranes, which can lead to the development of anaemia.

Lutsenko MT, Andrievskaja IAE. 20 July 2013.

Deuterated thiazolidinone analogues as agonists for follicle stimulating hormone receptor WO2013117299 (A1). This world patent outlines the invention of low-molecular-weight hormone mimetics that selectively activate follicle-stimulating hormone receptors (FSHRs). Specifically, this patent details the exact composition of deuterated thiazolidinone analogues for use as agonists for FSHRs for the treatment of fertility disorders.

Yu H, Donnelly M. 15 August 2013.

Treatment of pelvic organ prolapse WO2013116310 (A1). This patent application discusses methods and devices for the diagnosis and treatment of pelvic organ prolapse. The application proposes a multiple sensor-enabled device, which can be inserted vaginally, that can relay real-time patient data, including information about physiology, the position and movement of the urethra, and pelvic floor and vaginal muscular strength. It is hoped that the device can be used to assess urinary incontinence, sexual health issues, and faecal incontinence.

Iglesias RJ. 8 August 2013.

Method and system to monitor, detect, diagnose and predict the separation/rupture of the uterine scar associated with vaginal birth after caesarean procedures US2013197324 (A1). This US patent describes a system and method of obtaining and transmitting uterine electromyography (EMG) signals. Various embodiments are outlined, including method of using EMG for monitoring and diagnosing possible uterine rupture. It is claimed that leads placed near a prior uterine scar can detect signals when the lower uterine segment thins and separates during labour, and therefore this could be used to identify women at increased risk for rupture.

This application claims priority to US Provisional Patent Application ser. no. 61/514,212 filed 2 August 2011, which is hereby incorporated by reference in its entirety for all purposes.

Waterhouse T, Rainer F, McCrary J, Williams J. 1 August 2013.

Legal matters

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

The implications of the proposed European Union data protection reform on biomedical research

An amendment to proposed draft European Union (EU) data protection reform has been presented to the EU Parliament's Committee on Civil Liberties, Justice, and Home Affairs, which it is argued will have an impact on medical research and impose changes to practice. The Albrecht amendment to the proposed data protection regulation involves changes to consent, the right to be forgotten, and public interest exemptions. Consultation is underway, and a decision is expected in early 2014.

Clinical trials

  1. Top of page
  2. Assisted reproductive safety
  3. Supplementation in pregnancy
  4. Dual osteoporosis treatment
  5. Magnetic resonance imaging (MRI)-assisted versus conventional autopsy
  6. USA health economics
  7. New reports and guidelines
  8. Innovations and Patents
  9. Legal matters
  10. Clinical trials

Clinicians keen to keep up to date regarding clinical studies that are currently recruiting may find the following informative.

The valve of hyaluronic binding selection (PICSI) in improving IVF outcome
Registration http://clinicaltrials.gov/ct2/show/NCT01916213
Description This randomised trial aims to compare the effectiveness of routine sperm selection using intracytoplasmic sperm injection (ICSI) with selecting mature sperm using PICSI (selecting for sperm that bind hyaluronan) on implantation and fertilisation rates for couples with male-factor fertility problems.
Outcome measures Primary: Implantation rate. Secondary: Fertilisation rate.
Study site New York, USA. Anticipated study end date: March 2015.
P-wave duration and dispersion in intrahepatic cholestasis of pregnancy
Registration http://clinicaltrials.gov/ct2/show/NCT01906827
Description This observational study aims to investigate maternal P-wave duration and dispersion changes in pregnant women who have intrahepatic cholestasis of pregnancy.
Outcome measures Primary: Changes in the range of P–wave duration and dispersion. Secondary: Not specified.
Study site Ankara, Turkey.Anticipated study end date: June 2014.
Study of antibiotic-induced vaginal yeast infections in healthy women
Registration http://clinicaltrials.gov/ct2/show/NCT01915251
Description This observational study aims to investigate how a common antibiotic drug affects bacteria and yeast in the vagina, and in other parts of the body, to determine whether the antibiotic increases the risk of yeast infections.
Outcome measures Primary: Microbiomic profile; immunologic profile. Secondary: Not specified.
Study site Maryland, USA. Anticipated study end date: July 2023.
Short term effects of live music in newborn infants
Registration http://clinicaltrials.gov/ct2/show/NCT01914341
Description This randomised study aims to assess the effects of live music on the physiological parameters of newborn infants. The mother will be questioned regarding the effects of music on both her own and the newborn baby's wellbeing.
Outcome measures Primary: Heart rate. Secondary: Oxygen saturation; breathing rate; apnoea; bradycardia; tachycardia; heart rate variability parameters; perfusion index, pulse transit time; state–trait anxiety inventory; state of the child; additional music questions.
Study site Baden-Württemberg, Germany.Anticipated study end date: June 2014.
Ultrasound measure of the thickness of the lower segment in women having a history of caesarean
Registration http://clinicaltrials.gov/ct2/show/NCT01916044
Description This randomised trial aims to assess the efficiency of lower uterine segment ultrasound measurement in reducing fetal and maternal morbidity and mortality in women with a history of caesarean section.
Outcome measures Primary: Maternal morbidity. Secondary: Fetal mortality; newborn morbidity; maternal morbidity; rate of iterative caesareans.
Study site Poissy, France.Anticipated study end date: November 2016.