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The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy.
Calcium is an important element of body composition1,2 as well as normal physiological functions3. A neonate's body has around 20–30 g calcium present at birth2,4–6 and this amount has to be supplied by the mother since human body cannot synthesise calcium2. Therefore, if the mother has a shortage of calcium, the foetus might be affected.
In a non-obstetric population, the optimization of cardiac output (CO) had been shown to improve survival and to reduce postoperative complications, organ failure and the length of stay1. CO monitoring might be very useful in the obstetric population as well, as physiologic changes of CO during pregnancy are mandatory for a normal outcome. An uncomplicated pregnancy is associated with a 50% increase in maternal CO, which is mediated by plasma volume expansion and a decrease in peripheral resistance2. An aberrant change of this maternal CO might influence pregnancy outcome: pregnancies complicated with foetal growth restriction and/or preeclampsia are characterized by increased total vascular resistance and reduced systolic function (i.e. lower CO and stroke volume (SV))3–5.
Management of the antenatal compromised airway is a situation that can at best be controlled and managed in a way that is safe for both mother and baby. As the 16th century author, Miguel de Cervantes wrote “Forewarned, forearmed; to be prepared is half the victory”, in a similar fashion we, as clinicians involved in the management of neonatal airways must recognise and prepare for all eventualities in order to produce the best outcomes for our patients. In this review, we discuss strategies in managing the compromised neonatal airway along with specific pathologies that may cause post-natal airway compromise. With each sub-group of pathologies, we suggest potential strategies that can be considered in their management.
Artificial reproductive technology (ART) was first introduced to clinical practice in the late 1970s1 and has subsequently resulted in approximately 5 million births worldwide2. Globally, the rates of assisted conceptions continue to rise3. In 2011, approximately 1.5% of all pregnancies in the US were conceived using ART4. Since its introduction, much interest has been generated regarding the effects of ART on the developing fetus and potential adverse impacts on the health of the mother. In particular, early studies suggested an increase in fetal genetic and structural anomalies, and a high risk of perinatal complications. As experience with pregnancies conceived using ART has increased worldwide and more data regarding the outcomes of ART-conceived pregnancies have been reported, many of the initial worries have been shown to be unfounded. However, concern still exists regarding whether any adverse fetal and maternal outcomes result from the use of this technology. Many studies have reported higher risks of fetal complications following the use of ART including an increase in perinatal mortality, even in singleton pregnancies5,6. However, interpretation of these data are far from simple and it is important to consider that observations of higher rates of complications do not equate to a causal relationship between adverse pregnancy outcomes and the use of ART7. There are multiple confounding factors that may account for these associations, many of which are difficult to control for in large-scale studies.
The ability to obtain fetal material that could be used for prenatal genetic diagnosis without requirement for an invasive test was a watershed moment in antenatal care. Cell-free fetal DNA (cffDNA) was identified in the maternal plasma by Lo and colleagues in 19971 and despite being technically challenging, non-invasive tests for fetal sex determination, fetal rhesus D (RHD) genotyping, some single gene disorders and the major aneuploidies are now being offered in clinical practice throughout the world2. Progress continues at pace and recent developments in next generation sequencing (NGS) are driving significant advances in research and in the clinical application of non-invasive prenatal testing (NIPT) and diagnosis (NIPD) (Table 1).
In an era of evidence-based medicine, physicians sometimes forget the value of anecdotes in stimulating thought about clinical problems. Our recent report on typhoid fever in a pregnant woman at 12 weeks of gestation is a good example. In spite of culture-proven diagnosis and appropriate treatment of the mother with antibiotics, fetal loss occurred at 16 weeks of gestation. Salmonella typhi was found in the fetal lung on autopsy, consistent with vertical transmission of the organism. None of the clinicians caring for the patient had imagined that gram-negative bacteria could cross the placenta and kill the fetus in spite of early diagnosis and treatment with appropriate antibiotics.
The possibility of prenatal screening for genetic disorders was raised as early as the mid-1950s, and with the introduction in 1966 of amniocentesis for sampling fetal material, it became possible to identify pregnancies with trisomy 21 (Down syndrome), the most common prenatal genetic abnormality. The fetal cells in the amniotic fluid could be cultured, then harvested, followed by chromosome spreading on microscope slides. These chromosome spreads, each representing the chromosomes from a single cell nucleus, could be stained, visualised by light microscopy and counted to establish the chromosome number. However, diagnosis of Down syndrome was expensive, and in the early days of amniocentesis, there was an associated risk of miscarriage; most countries therefore recommended this procedure only for women who were identified as having a raised risk of chromosome abnormality. As it is well established that raised maternal age increases the risk of Down syndrome, amniocentesis was first offered only to women above an age cut-off (usually 35). However, although the risk to an individual woman of having a Down syndrome pregnancy is greater in this age group, the majority of Down syndrome babies are born to younger women, due to the preponderance of pregnancies in the younger group.