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Medicines in maternal and neonatal care: current practice and future developments.
This is a report of a joint meeting of the Forum on Maternity and the Newborn with the Section of Pharmaceutical Medicine & Research of the Royal Society of Medicine, held on Thursday 13th April 2006.
The report is to be published in part in the Midwives Journal of the Royal College of Midwives. It is reproduced here with their consent and our thanks.
Chairs (afternoon session): Dr Anita Holdcroft, Reader in anaesthesia and honorary consultant anaesthetist, Imperial College London and Dr Andrew Zambanini, Director, Clinical Development, Cardiovascular and Metabolic Medicines Development Centre, GlaxoSmithKline
A journey through THE FIRST TRIMESTER OF pregnancy
Case study 1 - Diabetes
Dr Jo Modder (JM), consultant obstetrician at University College London Hospitals NHS Trust. Obstetric Lead, Confidential Enquiries into Maternal and Child Health, (CEMACH), London
The patient with Type 1 diabetes mellitus has an absolute deficiency of insulin, and will die if she does not receive it. In Type 2 diabetes there is a relative deficiency of insulin and insulin resistance; the tissues do not respond fully to insulin. I am concentrating here on the first trimester of pregnancy, so that gestational diabetes (GDM) will not be a topic. Women with type 2 diabetes are usually the older group, often Asian or African, and more heavily built.
Women with both types of diabetes have a twofold increased risk of fetal congenital anomalies - 41.8/1000 live and stillbirths (CEMACH 2005, 3,800 women, the largest dataset for pregestational diabetes). Among these there is a threefold increase in both cardiac and neural tube defects. A daily dose of 4 mgs. of folic acid taken around the time of conception is known to reduce the incidence of neural tube defects in women with a previously affected baby (Cochrane 2006). Accordingly it is recommended that women with both types of diabetes commence 5 mgs. of folic acid (the UK formulation) daily prior to conception or as soon as possible, and until 12 weeks (Diabetes NSF 2001; Diabetes UK Care Recommendation 2005); unfortunately less than 40% of these women comply with the advice. It is probably advisable for a full blood count and possibly a vitamin B12 assay to be carried out before starting folic acid, to avoid its masking the megaloblastic anaemia of pregnancy.
Poor glycaemic control is associated with increases in miscarriage, congenital anomaly, and increased perinatal mortality rates (Karlsson et al. 1972; Miller et al 1981;Kitzmiller et al. 1996); with the good control which vitally should be achieved before conception the rates are similar to those of the general pregnant population. By good control we mean levels of glycosylated haemoglobin (HbA1c) below 7%, which few women have achieved when entering pregnancy, or even in the third trimester, the time of organogenesis; the preparation of women for pregnancy, when it can make a difference, is very poor. This applies also to the 75% of women with type 2 diabetes who do not use insulin, many of whom are not changed onto insulin before they become pregnant, as should happen to achieve improved control.
The body's requirement for insulin increases rapidly during pregnancy, and changes continuously throughout pregnancy. To maintain a normal fasting blood glucose a dose of a long-acting insulin is given at night, while doses of the shorter acting soluble human insulin are given with each meal to minimise subsequent high blood glucose levels. Treatment is not without the risk of hypoglycaemia, all the more likely for pregnant women, particularly those with children, since it requires a high degree of organisation. Insulin stimulated antibody formation may aggravate this, but may also lead to placental transfer to the baby, possibly resulting in macrosomia, new blood vessel formation with retinopathy, and if the antibodies persist after birth the development of type 1 diabetes in the child. The newer insulin preparations have been little tested in pregnancy, and each has advantages and disadvantages.
Diabetics with nephropathy will often be taking ACE inhibitors before they become pregnant; these are known to have been associated with increased miscarriage rate and stillbirth, fetal growth retardation, skull ossification and oligohydramnios, although as for statins these risks are not so high that inadvertent use in the first trimester should lead to termination of a pregnancy. They should be discontinued before pregnancy, when those who are hypertensive should change its treatment to methyldopa.
Metformin has some advantageous effects on glucose metabolism, it improves insulin sensitivity and is not a cause of of hypoglycaemia, but it does cross the placenta. Limited retrospective studies have suggested that it reduces the miscarriage rate and prevents the onset of gestational diabetes, but there are insufficient randomised controlled trials to prove metformin's safety. Insulin should be substituted for metformin before pregnancy, but if this has not been done it should not be discontinued until a woman is getting specialist advice. Glyburide has some advantages but can cause hypoglycaemia; there is little transfer across the placenta. The cholesterol lowering statins can and should be discontinued during pregnancy as they may be the cause of congenital anomalies.
Case study 2 - Epilepsy
Dr Naghme Adab (NA), Consultant Neurologist, University Hospital Coventry & Warwickshire NHS Trust, Warwickshire
Active epilepsy affects 0.5 to 1% of our population, and of this number a third are women of childbearing age; 1 in 200 pregnancies are exposed to anti-epileptic drugs (AEDs). More than 100 court cases relating to the effects of anti-epileptic drugs (AEDs) on the unborn child are ongoing.
Could these and other adverse effects be associated with the fits themselves or to genetic effects or to the mothers' lower socio-economic background? The list is substantial: increased perinatal mortality and stillbirth; intrauterine growth retardation; major congenital malformations; minor anomalies including dysmorphic features; developmental delay and behavioural problems. The risk for children of mothers with epilepsy who are not on AEDs is similar to that of the general population (malformation rate 2-3%), whereas there is a 2-3 fold increase in children of mothers taking them. The association with fits is difficult to interpret: women not requiring medication have milder or fewer fits; women who take more than one drug, which is associated with a 6 to 25% risk, have the more severe disease. Credence is added to the belief that the drugs are causative by dose related effects and the specific pattern of malformations. A prospective study (the UK epilepsy in pregnancy register) comparing sodium valproate (VPA) with carbamazepine and lamotrigine has shown a significant increase in major malformations following first trimester exposure to VPA (n= 715, malformation rate 6.2%) compared to carbamazepine (n= 900, malformation rate 2.2%); the incidence when women were taking lamotrigine was also lower (n= 647, malformation rate 3.2%), though at doses above 200 mgs. the malformation rate was similar to that of VPA at doses of 1000 mgs. or less (Morrow J. et al. 2006).
The value of research has had important limitations. There has been wide variation in the definition of malformations, small sample sizes and a lack of ideal control groups. Few studies explored the likely confounding factors. Trimethadione, phenytoin, VPA, and carbamazepine have all shown characteristic patterns of dysmorphic abnormalities affecting the mouth, eyes, ears, nose and digits. The concern is that these may be markers of a teratogenic syndrome and thus indicate more serious problems such as major malformations or developmental delay; the syndrome associated with exposure to phenytoin includes intrauterine growth retardation, dysmorphic features in the face, cleft lip and palate, heart defects, hypoplasia of the nails and learning difficulty. That associated with VPA includes characteristic facial abnormalities, heart and neural tube defects and hypospadias, as well as learning difficulty. Dysmorphic features affect about 5% of the general population, and can be associated with other conditions such as maternal diabetes or excessive alcohol use.
There has been little well-conducted research into the long-term effects of exposure to AEDs. Our own study showed significant defects in verbal IQ where the children had been exposed to VPA whether in single or combined therapy, and a higher proportion of them had moderate to severe dysmorphic features, with a significant dose effect correlation. Only in the VPA group was there a statistically significant correlation between the lowest verbal IQs and dysmorphic features. Interestingly there was also an association between lower verbal IQ and more than five tonic-clonic seizures occurring during pregnancy. However there are biases in the research, and caution is required when drawing conclusions about absolute effects. There is now sufficient evidence that VPA carries significant risks at doses above 1000 mgs. but it is important to establish whether lower dose regimes are any safer. There is uncertainty about the long-term effects of carbamazepine, and about the risks of newer AEDs for major malformations and later outcomes.
Unfortunately VPA is still the treatment of choice for idiopathic generalised epilepsy, being most effective against seizures, which are themselves known to be harmful; more reliable evidence may be provided by well designed controlled prospective studies with large sample sizes and in which data about confounding factors are collected. The aim of epilepsy treatment must be to achieve a balance of risks, avoiding convulsive seizures while minimising the risks to the developing fetus. VPA may need to be avoided in pregnancy where possible.
Morrow J, Russell A, Guthrie E, Parsons L, Robertsons I, Waddell R, Irwin B, McGivern RC, Morrison PJ, Craig J. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. JNNP Feb 2006; 77: 193-198.
Case study 3 - Antibiotic prescribing
Dr Alison Bedford Russell (ABR), Consultant Neonatologist, Heart of England NHS Trust, Birmingham and Senior Lecturer, Warwick Medical School
All antibiotics, particularly broad-spectrum antibiotics, which are present everywhere in the food chain, alter the natural microflora, with possible increases in antibiotic resistance and the pathogenicity of organisms. Once organisms become antibiotic-resistant they are readily disseminated within hospitals and the community. This has resulted in the well-known exponential increase in infection by superantigens such as MRSA (methicillin resistant staphylococcus aureus) which bypass the processes which usually protect T cells from activation. Used in the peripartum period antibiotics may impair the immune health of children.
The use of narrow spectrum antibiotics particularly benzyl penicillin has brought a reduction in group B streptococcal infections in newborn babies, but it is a matter for concern that the overall rate of early onset neonatal sepsis remains unchanged, and that this is due to an increase in E. coli infections; most of these are resistant to ampicillin (the form of penicillin most profitable for drug companies) which is more likely to have been prescribed for mothers in labour. Studies suggest that antibiotics given to mothers do alter the developing indigenous flora in the short term, and the "replacement flora" may not be less harmful than those intended for eradication (Stoll et al. 2002; Kenyon et al. 2001). Widespread use of broad spectrum antibiotics within a maternity unit will increase local persistence of resistant organisms and favour opportunistic transmission within the unit.
Risk factors are now recognised for colonisation and infection of babies, especially premature babies, with candida. Chief among responsible antibiotics are the cephalosporins, but delayed feeding, total parenteral nutrition, and prolonged mechanical ventilation are significant. Vancomycin is the antibiotic of choice for infections with coagulase negative staphylococci, often causing the development of resistant enterococci; co-amoxiclav is associated with an increase in necrotizing enterocolitis and other gram negative infections, and erythromycin is a frequent cause of resistance to the group B streptococcus while conferring no outcome benefit except on the sub-group analysis of singletons. It is often prescribed for chorioamniitis but without microbiological surveillance.
Our immune system exists mainly in the gut, and there is epidemiological evidence that its health is adversely affected by antibiotic attack on enteric organisms, leading to the huge increase in atopic and allergic conditions in childhood in recent decades. It is not impossible that this is also responsible for the current increase in the incidence of diabetes. It has been shown in animal experiments that a germ-free environment in the gut leads to disordered immunity and failure to thrive; the "hygiene" or "clean child" hypothesis suggests that a disturbance of immunity in childhood occurs as a result of decreased microbial exposure in early childhood, a hypothesis which has subsequently been extended to encompass other immune-mediated pathologies, notably autoimmunity. Not only is the presence of enteric organisms essential for immune health, but the type of organism has significance too; acquired from the mother's gut during labour, the first species to colonise a newborn baby's intestine are E. coli and enterococci, followed shortly by bifidobacterium; this doubtless explains the proximity of the baby's mouth to the mother's anus during the majority of spontaneous births.
Healthy gut colonisation in the pre-term baby is delayed, and the colonisation which occurs is with coagulase negative staphylococci. The factor most clearly associated with an increased risk of atopy is the use of broad-spectrum antibiotics (Bennet et al. 1986); strong suspicion attaches to feeding with formula milk (Hall et al. 1990), delivery by caesarean section (Gronlund et al. 1999), and separation of the mother and baby on the first night (Montgomery et al. 2000). Good longitudinal studies are needed to link peripartum antibiotic use with immunological health problems in the later life of UK babies.
It is vital to improve awareness of the effects of antibiotic resistance on babies and of the responsible pathogens, using surveillance systems, engaging with microbiologists, and investigating and limiting the use of antibiotics by both mothers and babies. Colonisation with organisms without infection does not warrant treatment, and treatment should be stopped as soon as there is no persisting evidence of infection; and if prescription is unavoidable, narrow spectrum antibiotics should be used. The classic microbiological dictum of never using an antibiotic unless one needs to and never using a broad-spectrum antibiotic when a narrow-spectrum one will do applies more than ever before.
Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons JA, Donovan EF, Stark AR, Tyson JE, Oh W, Bauer CR, Korones SB, Shankaran S, Laptook AR, Stevenson DK, Papile LA, Poole WK. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med. 2002; 347: 240-247.
Kenyon Sl, Taylor DJ, Tarnow-Mordi W et al for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, pre-labour rupture of fetal membranes and preterm labour: the ORACLE 1and II randomised trial. Lancet 2001; 357: 979-994.
Gronlund M-M, Arvilommi H, Kero P, Lehtonen O-P, Isolauri E. Importance of intestinal colonization in the maturation of humoral immunity in early infancy: a prospective follow-up study of healthy infants aged 0-6 months. Arch Dis Child 2000; 83: F186-F192.
Montgomery SM, Wakefield AJ, Morris DL, Pounder RE, Murch SH. The initial care of newborn infants and subsequent hayfever. Allergy 2000; 55: 916-922.
NA: There is little to recommend changing a woman's AED from VPA if she is already pregnant. For women planning pregnancy it would be an advantage to reduce the VPA dose to below 1000 mgs. if it will control her seizures adequately, which might not be the case if her regime was changed to lamotrigine; and with this drug there is a teratogenic dose effect. At present there is no easy solution.
ABR: There is no data to confirm my impression that antibiotics taken in mid-pregnancy have no adverse peripartum effects. The use of probiotics by mothers in late pregnancy and by newborns in early life is known to be effective in reducing the carriage of resistant organisms, and it could be an advantage for women to continue taking them for a period after delivery.
ABR: A lamentable mix of antibiotics is being given at present to mothers suspected of sepsis. It is important to run tests for the identification of infecting organisms immediately prior to instituting antibiotic treatment, and since the most severe infections are usually caused by streptococci and gram negative organisms the combination of penicillin and gentamicin seems to be the right choice.
PB:It is important to identify and follow up long-term adverse effects caused by medication taken by mothers and neonates. How is this to be done? ABR: It is to be hoped that the European Union proposals on medicines for children and community networks will lead to the necessary research being undertaken, with collaboration between disciplines. Unfortunately the expense of long-term research militates against the provision of funding for it; case control studies may be a solution.
Issues around analgesia in pre-term and term labour
Dr Bernadette Loughnan (BL), Consultant Anaesthetist, Northwick Park Hospital, Middlesex
The ideal labour analgesic should be cheap, easy to administer, free of adverse effects on the mother and infant and have minimal effect on the labour.
Pre-term births - before 37 weeks gestation - carry a high rate of instrumental intervention and a 75% rate of perinatal mortality and morbidity. Studies of the mode of delivery are difficult to perform, and while the outcome for the babies is better following elective CS (ECD), the classical method used in the earliest cases may lead to excessive blood loss requiring transfusion and adverse effects on subsequent fertility. A review paper (Lumley 2003) covering six RCTs, and incorporating a meta-analysis of other data, suggests that ECD of very premature infants has increased markedly in the last 20 years. Recruitment to studies is difficult, and cases are often lost as circumstances change urgently. Opiates, with their well-known adverse effects on the baby, are usually chosen for general anaesthesia, and it might seem that anticipatory epidural placement would be an advantage, but the difficulty of predicting when delivery is imminent can leave the epidural in place for long periods.
Entonox can be useful in early labour, particularly in conjunction with the support of partner and midwife , and progress is unaffected, with some mothers able to deliver using nothing else; hydrotherapy and TENS share its advantages. The analgesic effect of pethidine is uncertain, but it has the advantages of being cheap, easily administered by midwives and requiring no special equipment; while it has no negative effect on the progress of labour, it may cause the infant respiratory depression.
Epidural analgesia is very effective, with a low incidence of severe complications; however it is expensive in equipment and manpower, requiring an anaesthetist to initiate and supervise it, may slow the progress of labour, and may rarely cause subsequent back pain. Remifentanil, an ultra-short acting opiate, has taken its place as the epidural analgesic of choice (Thurlow 2002), although it does have the potential to cause respiratory depression in the mother.
Our RCT (Loughnan et al. 2000) had 614 mothers allocated randomly to pethidine and epidural, with opt-out permitted at any time. The analysis of labour outcome was by Intention To Treat (ITT), ignoring crossover during labour from one method to the other. This avoids results being confounded when mothers switch from pethidine to epidural in long labours, which gives an excess of deliveries by caesarean section. Using ITT analysis the two groups had similar vaginal and CS delivery rates.
Although the ideal analgesic agent for labour does not exist, our trial, supported by meta-analysis of others, confirms the good performance of the epidural.
Lumley J. Method of delivery for the preterm infant. BJOG: 2003; 110 (Suppl 20): 88-92
Thurlow JA, Laxton CH, Dick A, Waterhouse P, Sherman L, Goodman NW. Remifentanil by patient-controlled analgesia compared with intramuscular meperidine for pain relief in labour. Br J Anaesth 2002; 88:374-8
Loughnan BA, Carli F, Romney M, Dore CJ, Gordon H. Randomised controlled comparison of epidural bupivacaine versus pethidine for analgesia in labour. Br J Anaesth 2000; 84: 715-9.
Neonatal research: a mother's view
After seven miscarriages, one of them a son at 21 weeks, my husband and I were thrilled to have a viable pregnancy, but at 29 weeks, on my 40th birthday, my waters broke. In the hope that labour would be delayed and that the baby would continue to grow we agreed to hospital admission, but after six days my baby's cord prolapsed. My husband, an anaesthetist on the same maternity unit, was setting up an epidural at that time, but was able to give me the necessary general anaesthetic, and Isis was delivered by CS nine minutes later.
Based on some of the information I had been given during the pregnancy I feared for her health, worried that she would be brain damaged or otherwise ill, and very relieved that she did not have to be transferred from the Chelsea and Westminster Hospital due to a lack of cots in the neonatal intensive care unit. I and all the mothers there had been denied the pregnancy and birth experience which we had anticipated, and we felt guilty for this failure.
Now Isis was the patient, and being given treatment which was beyond my control and drugs of which I was ignorant; for some time the staff were too busy to see me, and the first doctors I saw there were engaged in research. These two women looked very serious; I feared the worst and was angry that they had not been properly introduced, and because they were so intrusive and insensitive in bothering us to agree to allow Isis to be entered into their trial within 24 hours of her birth, when we were exhausted. We understood when we were told that the RCT protocol required this early entry, but I must admit that I had been quite rude to them. Our immediate reaction was to refuse, despite being well aware of the huge benefits to our baby and others due to research, but eventually we agreed to allow Isis to be entered into a probiotic trial. Our reasons were partly selfish; this was a nutrition-based trial, and she would have an advantage because her growth and development would be observed in detail. She would not be subjected to additional pain, and importantly I needed the good opinion of the researchers, who would be taking over her clinical care very shortly.
Isis thrived, and avoided infection; we mothers all believed that this must be due to the probiotic in her diet, although course we did not know whether she was in the group receiving it. Mothers who had refused to enter the trial ascribed this to problems in communication. Confronting emotional parents is unhelpful to recruitment for research, and it might be useful to make easily legible literature describing ongoing research available to women during their pregnancies. Before meeting parents for the first time researchers should inform themselves about the birth history and progress of the baby, know her name if possible, and be able to answer some basic questions about her condition; if there is to be trust this is essential. They need to be clear about any advantages or disadvantages of the trial for this special baby, and about the possible benefits accruing from the results of the trial. At a personal level researchers must speak slowly and clearly, and must be aware that they are trying in every way to gain parents' trust.
For you in research a mother is one of a group; for me she is an individual. Ask us in the right way, and we will give more back to a profession which has done so much for babies past and future.
Where do we go from here? A wish list.
Professor Sir Alan Craft (AC), James Spence Professor of Child Health at the University of Newcastle upon Tyne and Chairman, The Academy of Medical Royal Colleges
Medicines have played some part in the present improved health of children, but the majority of those given to children in the UK are either unlicensed or off-label. Studies leading to drug licensing in children are more difficult and the pharmaceutical industry is not incentivised to become involved with them. As a result children are not guaranteed the safe and effective medicines which should be their fundamental right. They are usually under-dosed rather than overdosed, for fear of adverse effects. Knowledge leading to the formulation and prescription of drugs for children and to the avoidance of errors in dose calculation and of long-term ill effects lacks the essential evidence base.
Body weight and composition varies through early life. The lipid/water ratio changes from the early excess of water which renders water-soluble drugs more active. The livers of small babies are larger in relation to body weight, and while this provides a greater opportunity for the hepatic extraction and metabolic clearance of drugs, it also results in a greater potential for their activation to toxic metabolites. Enzyme functions are immature for the first year, but especially in the first two months, with slowed metabolic clearance, less drug activation but also less removal of activated metabolites. They have relatively larger brains, with a greater blood flow to the central nervous system (CNS) and higher permeability of the blood-brain barrier, greatest in the first two years of life; this renders the CNS more vulnerable to water-soluble drugs. Immature renal function, particularly in the first two months of life leads to the slower elimination of renally cleared drugs and their metabolites. Limited serum protein binding in the first three months can increase the concentration of free drugs in the circulation.
We now have the National Service Framework (NSF) for Mothers and Children and its Standard for Hospital Services and Standard 10, Medicines for Children and Young People. The vision of the NSF is that all children and young people receive medicines that are safe and effective, in formulations that can be easily administered and are appropriate to their age, having minimum impact on their education and life style. Medicines are to be prescribed, dispensed and administered by professionals who are well trained, informed and competent to work with children to improve health outcomes and minimise harm and side-effects from medicines. Children and young people and their parents or carers should be well informed and supported to make choices about their medicines and competent in their administration. The required standard is that children, young people, their parents or carers and health care professionals in all settings make decisions about medicines based on sound information about risk and benefit. They must have access to safe and effective medicines that are prescribed on the basis of the best available evidence.
Other markers are of good practice are equitable access, good decision support material, and the involvement of children and their carers in decision making; good and timely information for children and young people; the incorporation of drugs for children into the clinical governance procedures of Hospital and Primary Care Trusts; and the maximisation of the contribution of pharmacists to the effective and safe use of medicines for children.
The rationale for change is that children and adults are different, and safety needs to be improved. Although medication errors are not more frequent with children, they are three times more likely to cause them harm. They must not be exposed to so many unlicensed medications; there are issues of compliance and the question of when children should take responsibility to be addressed. With improved prescribing there will be fewer errors; better formulations of drugs, sugar-free if possible, are required.
The College of Paediatricians has met with the ABPI and produced recommendations on the following lines:
· Existing researchers need to be brought together into a multidisciplinary network .
· We must develop leadership in paediatric clinical pharmacology by building on existing talent, attracting overseas experts, offering opportunities for subspecialists, and developing strong links with adult pharmacology.
· The number of training opportunities with guaranteed employment must be increased.
· Trainees in paediatric clinical pharmacology and pharmacy must be supported.
· We must encourage funding organisations to earmark money for training and research.
· A strong partnership with industry has to be promoted.
The Department of Health has provided £20 million to support this, and the Medicine for Children Network is now being run from Liverpool. There are very few paediatric clinical pharmacologists in the country and little prospect of improving on the low number; adult clinical pharmacology is also in a very poor state. However willing parents are the Data Protection Act hinders our ability to collect the data necessary for effective research, and continental Europe is becoming a more attractive area in which to set up research.
AC: Since most paediatric clinical pharmacologists are now working in industry we can hope and expect that industry will recognise the advantage to them of becoming involved in research with neonatologists and other paediatricians, as long as the infrastructure is right.
AC: It has been the case that numbers of new drugs have been developed for the treatment of childhood cancer, and this explains the greater ease with which such patients have been recruited into research. It is now unthinkable that new drugs will be introduced without the underpinning of research.
AC: We can expect the science underlying pharmacology, recognised to be a gap in the training at present, to be included in the Paediatric Master Course currently under development.