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Predicting pre-eclampsia

Pre-eclampsia remains unpredictable, despite numerous biochemical and biophysical efforts to provide pointers. Working on history taking may prove of some value so North et al (BMJ 2011;342:d1875) embarked on an international study of over 3000 healthy nulliparous women which screened for pregnancy endpoints (the SCOPE study).

The women were interviewed at the start of the second trimester, routine biometry and Doppler studies were carried out around 20 weeks and the later development of pre-eclampsia tracked. It turned out that 5% did show signs and symptoms of pre-eclampsia with the following points on history indicating an increased risk: young maternal age, higher mean arterial blood pressure, raised BMI, family history of pre-eclampsia, family history of coronary heart disease, the woman having a low birth weight, vaginal bleeding for at least 5 days during early pregnancy or a duration of the sexual relationship of six months or less. The only protective predictor was a previous miscarriage of at least 10 weeks gestation with the same partner.

Adding the ultrasonic data did not improve the SCOPE prediction tool which raises the predictability of history taking to about 10%. Maybe adding the biochemical markers will increase the value of this interesting but inconclusive line of investigation.

Nifedipine & preterm labour

The management of preterm labour involves the acute suppression of uterine contractions. By inhibiting the end-organ response it is presumed the initial stimulus will not remain operative or the incident producing it has passed. It is a conveniently uninvestigated aspect of preterm labour research – so are randomized trials using placebo controls which are scarce and nifedipine has never been subjected to this gold-standard form of investigation (Caritis AJOG 2011;204:95-6).

Most trials of uterine activity suppression test one drug against another and look at relative efficacy and side-effects rather than neonatal outcomes. However in the present ethical climate it may be that comparative efficiency is the best that can be hoped for and the best evidence comes from a meta-analysis by Conde-Anudelo et al (AJOG 2011;204:134 e 1-20).

Their work shows nifedipine to be superior to beta-adrenergics and magnesium sulphate for tocolysis of women in preterm labour, so if a decision is made on clinical grounds to suppress the myometrium then there is guidance in favour of nifedipine for the person in charge of the case.

Hot flush treatment

There are limited non-hormonal treatments for women seeking relief from hot flushes. Peri- and postmenopausal women may not wish to take estrogens and selective serotonin reuptake inhibitors (SSRIs) offer a reasonably good option for decreasing the frequency, severity or bothersome effects of hot flushes.

A report by Freeman et al (JAMA 2011;305:267-74) indicates that the SSRI escitalopram is effective in controlling flushes in healthy menopausal women.
As usual in controlled trials for flushes about one third of volunteers had a 50% reduction in symptoms on the placebo but more than half had a similar beneficial effect from 10 – 20 mg per day of escitalopram over 8 weeks. The active substance had few side effects and it was convincing that 3 weeks after the trial ended those who took the escitalopram had the return of more hot flushes than those “coming off” the placebo.

For the record the participants had at least 4 flushes or night sweats a day before treatment and there were no racial differences between African-American and white women who were equally represented in the sample population. Estrogens are the treatment of choice for menopausal symptoms but escitalopram appears to be an option in reducing the frequency, severity and bother of menopausal vasomotor symptoms.

Treatment of depression in pregnancy

Women during their childbearing years are susceptible to depression. In developed countries more than 10% of women take antidepressants during their reproductive life - most commonly selective serotonin reuptake inhibitors (SSRIs). The safety of these drugs in pregnancy is critical and a study by Pedersen et al from Denmark adds to prescribing principles (BMJ 2009; 339: b3569).


The researchers correlated congenital malformations with maternal antidepressant use in half a million children and found no overall increased risk. However the drugs were associated with septal defects of the heart. This was found for all SSRIs, especially when combinations were used or different drugs were prescribed serially. The absolute increase was from a background rate of 0.5% to 0.9% for single medications and 2% for multiple prescriptions.


This risk must be weighed against the dangers of not treating major depression or using psychotherapy. The American College of O&G has stated that women can continue or start SSRI antidepressants in pregnancy but should be appraised of the risks, however small (Chambers BMJ 2009; 339: b3525).

Preterm infants and infection

Preterm infants are at risk of a host of morbidities. Most obviously their immature respiratory and metabolic systems place them at a disadvantage while their fragile cardiovascular anatomy and physiology makes them prone to cerebral and gastro-intestinal incidents.

Also linked to poor outcomes, especially in very low-birth-weight infants of less than 1500g, is infection. About 20% of these babies will develop serious infections while in intensive care units. Nosocomial infections occurring after 3 days of age carry major risks of mortality or impaired neuro-development and the smallest are the most vulnerable. There are enormous short-term costs of hospital treatment plus the long-term financial implications of looking after mentally compromised survivors.

Hard on the heels of encouraging magnesium sulphate research to reduce cerebral palsy risk come data on the use of lactoferrin to lower the risk of neonatal infections. Lactoferrin is the major whey protein in human milk and has many functions in early immune processes (Kaufman JAMA 2009; 302:1467-8). Apart from antimicrobial activity, it promotes healthy gut flora and enhances the immature immune system. It is found in higher quantities in colostrum than mature milk, again suggesting a natural boost immediately after delivery.

Manzoni et al (JAMA 2009; 302: 1421-8) studied the administration of bovine lactoferrin, with or without an adjuvant against placebo to a series of very low-birth-weight infants and found some promising results. Subjects receiving the lactoferrin had bacterial and fungal sepsis rates of 6% whereas the placebo group rate was 17%.

The smaller the infant the greater the impact of the lactoferrin so another promising door appears to be opening in the care of preterm infants.

The screening process

The future of cervical screening is being carefully scrutinised. There is no doubt that cytology is one of the most valuable of all screening modalities, being able to detect pre-cancerous lesions while they are amenable to curative procedures that prevent more serious disease.

The profession and the public are analysing the role of all population screening strategies with the harms being objectively assessed as well as the benefits. There is a temptation to become caught up in the preventative fervour of prophylactic screening without looking at the downside implicit in all programmes. These negative aspects are derived from an over-reaction to minor deviations or difficult-to-interpret results, as well as the psychological and emotional fall-out generated by false positives. There is a spectrum of under-recognised harm from a pre-occupation with abnormal labels, through to the financial interests of business to grow the screening industry.

Health professionals exhort their patients to prevent disease and it is easy to slip into the simplistic mantra of early detection being the equivalent of prevention. Screening is no more preventative than insuring your home is preventative of its burning down. While reminding ourselves of the differences between screening and prevention, it is as well to remember the fundamentals of an effective screening test which should have the following characteristics (Clark Cancer Control 1995;2:485-92):


1. The disease sought should be an important health problem
2. A presymptomatic stage of the disease should exist
3. The natural history of the disease should be well understood
4. There should be an acceptable screening test available
5. Screening tests should be acceptable to the population being tested
6. Outcomes after presymptom diagnosis and treatment should be better than those after symptoms
7. Reduced morbidity/mortality should outweigh harms from false-positive tests
8. Benefits of the test should be achieved at acceptable risk

So does population based cervical cytology measure up to these ideals?

The massive reduction in deaths from cervical cancer in countries where programmes have been introduced does not preclude its re-evaluation as every intervention must be reconsidered in the present economic melt down. Fortunately cytology does hold up cost-effectively in developed countries like the United States where the burden of the disease has decreased by 75% but there are other strategies which need to be considered in developing countries where the costs of clinics, laboratories administration and personnel are prohibitive.

The role of HPV DNA testing in screening is starting to emerge. At present HPV tests are used to triage women with equivocal cytology who may or may not need colposcopy.

The next focus for HPV tests has been in women over the age of 30 years. These women are past the stage of self-limiting infections, and if they are HPV negative with normal cytology then they may constitute a group in whom fewer smears are necessary. Less frequent screening carries large financial implications.

Castle et al (Obstet Gynecol 2009;113:595-600) looked at the number of women who had oncogenic HPV positive tests in the general population of California and evaluated their cytology at the same time. Those between 30 and 34 years had 10% HPV oncogenic positive results but this dropped to around 5% in women older than 40 years. In the entire population the HPV positive rate was lower than anticipated thus not realising epidemiologists' fears of a sharply increased need for further investigation if widespread HPV screening is introduced. Conversely women with negative HPV tests plus negative cytology had a very low risk of incipient precancer and their screening can safely be extended beyond 3 years.

In some practices an “annual smear” has become traditional and women may be reluctant to give up their routine check-ups for fear of failing to detecting early disease. Cotesting with both cytology and HPV DNA may resolve this issue.

When to stop screening is an unsettled matter. There is no point in cytological screening in women who have had their cervix removed by hysterectomy for benign indications. Vault smears are not justified, but for older women with a cervix, when should screening end? Recommendations vary from country to country with 65 or 70 being the most frequently advised age on both sides of the Atlantic but this is in low-risk women who are asymptomatic. Certainly the latest data from Denmark (Rebolj et al (BMJ 2009; 338:b1354) indicates that negative smears in women in their fifties have the same predictive value as women in their thirties suggesting continued vigilance is a good idea.

Finally, Strander (BMJ 2009:338:b809) believes the story will unfold as the technology improves with computer generated risk factors guiding the frequency and duration of screening. Surely algorithms can be devised which include lifestyle considerations plus previous cytology and HPV results which would streamline services, save unnecessary retesting as well as indicating when to stop screening?

Breast Cancer Screening

The national routine breast screening programme in the UK has doubled the number of women screened in the last 10 years and it is now approaching 2 million per year. This is due to more women availing themselves of the service and an extension of the previously restricted age offer to 50 - 65 year-olds by a further 5 years. The latest data reveal twice the number of cases detected compared with a decade ago, with most being invasive and half being less that 1.5cm in size which are not detectable by hand (Mayor BMJ 2009;338:315).

The claim is made that the programme is serving an “increasing number of women's lives” but this is not a universally accepted point of view.

A spirited rebuttal to unconditional screening programmes is made by Gotzsche et al (BMJ 2009;338:446-8) in which the point is made that mammography has a downside - cost, discomfort, false-positive findings and over-treatment. The authors castigate programmes whose information leaflets fail to mention the harmful effects of screening and over-emphasize the benefits. They argue that choices about screening can only be made by healthy women if the cons as well as the pros are presented. They looked at 31 leaflets from publicly-funded programmes and found them all to be biased so they have produced their own evidence-based contribution (see www.bmj.com).

Women should not be coerced or made to feel guilty if they choose not to undergo screening - informed choice implies unbiased information.


While on the topic of screening for women, the latest figures of cervical screening in the UK are quoted by Kmietowicz (BMJ 2009;338:497). Since the national programme was introduced 30 years ago, the number of diagnoses of cervical cancer have halved. The disease has dropped from the 6th to the 13th most common cancer in women and mortality rates have plummeted. The only negative data show fewer young women are taking up screening invitations but, as a group, those under the age of 35 remain vulnerable.

Antioxidants and cancer prevention

Antioxidants are the hope of the healthy. Millions of people take supplements, usually vitamins or antioxidants, in the hope that these extras will prevent chronic conditions. The supplement industry is vast but many of the popular products so eagerly ingested lack scientific evidence of benefit.

The latest casualties are selenium and vitamin E for the prevention of cancer in men. In the largest randomised controlled trial ever undertaken, comprising over 35 000 people, these substances were no more effective than placebo in reducing the rates of prostate or any other cancers in middle-aged and elderly men. The trial was supposed to last 12 years but was stopped half-way when an interim audit shown no effect of each agent or a combination (Lippman et al JAMA 2009;301:39-51).

In a second smaller trial of 15 000 male doctors - also middle-aged - vitamins E and C were pitted against placebo and, again, after 8 years there was no decreased risk of any cancer found (Gazanio et al pp 52-62).

It seems clear that healthy men and women do not lower their chances of developing cancer by taking vitamins C, E or selenium. Half of all American adults take supplements. Will these definitive studies change their habits?

At the other end of the age spectrum, other additives have also not been faring very well. Theoretically, giving preterm infants high doses of polyunsaturated fatty acids in their diets could assist brain structure and function. Babies born before 33 completed weeks of gestation are at risk of developmental and behavioural problems, but it is unclear whether standard or high dose fatty acids in their early feeds will make any difference to long-term outcomes.

Makrides et al (JAMA 2009;301:175-82) supplemented the diet of the mothers whose expressed breast milk formed the bulk of the infant's nutrition. The intervention group took capsules containing tuna oil while the controls had a standard diet, resulting in the babies receiving either high or low doses of docosahexanoic acid (DHA) from birth to the date when they would have reached term in utero. Examining both groups at 18 months there was no difference in the neuro-developmental outcome between those receiving the DHA supplementation or not. However, the girls did better than the boys which may lead to even higher dose trials.

Miscarriage and the next pregnancy

Women who miscarry their first pregnancy are naturally distressed, but what reassurance about the next pregnancy is appropriate? If she conceives again and the pregnancy continues to viability, is she at increased obstetric risk, or not?

Battacharya et al (BJOG 2008;115:1623-9) followed up a large group of women who experienced a spontaneous early pregnancy loss and compared them to women whose first pregnancy reached viability and to women having their second pregnancy after a first normal outcome.

Unsurprisingly, the lowest risk was found in the group who had an initial uncomplicated pregnancy, followed by primigravidas, then those who had experienced a miscarriage. One miscarriage was associated with more obstetric complications, such as threatened miscarriage, pre-eclampsia, induced labour, instrumental delivery, preterm delivery and a low birth-weight infant, compared with those who had a successful pregnancy. Compared with primigravidas, they were more at risk of threatened miscarriage, induction, preterm labour and post-partum haemorrhage.

It is not clear whether this expectation of behaving like a “virtual primigravida” is related to the way the miscarriage was dealt with - by surgical evacuation, expectant management or medical evacuation. It is equally unclear whether waiting before trying for a replacement pregnancy will give a woman a better chance of a successful outcome. Steer suggests that an interval of 18 months may improve her chances (Editor's Choice BJOG Dec 2008).

Interesting article on drug makers and journals

The New York Times has an interesting article on HRT and a drug maker.

Flu immunisation in pregnancy

Pregnant women should be vaccinated against influenza viruses. Being immunised reduces their chances of being hospitalised during pregnancy and decreases the risk of fetal anomalies. Although immunisation with inactivated flu vaccine is recommended by the World Health Organisation and national health bodies, few mothers receive the vaccine and little is known about its effect on neonates.

What is known is that natural maternal antibodies protect babies in the first few months of life but there are no data on whether vaccinating the mother also offers protection. Zaman et al (NEJM 2008;359:1556-64) now report on a trial that looked at the effectiveness of a trivalent inactivated vaccine in reducing flu in pregnant women and their offspring for 6 months after delivery.

Compared to mothers and infants not given the vaccine, babies whose mothers received the vaccination intervention had a two-thirds reduction in the risk of having laboratory- proven flu while the mothers had a one-third reduction in their likelihood of respiratory fever. The study was carried out in Bangladesh and showed that the remarkable effectiveness of the vaccine conveyed infant immunity for a longer duration than that offered by passive antibody acquisition from the mother. The “two for the price of one” benefit to mother and infant is an additional incentive, with 5 pregnant women needing to be treated to prevent one illness in her or her baby.

The cost of time saving

In developed countries people turn their clocks forward in spring and backwards in autumn. Forward-turning in spring means an hour is “lost” which usually means an hour less sleep and this reduction can be stressful until people's physiology adjusts. But can losing one hour of rest have a real effect? It seems so if the incidence of myocardial infarcts is anything to go by.

Janszky & Ljung from Sweden (NEJM 2008;359:1966-8) showed that coronary events are more common when people are deprived of their extra hour when they turn their clocks forward. Hospital admissions for infarcts rose significantly across the land, especially 2 days after change-over, compared to 2 weeks earlier or 2 weeks later. The effect was consistent over many years and most pronounced in people younger than 65 years old.

As if to prove the point, the opposite effect was found in autumn when the Swedes had fewer than average heart attacks immediately after the “extra hour” was added. The work suggests there are subtle relationships between sleep patterns, stress and cardiac events.

The Six Habits of Highly Respectful Physicians

A good article on The Six Habits of Highly Respectful Physicians in the New York Times.

Is there a cognitive cost of being a twin?

Multiple pregnancies have come under intense scrutiny because they are associated with prematurity and growth restriction. In developed countries, high rates of multiple pregnancies following assisted reproductive technology have been cited as a reason why preterm delivery rates remain stubbornly high and perinatal statistics have plateaued.

Long-term outcomes of twins take decades to be determined and it is described that twins born in developed countries half a century ago had lower IQs and academic performances than singletons. However, recent figures from Scandinavian studies show no differences between singletons and twins as measured by all cause mortality and academic achievement (Christensen & McGue BMJ 2008;337:a651:245-6). Perhaps modern antenatal care and catch-up interventions have nullified the discrepancies, but there is strong evidence that disadvantage no longer applies in these sophisticated environments.

It is of interest that a Taiwanese study of twins born in the mid-1980s shows that the subjects had lower academic achievements than singletons and had a lesser probability of attending college (Tsou et al pp 277-80). Is it possible that developing socio-economic factors play a role still, while these factors have been eradicated in developed countries?

HRT and quality of life

Women take hormone replacement therapy (HRT) to improve their quality of life. Symptoms such as hot flushes, sleep difficulties, vaginal dryness, unsatisfactory sexual function and emotional disturbances are the main indications for commencing HRT. These will remain the reasons for prescribing HRT despite the Women's Health Initiative trial casting doubt on the balance of benefits for women starting treatment 10 to 15 years after the menopause.


Another study running in parallel to the WHI trial was the women's international study of long duration oestrogen after the menopause (WISDOM) investigation (Welton et al BMJ 2008;337:a1190 (550-3). It was scuppered by the WHI results but there were sufficient data to look at quality of life outcomes over one year in women taking combined HRT or placebo. The domains in which the replacement therapy proved significantly better were vasomotor symptoms, sexual functioning, sleep problems, night sweats, vaginal dryness and aching joints or muscles. On the downside, more women complained of breast tenderness and vaginal discharge.


These women were also initiating treatment a considerable time after their menopause which is not ideal but the fact that they derived benefits restores some faith in the role of HRT in its primary function - symptomatic relief of hypo-estrogenic effects. There was no discernable influence on depression or other climacteric symptoms over the short-term. The jury is still out on the possible protective effects on cognitive function, protection from Alzheimer disease and cardio-vascular effects when HRT is started soon after menopause and continued for many years.


Another feature of HRT may be its effect on gastro-esophageal reflux. Jacobson et al (Arch Int Med 2008;168:1798-804) report on a large observational study in which women using estrogens were more at risk of experiencing heartburn than non-users. Their odds ratio was 1.66 and those taking combined HRT had only slightly less risk. The larger the dose and the longer the duration of use, the greater the likelihood of symptoms. The absolute risk is approximately 1 in 4 women will report such effects, and taking estrogens increases a woman's chances of being in the symptomatic category.

UK breast screening

“All screening programmes do harm; some do good as well and, of these, some do more good than harm”. This is the leading statement in an article by Gray et al discussing the introduction of the UK national breast screening programme 20 years ago (BMJ 2008;336:480-3). To maximise the good - early detection - and minimise harm - unnecessary investigations - any programme has to have ongoing quality assurance to ensure minimum standards and set improvement targets. The quality of any service depends on the skill and experience of those running it, as well as the resources allocated, especially the equipment.

The UK scheme aims to detect 5 breast cancers for every 1 000 women screened and send less than 70 per 1 000 for unnecessary further testing. All women aged 50 - 70 years are offered screening every 3 years with 2 views now the norm, resulting in more than 18 million sets of mammograms since the programme's inception. It is estimated that 100 000 breast cancers have been detected with the saving of about 1 400 lives per year (Mayor p 527).

Multidisciplinary centres have replaced diagnostic clinics and employ radiography experts, pathologists, surgeons, radiotherapists and oncologists, resulting in better comprehensive services with faster turn-around times and improved data collation. Since the screening programme was introduced, breast cancer in the UK is no longer the most common cause of death from cancer in women.

Overweight in pregnancy

Being overweight or obese is endemic in the United States. A body mass index between 25 and 30 is overweight, over 30 obese, over 35 grossly obese and over 40 morbidly obese. According to these criteria, more than 25% of women are obese when they conceive. There are 4 million births each year in the US, so about a million deliveries involve obese women.

The consequences are enormous. Routine care is more difficult starting with basic clean-catch urine specimens and venipuncture no longer being straightforward. Palpation, blood pressure measurement and ultrasound readings are compromised so monitoring presents problems. Co-morbid conditions of diabetes and hypertension are exacerbated or develop during pregnancy so these pregnancies move towards the high-risk category with increasing surveillance requiring more frequent visits, wider investigations and greater expense.

As BMI increases, so do complications and caesarean section rates, both of which add to costs according to an in-depth study by Chu et al (NEJM 2008;358:1444-153). Their research showed the increased use of all antenatal facilities with rising obesity and these strongly favoured doctors rather than nurses as well as more frequent outpatient attendance and longer in-patient stays. The greater the BMI, the greater the complications and the costs, which is a huge concern to health management organisations.

There is a strong association of rising BMI with decreasing socio-economic status in the US, so it appears those who can least afford to are placing themselves at risk and need most medical care at greater financial hardship.

May Jass Out

These are genuinely interesting times as new means of investigating old problems are being found. The work on the genetic signatures of breast tumours, the anti-immune treatment of vulvar neoplasia and the detection of the fetus' Rh blood group are all developments that could have implications for practice - and all published in one month.

Equally important is the information about the acceptability of medical evacuation after a miscarriage and advice about HPV screening as a routine. These articles could inform a change in our practice.

Also practically, it seems safe to prescribe bisphosphonates to post-menopausal women but giving testosterone to pre-menopausal women with unhappy sex lives looks unpromising.

Finally, the trends in exclusive breast feeding appear to be improving in developed countries and we can all influence attitudes in this regard. Perhaps in 10 years time mothers will regard 4-6 months of breast feeding as a positive action to benefit their children. Let us hope so.

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Cord blood storage - a new idea

Commercial opportunists encourage new parents to have their baby's cord blood stored for the next 25 years in case it could save his or her life in the future. Indeed, stem cell transplants from cord blood are used for the equivalent of bone marrow donations, often to patients with leukaemia. There may also be future advances where mesenchymal cells could be useful in treating chronic disorders and these potential applications have encouraged private businesses to lure the up-front costs of £1500 for the collection and storage of neonates' cord blood.

But the odds of the blood ever being used are low - estimated to be between 1 : 2 700 and 1 : 20 000 - and the commonest indication, childhood leukaemia, may require stem cells from a donor who does not have the carcinogenic mutation. Also, insufficient blood is available, so cord banks offer a more realistic solution and that is the view of all recognised expert groups, including the Royal College of Obstetricians and Gynaecologists. The problem is that cord banks developed altruistically have not taken off in the public sector, with less than 1% of live births contributing their cord blood in Europe.

A possible public / private partnership has been initiated by Virgin Health in the UK whereby, for the same cost, 20% of the blood is set aside for personal use and 80% donated to a communal bank (Fisk & Atun BMJ 2008;336:642-4). It is an intriguing proposition and may offer an alternative for those wishing to protect their own interests - no matter how remote - and assist those less financially well-off.