Tag Archives: Pregnancy

A Cluster RCT of an Internet-Based Programme to Promote Activity and Reduce Postpartum Calorie Intake in Poor Hispanic Women

When I read the introduction and methods section of a research paper I often try to guess the result before I read on. In the case of the paper above [1] I guessed a null result. I guessed wrong. In this cluster RCT (12 clusters, 371 patients), a carefully designed and piloted internet-based intervention to nudge women to healthy living reduced mean mass by a statistically significant 2.3kg compared to standard care. There was no effect on exercise as assessed by a pedometer. The authors express surprise that there was ‘no’ reduction in calorie intake, but they over-interpret this finding. The variance in measured calories was very wide and the p-value was 0.06. They make the mistake of reifying the 95% limits on the confidence interval.

The 2.3kg mean intervention effect may strike some as nugatory. However, a relatively small reduction in mass can have a worthwhile metabolic and health effect, as we showed in a study of liver function tests.[2] Postpartum weight loss is important because it is associated with long-term obesity, is largely truncal, and increases risk in any subsequent pregnancy. Dr Ponnusamy Saravanan from CLAHRC WM is collaborating with Prof Kamlesh Khunti (Director of CLAHRC East Midlands) in tackling the problem.

— Richard Lilford, CLAHRC WM Director

References:

  1. Phelan S, Hagobian T, Brannen A, et al. Effect of an Internet-Based Program on Weight Loss for Low-Income Postpartum Women: A Randomized Clinical Trial. JAMA. 2017; 312(23): 2381-91.
  2. Lilford RJ, Bentham L, Girling A, et al. Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study. Health Technol Assess. 2013; 17(28): 1-307.
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The Brain Speaketh Unto the Gut and the Gut Answereth Back

In the previous News Blog I mentioned the hypothesis that an altered gut microbiome may trigger chronic fatigue syndrome.[1] I promised more on the topic. Many years ago I chaired the Scientific Advisory Committee for the MRC Oracle study. This was a study of antibiotics versus no antibiotics to prevent preterm labour.[2] There were no differences in short-term outcomes in children of the antibiotic versus control mothers. But CLAHRC WM associate Sara Kenyon and her colleagues followed the children up to the age of seven. The results show markedly higher levels of cerebral palsy in the intervention (antibiotic) group over the control (no antibiotics) group, and in one of the two antibiotics used the risk of other functional impairments was also increased.[3] I was also inclined to pass this off as a chance finding – type 1 error. Now I am not so sure – recent evidence in Nature [4] shows that antibiotics in baby mice cause changes on their frontal cortices, affect the blood-brain barrier, and alter behaviour. These changes are partially preventable by probiotic administration. If maternal antibiotics are bad for the baby brain, then presumably so is neonatal antibiotic administration. It would be interesting to follow up neonates of given gestational age, mass and clinical condition to compare outcomes in those given antibiotics and non-antibiotics. Yes, I know it will be confounded by indication for antibiotics, so a null result would be more informative than a positive result.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Biological Underpinnings of Chronic Fatigue? NIHR CLAHRC West Midlands News Blog. 21 April 2017.
  2. Kenyon S, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001; 357: 979-88.
  3. Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, Taylor DJ. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet. 2008; 372: 1319-27.
  4. Leclercq S, Mian FM, Stanisz AM, et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat Commun. 2017; 8: 15062.

Computer Interpretation of Foetal Heart Rates Does Not Help Distinguishing Babies That Need a Caesarean from Those That Do Not

In an earlier life I was involved in obtaining treatment costs for a pilot trial of computerised foetal heart monitoring versus standard foetal heart monitoring (CTG). The full trial, funded by NIHR, has now been published in the Lancet,[1] featuring Sara Kenyon from our CLAHRC WM theme 1. With over 46,000 participants the trial found no difference in a composite measure of foetal outcome or intervention rates. Perinatal mortality was only 3 per 10,000 women across both arms and the incidence of hypoxic encephalopathy was less than 1 per 1,000. Of course, the possibility of an educational effect from the computer decision support (‘contamination’) may have reduced the observed effect, but this could only be tested by a cluster trial. However, such a design would create its own set of problems, such as loss of precision and bias through interaction between method used and baseline risk across interventions and control sites. Also, the control group was not care as usual, but the visual display IT system shorn of its decision support (artificial intelligence) module.[2] Some support for the idea that control condition affected care in a positive direction, making any marginal effect of decision support hard to detect, comes from the low event rate across both study arms. Meanwhile, the lower than expected baseline event rates mean that any improvement in outcome will be hard to detect in future studies. So here is another topic that, like vitamin D given routinely to elderly people,[3] now sits below the “horizon of science” – the combination of low event rates and low plausible effect sizes mean that we can move on from this subject – at least in a high-income context. If you want to use the computerised method, and its costs are immaterial, then there is no reason not to; economics aside there appear to be no trade-offs here, since both benefits and harms were null.

— Richard Lilford, CLAHRC WM Director

References:

  1. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet. 2017.
  2. Keith R. The INFANT study – a flawed design foreseen. Lancet. 2017.
  3. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.

Pregnancy Before Age 16 – Dropping Quite Rapidly From a Peak in 1997

Tracking four databases, a recent study finds sharply falling ‘teenage pregnancy’ rates in England, starting in 1997 and accelerating in 2007.[1] Rates have fallen fastest in the most deprived areas, albeit from a very high base. The reduction has been much larger in England than in other European countries where the decline is also observed. It is difficult to know exactly why, but proximal causes (increasing availability of long-acting contraception) and distal causes (gradually improving educational standards in England) are both correlated in this study with lower teenage pregnancy. I think we should go even further in removing barriers to use of contraception in young people – for instance it should be available without prescription, or if prescription is required it should be available on site, given evidence cited in a previous News Blog.[2]
— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wellings K, Palmer MJ, Geary RS, et al. Changes in Conceptions in Women Younger Than 18 Years and the Circumstances of Young Mothers in England in 2000-12: an Observational Study. Lancet. 2016; 388: 586-95.
  2. Lilford RJ. Contraception – a Huge Cause of Controversy Around the World. NIHR CLAHRC West Midlands News Blog. August 8, 2014.

Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain

This News Blog has frequently discussed synaptic pruning [1] [2] – a process that occurs in the foetus at mid-gestation, children at around the age of two, and in late adolescence. Abnormalities in neural synaptic pruning are associated with diseases, such as schizophrenia and autism.[3] It turns out that there is another period of synaptic pruning – during pregnancy. Functional MRI shows that many areas of grey matter shrink in pregnancy. Greater pruning is associated with higher scores on standard questionnaires measuring a mother’s attachment to her baby.[4] More brain does not necessarily mean better brain.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening Up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. van Spronsen M, Hoogenraad CC. Synapse Pathology in Psychiatric and Neurologic Disease. Curr Neurol Neurosci Rep. 2010; 10(3): 207-14.
  4. Hoekzema E, Barba-Müller E, Pozzobon C, et al. Pregnancy leads to long-lasting changes in human brain structure. Nature Neurosci. 2016.

If You Want to Reduce Partner Violence or Teenage Pregnancy, Then Teach Algebra and History?

There is little doubt that highly educated men are less likely than poorly educated men to perpetrate violence against their partners,[1] and that highly educated women are less likely than poorly educated women to get pregnant in their teens.[2] But what is going on here – which way does causality run? Certainly, an educated man is likely to earn more than one less educated. More money means less stress, and since stress is a harbinger of partner violence, it is plausible that education leads to less violence through this mediating (intervening) variable. Alternatively, the kind of person who acquires education may be the sort of person who is less innately pre-disposed to violence than a person who does not acquire education. A person who seeks out education may have greater mental resources, such that a wider range of responses are available to him – and hence he is less likely to lash out. But could it be that education per se increases moral rectitude, even when the education is not targeted at moral behaviour? One can devise a theory for such an effect. Algebra, history and other ‘academic’ subjects exercise the capacity for abstract thought. Could the capacity spill over from the topic of instruction to influence behaviour more generally? Compassion, for example, is abstract – it requires the ability to imagine what another person is feeling. Teaching abstract academic subjects may spill over in to heightened sensitivity to the suffering of others. This hypothesis could be tested neurophysiologically – highly educated persons, on average, may manifest greater specific responses on functional neuro-imaging than those of similar IQ, but lower educational attainment, when confronted with a compassion-arousing event. The brain, after all, is a learning machine that is permanently altered by education. This might explain why sex education has a rather small effect on teenage pregnancy, but being educated is associated with a large effect. It is sometimes said that education refers to what is left when all the facts have been forgotten, or to quote BF Skinner more accurately, “Education is what survives when what has been learnt has been forgotten”?

— Richard Lilford, CLAHRC WM Director

References:

  1. Abramsky T, Watts CH, Garcia-Moreno C, et al. What factors are associated with recent intimate partner violence? findings from the WHO multi-country study on women’s health and domestic violence. BMC Public Health. 2011; 11: 109.
  2. Girma S & Paton D. Is education the best contraception: The case of teenage pregnancy in England? Soc Sci Med. 2015; 131: 1-9.

Update on Zika for News Blog Readers

A recent review of epidemiological evidence from the Center for Disease Control (CDC) in Atlanta confirms the association of Zika arbovirus infections during pregnancy with microcephaly in the infant, with a risk of about one in 100.[1] It is probable that the risk of neurological effects less serious than microcephaly is also increased. A recent BMJ paper [2] analyses a cohort of microcephalic children born of mothers with Zika virus infection in pregnancy. They did not just measure the size of the head relative to length and weight. All babies underwent CT scan, MRI, or both. They all manifested strikingly similar features on neuro-imaging, and these features are largely distinct from the other known causes of microcephaly, including those associated with infections with other viruses, such as cytomegalovirus. The famous philosopher of science William Whewell, argued that if information of different types all corroborate the same theory, then that is powerful support in its favour.[3] The CLAHRC WM Director thinks a causal role for the virus is pretty much settled – we may assume that the Zika virus is indeed a cause of severe (and perhaps less severe) neurological damage in the foetus.

— Richard Lilford, CLAHRC WM Director

References:

  1. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects — Reviewing the Evidence for Causality. N Engl J Med. 2016; 374: 1981-7.
  2. Aragao MFV, van der Linden V, Brainer-Lima AM, et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ. 2016; 353: i1901.
  3. Whewell W & Butts RE. William Whewell’s Theory of Scientific Method. Pittsburgh: University of Pittsburgh Press. 1968.

Cluster Trial of Home Visits for Newborn Children in Sub-Saharan Africa

Forty percent of childhood deaths in low- and middle-income countries (LMICs) take place within the first month after birth. Trials conducted in Asia have shown that an intervention whereby home-visits are made over this crucial period of life is effective. Would it work in Africa? To find out, Betty Kirkwood and colleagues randomised 197 clusters in Ghana to intervention and control.[1] Mothers in the intervention clusters were to receive two home visits in pregnancy and three in the first week after birth. Coverage was good and the proportion of mothers who adopted health promoting behaviours increased. These behaviours included use of anti-mosquito bed-nets, timely transfer to a facility when appropriate, breastfeeding, ‘kangaroo’ care, delayed bathing of the baby, and hand-washing. Reductions in neonatal mortality observed in this trial alone were not significant, but a significant 12% reduction in mortality was estimated when the data were combined with those from the Asian trials in a meta-analysis. The CLAHRC WM Director could not find out whether the study was rural or urban. Trials of women’s groups [2] provide positive results in rural areas but not slums. It would be interesting to examine the effect of place of residence further since half of all African people will soon be urban, and more than half of those people will live in slums.

— Richard Lilford, CLAHRC WM Director

References:

  1. Kirkwood BR, Manu A, ten Asbroek AHA, et al. Effect of the Newhints home-visits intervention on neonatal mortality rate and care practices in Ghana: a cluster randomised controlled trial. Lancet. 2013; 381(9884): 2184-92.
  2. Prost A, Colbourn T, Seward N, et al. Women’s groups practising participatory learning and action to improve maternal and newborn health in resource-limited settings: systematic review and meta-analysis. Lancet. 2013; 381(9879): 1736-46.

 

Abnormal Glandular Cells on a Smear Test: What Do They Mean?

When a woman has a smear test, two types of cell are sampled – squamous cells from the ectocervix, and glandular cells from the endocervix:

054 DC - Abnormal Glandular Cells

When abnormal cells are found they are mostly squamous cells from the ectocervix. But about one time in twenty they are glandular cells from the endo-cervix. The squamous cells, meanwhile, can have either a high-grade or a low-grade abnormality.

A recent Swedish study followed up over three million women who had had a cervical smear.[1] Over 15 years, over 3% of women with high-grade squamous cell abnormality and nearly 1% with low-grade squamous cells abnormality developed invasive cancer – almost always squamous cell cancer. But what about the much smaller population of women with abnormal glandular cells? Here about 2.5% developed cancer over the follow-up period – usually adenocarcinoma. The risk is greatest over the first few months, thereafter accumulating very gradually. The high risk post-smear is, of course, because the smear is the trigger for the biopsy. The very slow progression rate over subsequent years should be highly reassuring for any woman who has had an abnormal smear result. As cone biopsy is associated with worse pregnancy outcomes, the CLAHRC WM Director would advise women with abnormal glandular cells to have regular smear test and complete their families as soon as possible. Testing for different types of papilloma virus may help determine whether the risk is higher or lower than the above risk of 2.5%. This study shows the value of long-term registry data of the sort Sweden is famous for.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wang J, Andrae B, Sundström K, et al. Risk of invasive cervical cancer after atypical glandular cells in cervical screening: nationwide cohort study. BMJ. 2016; 352: i276.

Exposure of the Baby to a Rich Mixture of Coliform Organisms from the Birth Canal.

Previous research has pointed out that a good draught of such organisms seem to be healthy, as children brought up after delivery by Caesarean have a much higher incidence of atopic allergic reactions than those delivered through the birth canal.[1] Moreover, the colonic microbiome differs across babies born by vaginal vs. abdominal routes. Many have taken this evidence to heart, and have started to paint the baby’s face with a swab marinated in vaginal secretions. A balanced editorial in the BMJ [2] says that such a practice should not be recommended lest the baby be inoculated with less benign organisms called Beta Strep, resident in some vaginas. But if a woman wishes to practice such a procedure, she should not be inhibited from doing so, pending a trial big enough to determine the net long-term effects.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Neu J, & Rushing J. Cesarean versus Vaginal Delivery: Long term infant outcomes and the Hygiene Hypothesis. Clin Perinatol. 2011; 38(2): 321-31.
  2. Cunnington AJ, Sim K, Deierl A, et al. “Vaginal seeding” of infants born by caesarean section. BMJ. 2016; 352: i227.