“Research highlights” is a weekly round-up of research papers appearing in the print BMJ. We start off with this week’s research questions, before providing more detail on some individual research papers and accompanying articles.
- After in vitro fertilisation, how effective is elective single embryo transfer compared with double embryo transfer?
- Does dietary supplementation with B vitamins or omega 3 fatty acids prevent further cardiovascular events in people with a history of such problems?
- For pregnancies with intrauterine growth restriction at term, does induction of labour have adverse neonatal outcomes compared with expectant monitoring?
- Are breastfeeding women who undergo HIV seroconversion during the postnatal period at high risk of transmitting the virus to their infants?
- How do specific causes of neonatal death contribute to socioeconomic inequalities in neonatal mortality in England?
One embryo or two?
Concerns about the risks of having twins or triplets have led to a gradual reduction in the number of embryos transferred during in vitro fertilisation (IVF). D J McLernon and colleagues have now filled an important gap in the evidence base for this practice, answering additional questions on the effect of single versus double embryo transfer in different subgroups of women and on secondary outcomes such as miscarriage, preterm delivery, and low birth weight.
Their meta-analysis of individual patient data from randomised trials found that elective single transfer is safer than double and, although live birth rates are lower after single transfer in a fresh IVF cycle, this difference is overcome by replacement of an additional frozen single embryo. As using a frozen embryo avoids the need for surgery to harvest an egg, the authors argue in the full online version of the paper that “many would consider that this is a relatively small price to pay compared with the long term consequences of [multiple and] preterm birth.”
Managing intrauterine growth restriction at term
Intrauterine growth restriction at term is associated with increased perinatal morbidity and mortality. Obstetricians often induce labour in such cases to prevent negative outcomes and stillbirth, although this procedure is also has its risks.
K E Boers and colleagues conducted an equivalence trial in the Netherlands to establish whether induction is associated with worse neonatal outcomes than expectant monitoring, the other common approach to managing intrauterine growth restriction. Pregnant women who had a singleton pregnancy beyond 36 weeks’ gestation with suspected intrauterine growth restriction were randomly allocated to induction (n=321) or expectant monitoring (n=329). The difference in the incidence of the primary outcome—a composite measure of adverse neonatal outcome that included factors such as death before hospital discharge and admission to the intensive care unit—between the induction and expectant monitoring groups was not statistically significant.
“This is an important study, and will probably inform clinical care for the foreseeable future,” write editorialists Louise Kenny and Lesley McCowan. They suggest that the lack of difference in adverse outcomes supports the use of either strategy, depending on the wishes of the woman, although they advise that the trial did not measure the effect of suboptimal growth on stillbirth and that induction of labour may be more appropriate to prevent this “rare but devastating outcome.”
During manuscript review, peer reviewers pointed to the small number of women in each group and the large proportion of women that refused randomisation (452 out of the 1116 originally eligible for inclusion), who were on average older, better educated, and healthier than the women who were randomised. But as one of the reviewers noted: “It’s unlikely that a larger trial could be conducted . . . and I note that it took them four years to randomise this group of participants.”
Transmission of HIV via breast feeding
The risk of mother to child transmission of HIV is estimated to be as high as 25-35%. Transmission can occur in the uterus, during delivery, and during the breastfeeding period, although not much is known about the rates of infection via breast feeding.
According to Jean Humphrey and colleagues, who conducted a study of more than 4000 Zimbabwean infants and mothers who ever tested HIV positive during the 24 month study period, the risk of breastfeeding associated transmission can be as high as one in four. The proportion of infants who were infected at two years of age was higher in women who seroconverted during the postnatal period (that is, during maternal primary infection) than in those who did not appear to seroconvert during breast feeding (that is, were chronically infected; 24% v 14%).
The authors also found that among women who seroconverted postnatally, roughly two thirds of cases of breastfeeding associated transmission occurred during the first three months after infection, when antibody levels would be too low to be detected by diagnostic tests designed to detect HIV antibodies, such as ELISA. As such, repeat HIV testing of women during antenatal care would miss these women and would thus have only a modest effect on breastfeeding associated HIV transmission, they say.
Writing in a linked editorial, Jeffrey Stringer and M Bradford Guffey agree with this sentiment, adding: “only primary prevention will protect infants against transmission from mothers who are acutely infected but seronegative at the time of testing.”
Deaths in early life in England: what explains the gap between rich and poor?
The brilliant gapminder.org website, founded by Swedish professor of international health Hans Rosling, has an array of animated graphics about poverty and mortality, including this one on neonatal deaths worldwide. Unsurprisingly, the UK hardly figures on gapminder.org’s global charts. But even in the UK trends in neonatal mortality raise important questions.
Lucy Smith and colleagues’ retrospective cohort study analysed time trends in perinatal mortality in England to understand why poorer babies are at increasingly greater risk than richer ones, despite a government target to reduce the deprivation gap in infant mortality in England by 10% between 2003 and 2010. While all cause neonatal mortality fell from 31.4 per 10 000 live births in 1997-9 to 25.1 per 10 000 live births in 2006-7, excess deaths associated with deprivation increased from 32.3% in 1997-9 to 51.0% in 2003-5 and then decreased to 37.5% in 2006-7. Nearly 80% of the deprivation gap was explained by differences in deaths related to either immaturity or congenital anomalies.
In the full online version of the paper the authors say that research on the link between deprivation and prematurity should be a major priority: “Our lack of understanding about the everyday environmental influences on the risk of preterm birth and major congenital abnormalities seems to be a significant impediment to the development of a rational strategy for diminishing the influence of deprivation on measures of early childhood mortality.”