ART and preterm birth - What is the link?

Preterm birth is associated with a number of adverse health conditions contributing to increased rates of infant mortality, morbidity and long-term disability.[1] For example, 3-4% of very preterm and very low birth weight babies have Cerebral Palsy. [2]

Speaking at COGI 2018, Prof. Andrew Shennan explained that the issue is considerable, costing the NHS around £1 billion a year.  To be able to effectively tackle the problem, we must understand the key causal factors along with developing and improving management and prevention techniques.

 

Is ART driving premature pregnancy?

The link between ART and increased incidence of multiple pregnancy is well established.[3] In 2014, data from the Centers for Disease Control and Prevention (CDC) indicated that over 20% of all births following ART were multiple births.

Also established is the understanding that multiple pregnancy can result in higher rates of mortality and morbidity both for the mother and child.[2] One of the key complications resulting from multiple pregnancy is pre-term birth. In a thought-provoking session, Prof. Isaac Blickstein discussed why we therefore must consider the major impact that ART could be having on rates of premature pregnancy.

Using mathematical analysis of current preterm and Cerebral Palsy population statistics, Prof. Blickstein demonstrated that out of 100,000 spontaneous births, 2000 twins would be expected, of which 1685 would be very premature and 59 would have Cerebral Palsy.  In contrast, just 10,000 births by ART would be expected to produce 7400 twins, 740 very premature births and 26 cases of Cerebral Palsy.

But how about using real world data? Well, sharing data from a recent population trial, Prof. Blickstein indicated that the incidence of twins after ART born at <32 weeks increased 27-fold from 1987 to 2010 and has not reduced from the peak incidence in the last decade. He suggested that this high level of multiple pregnancy is a key driver of the issue of pre-term birth that we see today.  

 

Managing preterm birth

The speakers agreed that unfortunately there is no clear and definitive strategy to manage pre-term birth, especially in regards to multiple pregnancy. It was discussed that short cervical length is clearly associated with preterm labour and can be used in predicting and preparing for prophylactic intervention. These include:

-          Progesterone

o   While progesterone has been shown to be effective in singleton birth, it has not in multiple pregnancy, even if the delivery is high risk.[4]

-          Cervical Pessary

o   There is no clear evidence to the benefit of the cervical pessary, with some supporting studies and some suggesting no benefit at all.

o   However, Prof. Ben Mol discussed that the treatment could be effective for patients that have a short cervix (25-30mm). He recommended that it may especially be useful for women with multiple pregnancy, as progesterone is not shown to be effective.

-          Cerclage

o   Cerclage needs to be further researched in modern randomised controlled trials. However, Prof. Shennan explained that it could be beneficial in high risk cases.

o   Abdominal cerclage was not recommended as a first line treatment however could be effective for women who had a failed vaginal cerclage.

-          Lifestyle factors

o   Smoking and obesity were outlined as factors increasing risk of complication.

In the UK, Public Health England have announced they will aim to reduce preterm birth to 6% by 2025. While this may not necessarily be reached, it hopefully means that there will be budget available to help future research.


Sources:

[1] Keelan JA, Newnham JP. Recent advances in the prevention of preterm birth. F1000Res. 2017;6:F1000 Faculty Rev-1139. Published 2017 Jul 18. doi:10.12688/f1000research.11385.1

 [2] Kim Van Naarden Braun, Nancy Doernberg, Laura Schieve, et al. Birth Prevalence of Cerebral Palsy: A Population-Based Study. Pediatrics. Jan 2016, 137 (1) e20152872; DOI: 10.1542/peds.2015-2872

 [3] Multiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble? Seminars in Fetal and Neonatal Medicine, 19(4), 222-227, 2014 doi: https://doi.org/10.1016/j.siny.2014.03.001

 [4] Klein, K. , Rode, L. , Nicolaides, K. H., Krampl‐Bettelheim, E. , Tabor, A. and , (2011), Vaginal micronized progesterone and risk of preterm delivery in high‐risk twin pregnancies: secondary analysis of a placebo‐controlled randomized trial and meta‐analysis. Ultrasound Obstet Gynecol, 38: 281-287. doi:10.1002/uog.9092

Preventing bleeding in pregnancy

Postpartum haemorrhage (PPH) is a significant cause of maternal deaths, accounting for around 25% of maternal deaths worldwide (1). A high percentage of the deaths from PPH occur in low- and middle-income countries, a clear demonstration of the unfortunate difference in healthcare infrastructure that we see in the world today. In this blog we discuss what PPH is, the current guidance for managing the condition and whether it could be time to re-evaluate this guidance.

 

What is PPH?

PPH is characterised by significant blood loss at childbirth and associated with serious maternal morbidities including multiorgan failure. It is defined as blood loss of more than 500 mL from the female genital tract after delivery of the foetus (or >1000 mL after a caesarean section) (1).

Why does PPH occur?

During childbirth, a woman’s womb muscles contract in order to limit the bleeding following detachment of the placenta. PPH occurs when these muscles do not contract strongly enough or if the placenta has been left in the womb, resulting in significant blood loss.

Managing PPH – is time to update the guidance?

Naturally healthcare professionals’ preference will be to try and prevent PPH from occurring. Identifying factors that may pre-dispose a woman to PPH, for example placenta praevia or uterine fibroids is key to ensuring that clinicians can plan ahead and make available the necessary resources (1).

When managing PPH, the World Health Organisation (WHO) recommend oxytocin as the first choice, first line treatment (2). However, there are several alternatives. Ergometrine, ergometrine/oxytocin combinations, misoprostol and the newer uterotonic drug carbetocin have all been shown to be efficacious in preventing cases of PPH (3).

With this wide choice of first line treatments available, new research has aimed to answer the question: Do the current recommendations need to be updated?

One recent randomised control trial suggests that a change in guidance could be required. The researchers ask whether in resource-poor countries, oxytocin is the best choice? After all, oxytocin requires special storage conditions to remain stable and effective. This cold chain storage required to transport and store oxytocin may not be available or reliable, causing an increased risk in emergency settings (4). With the majority of cases of PPH occurring in low- and middle-income countries, there may be an need to recommend alternative treatments in a first instance.

Of course, while storage and transportation of a drug is important, efficacy and safety must also be considered. This has been studied in a recent Cochrane review, which suggested that oxytocin in isolation may not be the optimal choice for preventing PPH when compared with alternative treatments (3).

However the debate is not over. At the COGI congress held in London on 23rd-25th November, a special workshop is being held on ‘the prevention and management of bleeding in pregnancy: all about PPH’. Here data from the recent CHAMPION and iMOX clinical trials will be discussed alongside data from the Cochrane review and expert opinions.

We will be there to share with you the very latest in this fascinating discussion, providing a roundup of the key data and conclusions. We hope you are as excited as we are!

 

Sources:

  1. Chandraharan Edwin, Krishna Archana. Diagnosis and management of postpartum haemorrhage. BMJ. 2017; 358:j3875

  2. World Health Organisation. WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. World Health Organization. 2012.

  3. Gallos ID, Williams HM, Price MJ, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database of Systematic Reviews. 2018; 25(4).

  4. Widmer M, Piaggio G, Nguyen T, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med. 2018; 379(8):743-752