RNA-Seq provides a molecular SOS from fetuses sickened by their failing placentas

From the BMC Blog – On Medicine – by Professor Stephen Tong

Severe fetal growth restriction is a rare yet one of the riskiest obstetric complications, requiring clinicians make decisions based on ultrasound tests to avoid stillbirth. Professor Stephen Tong, author of a new study in BMC Medicine, explains how his team utilised molecular diagnostics in search of new tool to improve the accuracy of these tests.

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It may not be the loveliest to behold, but the placenta is beautiful in what it does. By providing a constant offering of oxygen and nutrients for the developing fetus to sip on, and spiriting away waste products, the placenta sustains life.While most placentas are remarkably reliable, some function sub-optimally, leading to placental insufficiency. Running short of its nutritional needs, the fetus slows in its growth and becomes ‘growth restricted,’ or small, in utero.Given it reflects poor placental function, it’s no surprise that fetal growth restriction has a strong link to stillbirth risk. A fetus beneath the 10th centile weight (corrected for gestational age) is at a 3-4 fold risk of demise. Luckily, most cases of fetal growth restriction occur around term gestation where, having reached a sufficiently mature stage of development, they can simply be delivered before a stillbirth happens.

Making risky decisions to avoid stillbirth

Severe fetal growth restriction (e.g. growth restriction arising before 32 weeks gestation) is one of the riskiest obstetric complications to befall an unborn baby. Arising from severe placental insufficiency, the stillbirth risk is exceptionally high. While mercifully uncommon, severe fetal growth restriction affects 0.2-0.5% of all pregnancies. In these rare cases, clinicians must judge the optimal time to deliver the fetus. They weigh the probabilities of stillbirth if the pregnancy is left to continue versus the risks of inflicting prematurity if the preterm fetus is delivered unnecessarily early. To help make these risky decisions, ultrasound based tests of fetal well-being are used to determine the likelihood that the fetus is significantly hypoxic (low in oxygen).While ultrasound monitoring for fetal hypoxia has definitely improved perinatal outcomes, it lacks precision. New clinical tools are needed to improve the accuracy of these existing tests. However, after three decades of intensive ultrasound research there may be no further offerings left undiscovered for this diagnostic modality.

Our team decided to hunt elsewhere and turned to molecular diagnostics.

An unusual approach leads to a new discovery

It is now recognised that many organs – including the placenta – steadily release messenger RNA (mRNA) into the bloodstream where they can be sampled and measured.

We gathered a consortium of researchers and specialists who lead referral units managing these high-risk pregnancies across Australia and New Zealand to collect blood samples from 128 cases of preterm fetal growth restriction.

An unusual aspect to our study design is the collection of the blood sample two hours before birth by caesarean section. We contemporaneously matched the mRNA profiles in the mom’s blood with pH of the umbilical cord blood at birth (which retrospectively told us the oxygenation of the fetus during its final moments in utero). This usually meant collecting blood in the anaesthetic bay just before patients were wheeled into the operating theatre. Dangling the incentive of a coffee voucher, we asked obliging anaesthetists to draw extra blood from the IV drip just after it was slotted in. By the end of the study, one beaming anaesthetist showed me her wallet heaving with coffee vouchers!

Another novel aspect is that for the initial discovery phase, we performed RNA sequencing on all 200+ samples (cases and controls). A bold and rather pricey undertaking.

We discovered a slew of circulating mRNAs with remarkably stark differences among pregnancies affected by severe preterm growth restriction compared to healthy pregnancies. Importantly, we went on to validate many of these findings in a new cohort of women from Imperial College and in a small cohort of altruistic women with pregnancies that sadly succumbed to stillbirth.

The future of testing for pregnancies at risk of stillbirth

One candidate stood out as being particularly promising: circulating levels of mRNA coding emp1 (a rather obscure gene) had a particularly strong association with many clinical parameters associated with severe placental insufficiency. In fact, it just might be a circulating molecule with the strongest association between poor placental function and stillbirth yet reported.

The next steps are to undertake additional studies to see whether in fact EMP1 mRNA (or any of our other lead candidates) can add further precision to existing clinical tests. We foresee a future where, whenever ultrasound findings cannot tell us how hypoxic the fetus is, levels of EMP1 mRNA circulating in the blood (or some other molecule) can swoop in and provide an answer.

If developed, such a test could decrease rates of stillbirth. Not only that but a ‘normal’ test result could give clinicians the confidence to leave some fetuses in utero for longer – ones that might otherwise be delivered early using today’s technology (to ‘err on the safe side’). A tool that allows us to safely advance gestation for some fetuses will decrease rates of severe complications of iatrogenic prematurity wrought by delivering unnecessarily early, vastly improving perinatal and lifelong health for these vulnerable babies.

Source – BMC Blog – On Medicine

Hannan NJ, Stock O, Spencer R, et al. (2020) Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth. BMC Med 18(1):145. [article]

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