A Peculiar Problem in Pregnancy and the Placenta

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A Peculiar Problem in Pregnancy and the Placenta

Complications and Diagnosis of Pre-eclampsia

When we consider our most important organ its intuitive to choose the heart, the lungs or even the kidneys. However, there’s another without which none of us would be here to have the discussion. This ephemeral organ provides us with the nutrients necessary for development, removes malevolent agents, provides our initial immunity and much more, before being cast off as we enter the world. We are, of course, talking about the placenta. Indeed, all our organs work together to support life and it’s arbitrary to imbue one with more importance than the others. Nevertheless, as our first organ, the significance of the placenta is irrefutable.

Placental dysfunction, along with several other factors, is known to contribute to the development of pre-eclampsia – a complex, multisystem hypertensive disorder of pregnancy. While the aetiology of pre-eclampsia remains largely unknown, the grave complications associated with it have driven development of novel methods for predicting its onset.

Pre-eclampsia and Epidemiology

Pre-eclampsia is traditionally defined as new onset hypertension and proteinuria in pregnancy1, however, the International Federation of Gynaecology and Obstetrics’ (FIGO) clinical definition describes it as sudden onset hypertension (>20 weeks of gestation) and at least one of the following: proteinuria, maternal organ dysfunction or uteroplacental dysfunction2. It is responsible for an estimated 70’000 maternal deaths, and 500’000 foetal deaths globally3. Pre-eclampsia affects around 4% of pregnancies in the US and is more common in low-to-middle income countries (LMICs), displaying an overall pooled incidence of 13% in a cohort from sub-Saharan Africa4. The risk factors for pre-eclampsia are shown in the graphic below.

Pre-eclampsia is associated with increased morbidity and mortality worldwide. In the US, pre-eclampsia is the foremost cause of maternal death, severe maternal morbidity, maternal intensive care admissions and prematurity5.

Classical classification of pre-eclampsia included early-onset (<34 weeks gestation) and late-onset (>34 weeks gestation). However, this classification lacks clinical utility as it does not accurately illustrate maternal or foetal prognosis. Therefore, the International Society for the study of Hypertension in Pregnancy (ISSHP) and contemporary studies prefer to classify pre-eclampsia as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia (after delivery).

Complications

Pre-eclampsia has been associated with acute and chronic complications for both mother and child. Worldwide risk of maternal and foetal morbidity displays adjusted odds ratios of 3.73 and 3.12, respectively (pre-eclampsia vs non pre-eclampsia)6.

Acute Maternal Complications

A range of neurological complications are associated with pre-eclampsia. The most obvious is eclampsia, defined as seizures in pregnant women commonly from 20 weeks of gestation or after birth7. Eclampsia has two proposed mechanisms: abnormal placentation reduces blood supply and causes oxidative stress, leading to endothelial damage; and elevated blood pressure in pre-eclampsia disrupts cerebral vasculature, causing hypoperfusion and damage8. In high-income countries (HICs), most women make a full recovery, however, more severe cases of eclampsia can result in permanent disability or brain damage7.

Stroke is a significant complication of pre-eclampsia, constituting 36% of strokes related to pregnancy9. The hypertension characteristic of pre-eclampsia can weaken the walls of blood vessels causing subarachnoid or intracerebral haemorrhage resulting in haemorrhagic stroke. Ischaemic stroke is also of concern due to blood clotting complications which will be discussed later.

Additonal neurological complications include visual scotoma, cortical blindness, cerebral venous sinus thrombosis, cerebral vasoconstriction syndrome and posterior reversible encephalopathic syndrome (PRES). Notably, the last three in this list frequently manifest postpartum without warning6.

HELLP (Haemolysis, Elevated Liver enzymes and Low Platelets) syndrome is a liver and blood clotting disorder and life-threatening complication of pre-eclampsia. HELLP syndrome most commonly presents immediately postpartum but can manifest any time after 20 weeks of gestation7. Microangiopathy, or small blood vessel disorder, leads to ischaemia and a subsequent increase in oxidative stress and inflammation, causing an increase in liver enzymes and participates in the initiation of HELLP. Thrombocytopenia, or platelet deficiency, is considered a product of platelet depletion resulting from heightened platelet activation triggered by widespread endothelial damage6.

Another blood clotting condition associated with pre-eclampsia is Disseminated intravascular coagulation (DIC)7, described as the dysfunction of the maternal blood clotting system resulting in multiple organ dysfunction syndrome10. DIC can cause excessive bleeding due to lack of clotting proteins, or the formation of clots due to overactive clotting proteins, ultimately causing organ damage10.

As described earlier, proteinuria is included in the diagnostic criteria for pre-eclampsia, suggesting involvement of the kidneys. This is caused by high concentrations of soluble FMS like Tyrosine kinase 1 (sFLT-1), a placental angiogenic factor, which inhibits proteins of the podocyte slit diaphragm6; the machinery involved in preventing the leakage of proteins into the urine11. Reduced levels of Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) stimulates Endothelin 1 expression6, known to promote podocyte detachment, further contributing to proteinuria12.

Finally, Pulmonary oedema, excessive fluid accumulation in the lungs, is an acute and life-threatening complication associated with pre-eclampsia, the likelihood of which is increased via administration of antihypertensive medications6.

Acute Neonatal Complications

There are several documented complications affecting the baby of a pre-eclamptic mother. Firstly, Intrauterine growth restriction (IUGR) can result in underdevelopment of the foetus because of deficient transfer of oxygen and other nutrients from mother to child13. This can result in low birth weight, particularly when pre-eclampsia occurs prior to 37 weeks of gestation7. In pre-eclampsia with severe symptoms, delivery frequently occurs prematurely, either spontaneously or through induction. Preterm delivery can result in complications such as neonatal respiratory distress syndrome and neonates often require ICU admission7. Additionally, there is increased risk of stillbirth in pre-eclamptic pregnancies with relative risk shown to be 1.45 (95% Cl 1.20-1.76)14. Other complications documented in neonates born through pre-eclamptic pregnancies include neonatal thrombocytopenia, bronchopulmonary dysplasia, and a range of neurodevelopment outcomes15.

Long-term Complications

The only known cure for pre-eclampsia is delivery. However, the complications for both mother and child can last long after even an uncomplicated delivery. After a pre-eclamptic pregnancy, women are increased risk of end stage renal disease (4.7-fold), stroke (4-fold) and vascular dementia (3-fold) later in life5. Women are also at increased risk of other cardiovascular disease (CVD) including chronic hypertension, coronary artery disease, congestive heart failure5, and ischaemic heart disease13. In offspring, IUGR increases the risk of development of hypertension and other CVD13. Finally, offspring have been shown to be at higher risk of increased body mass index, changes in neuroanatomy, reductions in cognitive function, and hormonal abnormalities13.

sFLT-1/PlGF ratio

The pathophysiology of pre-eclampsia is complex and enigmatic. However, placental dysfunction is known to be a factor in pre-eclampsia development. The placental-related angiogenic factors, sFLT-1 (anti-angiogenic) and PlGF (pro-angiogenic), have been implicated in this development. This ratio provides a useful measure of placental dysfunction as a sharp increase in sFLT-1 and decrease in PlGF has been shown approximately 5 weeks before onset of pre-eclampsia16.

Until recently, diagnosis of pre-eclampsia was one of clinical manifestation. However, studies such as PROGNOSIS17 and PROGNOSIS Asia18, along with others19,20, have shown strong utility of this ratio. The PROGNOSIS study showed that a ratio cutoff of ≥38 was useful for ruling out pre-eclampsia within 1 week with a negative predictive value (NPV) of 99.3% or 4 weeks with a positive predictive value (PPV) of 36.7%17. The definitions of pre-eclampsia used by ICCHP and American College of Obstetricians and Gynaecologists (ACOG) have a PPV of around 20%, but when used in combination with the sFLT-1/PlGF ratio, the PPV is enhanced to 65.5% for ruling in pre-eclampsia within 4 weeks.21.

Similar results have been shown in an Asian cohort in the PROGNOSIS Asia Study. Using the same cutoff value, this study reported an NPV of 98.9%18. Furthermore, in a sub analysis of this cohort that looked at Japanese participants, a cutoff of ≥38 displayed an NPV of 100% for ruling out pre-eclampsia within 1 week and a PPV of 32.4% for ruling in within 4 weeks22.

Accurate Identification is Essential

Like all clinical assays, those used to determine the sFLT-1/PlGF ratio are subject to rigorous quality control, essential to ensure accurate results and diagnosis. The complications of pre-eclampsia are severe and often life-threating for both mother and child. Early and accurate identification is imperative for optimal monitoring, management, and timely interventions to reduce the risk of the grave consequences associated with pre-eclampsia.

The utility of the sFLT-1/PlGF ratio has been shown over various large cohorts and provides improved identification when used in combination with established clinical definitions. While the enigma of pre-eclampsia persists, the dedication of the scientific community to unravel its complexities ensures a future where expectant mothers may benefit from more effective and tailored strategies to mitigate the risks associated with this puzzling condition. Continued research endeavours will undoubtedly shape the landscape of maternal-foetal medicine, fostering advancements that hold the promise of improved outcomes for both mothers and their unborn children.

At Randox Quality Control,  we’ve introduced our Pre-eclampsia Control to the Acusera IQC range for use with in vitro diagnostic assays for the quantitative determination of PlGF and sFlt-1 in human serum and plasma.

Our true third-party Pre-eclampsia control comes with clinically relevant, assayed target values, is liquid-frozen for user convenience, utilises a human-based, commutable matrix, and has a 30-day open vial stability.

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References

  1. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Obstetrics & Gynecology. 2013;122(5):1122-1131. doi:10.1097/01.AOG.0000437382.03963.88
  2. Poon LC, Shennan A, Hyett JA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre‐eclampsia: A pragmatic guide for first‐trimester screening and prevention. International Journal of Gynecology & Obstetrics. 2019;145(S1):1-33. doi:10.1002/ijgo.12802
  3. Karrar SA, Hong PL. Preeclampsia. StatPearls Publishing; 2023.
  4. Jikamo B, Adefris M, Azale T, Alemu K. Incidence, trends and risk factors of preeclampsia in sub-Saharan Africa: a systematic review and meta-analysis. PAMJ – One Health. 2023;11. doi:10.11604/pamj-oh.2023.11.1.39297
  5. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia. Circ Res. 2019;124(7):1094-1112. doi:10.1161/CIRCRESAHA.118.313276
  6. Dimitriadis E, Rolnik DL, Zhou W, et al. Pre-eclampsia. Nat Rev Dis Primers. 2023;9(1):8. doi:10.1038/s41572-023-00417-6
  7. NHS. Pre-eclampsia. Health A to Z. Published September 28, 2021. Accessed January 3, 2024. https://www.nhs.uk/conditions/pre-eclampsia/complications/
  8. Magley M, Hinson MR. Eclampsia. StatPearls Publishing; 2023.
  9. Crovetto F, Somigliana E, Peguero A, Figueras F. Stroke during pregnancy and pre-eclampsia. Curr Opin Obstet Gynecol. 2013;25(6):425-432. doi:10.1097/GCO.0000000000000024
  10. Costello RA, Nehring SM. Disseminated Intravascular Coagulation. StatPearls Publishing; 2023.
  11. Kawachi H, Fukusumi Y. New insight into podocyte slit diaphragm, a therapeutic target of proteinuria. Clin Exp Nephrol. 2020;24(3):193-204. doi:10.1007/s10157-020-01854-3
  12. Trimarchi H. Mechanisms of Podocyte Detachment, Podocyturia, and Risk of Progression of Glomerulopathies. Kidney Dis (Basel). 2020;6(5):324-329. doi:10.1159/000507997
  13. Turbeville HR, Sasser JM. Preeclampsia beyond pregnancy: long-term consequences for mother and child. American Journal of Physiology-Renal Physiology. 2020;318(6):F1315-F1326. doi:10.1152/ajprenal.00071.2020
  14. Harmon QE, Huang L, Umbach DM, et al. Risk of Fetal Death With Preeclampsia. Obstetrics & Gynecology. 2015;125(3):628-635. doi:10.1097/AOG.0000000000000696
  15. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal Preeclampsia and Neonatal Outcomes. J Pregnancy. 2011;2011:1-7. doi:10.1155/2011/214365
  16. Verlohren S, Galindo A, Schlembach D, et al. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol. 2010;202(2):161.e1-161.e11. doi:10.1016/j.ajog.2009.09.016
  17. Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. New England Journal of Medicine. 2016;374(1):13-22. doi:10.1056/NEJMoa1414838
  18. Bian X, Biswas A, Huang X, et al. Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia. Hypertension. 2019;74(1):164-172. doi:10.1161/HYPERTENSIONAHA.119.12760
  19. Hughes RCE, Phillips I, Florkowski CM, Gullam J. The predictive value of the sFlt‐1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2023;63(1):34-41. doi:10.1111/ajo.13549
  20. Nikuei P, Rajaei M, Roozbeh N, et al. Diagnostic accuracy of sFlt1/PlGF ratio as a marker for preeclampsia. BMC Pregnancy Childbirth. 2020;20(1):80. doi:10.1186/s12884-020-2744-2
  21. Verlohren S, Brennecke SP, Galindo A, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens. 2022;27:42-50. doi:10.1016/j.preghy.2021.12.003
  22. Ohkuchi A, Saito S, Yamamoto T, et al. Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study. Hypertension Research. 2021;44(7):813-821. doi:10.1038/s41440-021-00629-x

 

 


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