“Hi Doc, I feel unwell today and my blood pressure is going up … What is ongoing?”
For many pregnant ladies it starts as a daily discomfort while the pregnancy was apparently well progressing, however the well-trained physician will not lose any time before personally checking the blood pressure and urine to confirm the suspect and inform the lady accordingly: “I am afraid you are at risk of developing preeclampsia (PE)”. And this may be the start of unexpected troubles.
What is PE?
Preeclampsia (PE) is a multisystem progressive disorder of pregnancy affecting up to 5% of pregnancies and potentially leading to serious morbidity and mortality.
In its typical presentation it starts with high blood pressure, increased amounts of proteins in urine (proteinuria) and/or other lab signs of organ damage. PE usually begins after 20 weeks of pregnancy in women whose blood pressure had previously been normal. Weight gain and swelling (edema), to some extent normal in pregnancy, may develop very fast. In a few serious cases, the blood pressure continues to increase and complications, affecting and putting at risk both the mother and the fetus may appear. PE is the most common cause of pre-term birth.
Who is at risk?
PE typically affects women at their first pregnancy and is likely to relapse in following pregnancies of the same lady. Besides a PE in a previous pregnancy, the risk factors include pre-existing hypertension and/or diabetes, multiple pregnancies, pregnancy from assisted reproduction and autoimmune diseases.
However, the strongest risk factor for PE is oocyte donation: Studies report that the same women may develop PE after oocyte donation from different donors and the problem does not disappear if donated sperm is used: thus, it is a host (woman) issue. The case of oocyte donation is intriguing because it points to immune issues. Differently from a own oocyte pregnancy, in oocyte donation the fetus is entirely extraneous to the hosting mother from the immune point of view, and
The only effective treatment is early delivery, which is itself a negative outcome, whereas low dose aspirin is used as a preventive tool in pregnancies with risk factors for PE.
A large multi-country prospective study [Hoffman 2020] in otherwise unselected nulliparous singleton pregnancies demonstrated a significant preventive effect of aspirin in the reduction of pre-term deliveries. However, although significant, the clinical gain was very modest with a reduction of incidence of pre-term delivery from 13.1% to 11.6% (i.e. a decrease of 1.5%). Moreover, in a more recent larger size study [Lin 2022] involving pregnancies at high risk of PE low dose aspiring did not exert any preventive effect. In summary, there is a strong need for better effective interventions in PE, both for treatment and prevention.
The pathogenesis of PE involves an abnormal placentation with defective development of spiral arteries (lack of neo-vascularization) and reduced vascular flux in the uterine artery (lack of vasodilation). The strongly increased incidence of PE in pregnancies from oocyte donation (entirely allogenic) and a specific defect of T regulatory (Treg) lymphocytes points to an added immune defect (lack of innate immunity).
It has now been well understood that the placentation process is strictly related to the activity of the endogenous gasotransmitters with a primary role for an early and progressive increase of the release of hydrogen sulfide (H2S). This is an endogenous gasotransmitter released by homeostasis regulated enzymatic processes (release on demand) as well as intravascularly with non-enzymatic mechanisms (background activity). The gas interacts with the heme centre of metallo-proteins and also by modifications of enzymatic proteins and membrane channels (persulfidation), thus modifying the activity of thousands of proteins, as well as by epigenetic regulation of key genes.
H2S has been defined as the master regulator of pregnancy. Released by the granulosa cells and by the corpus luteum [Estienne 2019], it is involved in the immunotolerant shift of the endometrium in preparation of implantation [Wang 2020] (activates the FoxP3 gene inducing the differentiation of Tregs [Yang 2015]) and keeps the myometrium quiescent avoiding the expulsion of the pre-implantation embryo. Thereafter, it is increasingly released by the placenta [Lechuga 2019] to stimulate the neoangiogenesis [Chen 2017] and the vasodilation within the uterine district [Li 2020]. The release continues until final fetal maturation when a sharp fall of H2S triggers myometrial contractions and the labour [You 2017].
The clinical findings strongly confirm the role of H2S in PE. The placentae of PE patients exert a reduced expression of H2S-releasing enzymes [Holwerda 2012] and inhibition of the same enzymes in placenta explants inhibited trophoblast invasion in vitro, decreased placental growth factor (PlGF) and increased the release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) [Wang 2013]. In vivo, the blood level of H2S was 4-fold lower in PE pregnancies [Chaudhuri 2019a] and inversely correlated with diastolic and systolic blood pressure and with proteinuria [Chaudhuri 2019b]. Finally, H2S was shown to inhibit the secretion of sFlt-1 and sEng [Sanchez‑Aranguren 2020].
The enhancement of H2S signalling candidates as the first disease-modifying treatment for PE, but the drug industry could not yet provide a suitable drug because the modulation within a safe window of H2S concentration is not yet possible. It has been now shown that it is possible to increase the endogenous release of H2S, within the control of homeostatic mechanisms, by means of selected micronutrients [Dattilo 2022]. Briefly, a supraphysiologic dose of activated vitamin B6 (pyridoxal 5-phopsphate – P5P) can increase both the activity of the H2S-releasing enzymes and of the non-enzymatic system, which are both B6 dose-dependent. L-cystine and taurine synergize with B6 by increasing the availability of the substrate for H2S release, cysteine.
The above micronutrients (P5P + L-cystine + taurine) are safe, cheap and widely available and, if effective in inducing H2S signalling also in PE pregnancies, might lead to meaningful clinical improvements, which warrants clinical investigations.
• Holwerda KM et al (2012). Hydrogen sulfide producing enzymes in pregnancy and preeclampsia. Placenta 33 (2012) 518-521
• Lechuga TL et al (2019). E2β stimulates ovine uterine artery endothelial cell H2S production in vitro by estrogen receptor-dependent upregulation of cystathionine β-synthase and cystathionine γ -lyase expression. Biology of Reproduction, 2019, 100(2), 514–522
• Li Y et al (2020). Hydrogen Sulfide Relaxes Human Uterine Artery via Activating Smooth Muscle BKCa Channels. Antioxidants (Basel) 2020 Nov 13;9(11):1127
• Lin L et al (2022). A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China. Am J Obstet Gynecol 2022;226:251.e1-12
• Sanchez‑Aranguren LC et al (2020). Bioenergetic effects of hydrogen sulfide suppress soluble Flt‑1 and soluble endoglin in cystathionine gamma‑lyase compromised endothelial cells. Sci Rep 10, 15810 (2020)
• Wang K et al (2013). Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia. Circulation 2013 Jun 25;127(25):2514-22
• Wang B et al (2020). Trophoblast H2S Maintains Early Pregnancy via Regulating Maternal-Fetal Interface Immune Hemostasis. The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12
• Yang R et al (2015). Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. Immunity 2015; 43, 251–263
• You X et al (2017). Endogenous hydrogen sulfide contributes to uterine quiescence during pregnancy. Reproduction 2017 May;153(5):535-543