PE and eclampsia are the primary causes of maternal mortality (18%) in South Africa. An estimated 75% of HDP-related maternal deaths can be prevented.³

A history of spontaneous pre-term births, as well as conditions that compromise uteroplacental blood flow and contribute to vascular insufficiency (eg pre-existing hypertension, renal disease, diabetes, obstructive sleep apnoea, thrombophilia, and autoimmune disorders), increase the risk of HDP.^1,4

Hypertension in pregnancy defined

Chronic hypertension is defined as in-office measurements >140mmHg systolic blood pressure (SBP) or 90mmHg diastolic BP (DBP). Chronic hypertension results in complication in ~5% of all pregnancies, and prevalence rates are increasing due to delayed childbearing.^2,5

Gestational hypertension is defined as transient hypertension specific to pregnancy or the identification of chronic hypertension in the latter half of the gestational period. Risk factors for gestational hypertension, which can progress to PE, include multiple pregnancies (especially twins), a body mass index >30m², age (>35-years), or a family history (especially with a mother or sister affected).^4,5

According to the American College of Obstetricians and Gynecologists (ACOG), gestational hypertension typically presents after 20 weeks of pregnancy with BP >140/90mmHg on two occasions, or higher severe range pressures, necessitating prompt antihypertensive treatment.⁴

PE superimposed on chronic hypertension occurs in women living with pre-existing chronic arterial hypertension, either primary or secondary, who subsequently develop PE.⁵

Criteria for PE, and eclampsia

The ACOG criteria for PE include >300mg urine protein excretion in a 24-hour period or a protein/creatinine ratio ≥0.3. If these testing methods are unavailable, a urine dipstick can be used, with proteinuria defined as a reading of at least 1+.⁴

It should be noted that PE can be present in the absence of proteinuria if the patient has new-onset hypertension with thrombocytopaenia (platelets <100 000 x10⁹/l, renal insufficiency [double of baseline serum creatine or serum creatine >1.1mg/dl], pulmonary oedema, impaired liver function [aspartate aminotransferase and alanine aminotransferase more than twice the upper limit of normal]), or new-onset headache unresponsive to medications with no alternative cause.⁴

Untreated PE causes maternal complications in ~70% of cases and is associated with maternal morbidity in as many as 14% of women. Between 2%-3% of women diagnosed with PE, progress to eclampsia. Eclampsia is typified by generalised tonic-clonic seizures (typically intra-partum or post-partum up to 72 hours after delivery).^3,4

Aetiology of PE: A quick overview

Early-onset PE is characterised by incomplete transformation of spiral arteries, resulting in placental hypoperfusion and foetal growth restriction (FGR). In contrast, late-onset PE involves minimal alterations in spiral arteries, often leading to placental hyperperfusion without FGR.⁶

Normal pregnancy involves increased extracellular fluid and plasma volumes mediated by nitric oxide. However, early-onset PE sees a decrease in plasma volume around 14 to 17 gestational weeks, preceding clinical onset.⁶

Placental development in normal pregnancies involves vascularisation and trophoblast invasion. Endovascular trophoblasts invade spiral arteries, inducing transformation for optimal foetal growth.⁶

Syncytiotrophoblasts act as an interface, preventing direct blood mixing. A low-grade inflammatory response reacts to foetal trophoblasts in normal pregnancies.⁶

Reduced blood flow, defective spiral artery remodelling, and acute arteriosus lead to hypoperfusion in early-onset PE. Placental ischaemia-reperfusion injury contributes to hypertension, proteinuria, and thrombotic microangiopathy.⁶

Pro-angiogenic factors (vascular endothelial growth factor [VEGF], placental growth factor, and transforming growth factor-beta [TGF-β]) play roles in placental angiogenesis.⁶

Elevated soluble endoglin levels in PE block TGF-β1 and VEGF actions, contributing to the imbalance in angiogenic factors. Immune factors, type 1 t-helper (Th) 1 immunity, and inflammation are involved in PE, with cytokines indicating an exaggerated inflammatory response.⁶

The renin-angiotensin-aldosterone system (RAAS) and auto-antibodies (angiotensin [AT]-1AA) targeting angiotensinogen (ANG) AT-I receptors also play roles in PE. RAAS downregulation in PE results in increased sensitivity to ANG-II and AT-1AA.  Elevated AT-1AA levels may contribute to shallow trophoblast invasion and renal damage.⁶

Hydrogen sulphide (H2S), also implicated in PE, has vaso-relaxant and anti-inflammatory properties. Reduced cystathionine gamma-lyase and cystathionine beta-synthase enzyme expressions in PE affect H2S production, crucial for placental development.⁶

Despite more than six decades of research, the exact aetiology of PE remains elusive. An imbalance between angiogenic and anti-angiogenic factors, immune responses, low oxygen tension, and oxidative stress contribute to generalised maternal endothelial dysfunction in PE, causing hypertension, renal endotheliosis, and blood coagulation.⁶

Progesterone’s role in pregnancy

Progesterone plays a pivotal role in ensuring the success of a pregnancy. Naturally secreted by the corpus luteum (CL) in the latter part of the menstrual cycle, and subsequently by both the CL and placenta in early pregnancy, progesterone prepares the endometrium for embryo implantation. Following successful implantation, the CL persists in progesterone production. However, around eight to 12 weeks into gestation, the placenta assumes responsibility for this function, sustaining the pregnancy.⁷

Progesterone exerts different effects on the immune system through various receptors, including nuclear progesterone receptors (nPR), membrane progestin receptors (mPR), and progesterone receptor membrane components (PGRMC).⁸

During pregnancy, elevated progesterone levels have paracrine and endocrine actions, suppressing myometrial contractility, regulating inflammation in leukocytes, and modulating immune responses.⁸

The balance between nPR isoforms, progesterone receptor A and progesterone receptor B, influences progesterone  signalling, with shifting ratios during pregnancy impacting gene expression related to labour.⁸

Non-classical receptors, such as mPRs and PGRMCs, participate in extracellular signalling and cell cycle regulation. In T-cells, membrane-bound progesterone receptors influence signal transduction, calcium mobilisation, and transcription factor phosphorylation, affecting T-cell activation and proliferation.⁸

Progesterone's anti-inflammatory actions involve suppression of nuclear factor-kappa B and mitogen-activated protein kinase pathways, downregulation of pro-inflammatory genes, and modulation of immune cell activity.⁸

In reproductive tissues, progesterone  promotes an anti-inflammatory environment, inhibits cervical changes associated with labour, and modulates innate immune responses. Progesterone  influences immune cell populations, suppresses inflammatory cytokines, and enhances immune tolerance, contributing to a supportive pregnancy environment.⁸

Progesterone's effects on adaptive immune responses involve interactions with glucocorticoid receptors (GR) and progesterone receptors (PR). During pregnancy, regulatory T-cell (Tregs) proportions exhibit dynamic changes, suggesting alternative immunomodulatory pathways.⁸

Progesterone also modulates peripheral blood T-cell differentiation, favouring Th2 subsets with increased interleukin (IL)-4 production. Extracellular progesterone  concentrations during pregnancy suppress interferon-gamma (IFN-γ) production in CD8 T-cells.⁸

In the menstrual cycle, the progesterone-rich luteal phase associates with a decline in Tregs, leukocyte proliferation, and IFN-γ production, favouring a Th2 cytokine profile.⁸

Progesterone influences B-cell lymphopoiesis, suppressing B-cell development and influencing humoral immune responses. Despite promoting a Th2-dominant profile, progesterone negatively regulates high-affinity antibody production. The mechanism of progesterone  action on lymphocytes involves both genomic and non-genomic pathways through different receptors, including mPRs.⁸

Progesterone-induced blocking factor (PIBF), a progesterone-regulated gene, is a potent immune modulator, regulating cytokine synthesis, Th subtype differentiation, and proliferation.⁸

PIBF, abundantly expressed during pregnancy, is crucial for immune tolerance, as reduced concentrations are associated with spontaneous pre-term birth and pro-inflammatory cytokine profiles.⁸

Clinical application of progesterone

Clinical applications of progesterone include its use in treating infertility, preventing miscarriage, and managing pre-term labour.⁷

 The efficacy of progesterone in preventing recurrent miscarriage (or spontaneous abortion, which occurs during the first 20 weeks of pregnancy, typically within the first trimester) was investigated in two studies by Coomarasamy et al.^8,9

In the Progesterone in Recurrent Miscarriages or PROMISE trial, the researchers tested whether or not progesterone given to pregnant women with a history of repeated (≥3 consecutive or non-consecutive) unexplained early pregnancy losses would increase the number of pregnancies leading to live births after at least 24 weeks of gestation, compared with placebo.⁸

Participants (n=836) were randomised to progesterone (400mg twice daily as vaginal capsules) or placebo soon after a positive urinary pregnancy test no later than six weeks of pregnancy, until 12 completed weeks of pregnancy (or earlier if the pregnancy ended before 12 weeks).⁸

The primary outcome was live birth >24 completed weeks of gestation, clinical pregnancy at six-to eight-weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.⁸

 Secondary outcomes included pre-eclampsia, small size for gestational age (<10th percentile for birth weight), preterm pre-labour rupture of membranes, antepartum haemorrhage, and mode of delivery, as well as neonatal variables such as birth weight, arterial and venous pH, Apgar scores, and need for ventilation support.⁸

The rate of live births after 24 weeks of gestation was 65.8% in the progesterone group, as compared with 63.3% in the placebo group. There were no significant difference in secondary outcomes between the two groups. However, the team did note a 25% reduction in the risk of pre-eclampsia in the progesterone group.^1,8

In the Progesterone in Spontaneous Miscarriage or PRISM study, the live birth rate for women with one or more previous miscarriages, was 75% in the progesterone group compared with 70% in the placebo group. The potential benefit appeared to be most strong for women with three or more previous miscarriages, who had a live birth rate of 72% in the progesterone group compared with 57% in the placebo group. The team noted a 37% lower risk of pre-eclampsia among participants receiving progesterone.^1,9

Due to the shared aetiology of miscarriage and PE, it has been hypothesised that progesterone treatment may be effective in reducing the risk of PE. Melo et al recently conducted a systematic review to summarise evidence that micronised vaginal progesterone can reduce the risk of HDP.¹

Their review included 11 randomised controlled studies involving 11 640 women. In three studies vaginal progesterone was initiated in the first trimester and in eight studies it was initiated in the second or third trimesters.¹

The initiation of vaginal progesterone during the first trimester significantly reduced the risk of any HDP (29%) and pre-eclampsia (39%) compared to  placebo. However, initiation of vaginal progesterone in the second or third trimesters did not show a significant reduction in HDP or PE.¹

Conclusion

HDP impact ~18 million women globally. In South Africa, PE and eclampsia contribute to 18% of maternal mortality. The prevention of HDP and PE is crucial, and a recent systematic review report a potential protective effect of vaginal micronised progesterone, especially when initiated in the first trimester. Progesterone, a key hormone in pregnancy, exerts diverse immunomodulatory effects, impacting myometrial contractility, inflammation, and immune responses.

References

1. Melo P, Devall A, Shennan AH, et al. Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis. BJOG, 2023.
2. Mammaro A, Carrara S, Cavaliere A, et al. Hypertensive disorders of pregnancy. J Prenat Med, 2009.
3. Moodley J, Soma-Pillay P, Buchmann E, et al. Hypertensive disorders in pregnancy: 2019 National guideline. SAMJ, 2019.
4. Luger RK, Kight BP. Hypertension In Pregnancy. [Updated 2022 Oct 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430839/
5. Guedes-Martins L. Superimposed Preeclampsia. Adv Exp Med Biol, 2017.
6. Gathiram P, Moodley J. Pre-eclampsia: its pathogenesis and pathophysiolgy. Cardiovasc J Afr, 2016.
7. Coomarasamy A, Williams H, Truchanowicz, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med, 2015.
8. Shah NM, Lai PF, Imami N, Johnson MR. Progesterone-Related Immune Modulation of Pregnancy and Labor. Front Endocrinol (Lausanne), 2019.
9. Coomarasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. NEJM, 2019.