The mainstay of hypertensive treatment is lifestyle modifications and pharmacotherapy, options of which have remained stagnant for the past 20 years. Initial antihypertensives including thiocyanates, ganglion blocking agents (mecamylamine, hexamethonium) and catecholamine depletors (Reserpine, Raulwolfia alkaloids) were hampered by a narrow therapeutic index along with intolerable side effects and limited effectiveness. Hypertension treatment was transformed in the 1950s with effective treatments including thiazide diuretics, spironolactone, hydralazine and methyldopa [5], of which the latter remain the few medications used for hypertension in pregnancy today.

The 1970s saw the introduction of alpha- and beta-blockers, calcium channel blockers (CCB) with angiotensin converting enzyme inhibitors (ACE-i) and angiotensin II receptor blockers (ARBs) following in the 1990s. Unfortunately, during this boom of antihypertensive drug development, the impact of the thalidomide tragedy meant that instead of enforcing research to ensure the safety of medications in women, women of childbearing potential were ostracised from clinical drug trials. The 1977 Food and Drug administration (FDA) policy excluded women of child-bearing potential from clinical trials in drug development, thus leaving clinicians to decide blindly the risks and benefits of off-label prescribing in this population. The use of post-surveillance monitoring as the cornerstone of investigating maternal and fetal outcomes of medications in pregnancy has inherent bias, often giving conflicting evidence that is littered with confounding variables. Sildenafil, originally developed for treatment of hypertension, caused the “Pfizer riser” side effect for which it was promptly remarketed. By excluding women in clinical drug trials, side effect profiles whether good or bad, and pharmacokinetic sex differences in women are often missed leading to increased post-licensing side effects and overtreatment of women [6]. Nonadherence is a significant obstructor to current cost-effective antihypertensive treatment and women are 3 times more likely to be nonadherent when compared to men [7]. This may be explained by differing side effects as women are more affected by hyponatremia, hypokalemia and arrhythmia during treatment with diuretics, oedema with dihydropyridine CCBs and cough with ACE-i [2]. The reversal of the FDA policy excluding women from clinical drug trials did not occur until 1993, but as evidenced by the detrimental exclusion of clinically vulnerable pregnant women from COVID trials in 2020, the effects of such policies very much linger [8]. It is poetic that thalidomide, used as an unstudied and unlicensed antiemetic in pregnancy, should cause such a long-lasting impact and dearth of drug research in women.

Novel antihypertensive classes include small interfering RNA (siRNA) against angiotensinogen, Neprilysin and aldosterone synthase inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRA) and dual endothelin antagonists. Many new antihypertensive classes remain focussed on modulating blood pressure by blocking an aspect of the renin-angiotensin-aldosterone system (RAAS). Older antihypertensives that similarly targeted this system are incompatible with pregnancy or those planning pregnancy as they cause fetotoxicity including renal dysfunction, oligohydramnios, intrauterine growth restriction and death [9]. It seems a missed opportunity that newer antihypertensives are therefore equally restricted in pregnancy by the same mechanism of action. Endothelin-1 antagonists such as Bosentan, account for three of the ten “Pregnancy Prevention Programme (PPP)” enlisted drugs due to their teratogenic effect causing craniofacial malformations [10]. With one third of pregnancies in the UK being unplanned or ambivalent [11], it is paramount that new classes of antihypertensives target novel mechanisms that, from the outset, make them compatible with pregnancy.

Of the novel mechanistic targets, siRNA appear the most exciting for treatment in women as larger molecules are less likely to transfer across the placenta and off-target side effects are likely to be reduced. Furthermore real-world data from COVID-19 RNA vaccines were reassuringly efficacious in pregnant people without fetal or maternal harm [12]. siRNA targeting soluble FMS-like tyrosine kinase-1 (sFLT-1), an anti-angiogenic protein marker of pre-eclampsia, and hepatic angiotensinogen have already shown promise in pregnant and pre-eclampsia animal models [13, 14]. However, entrenched gender knowledge gaps in women’s health means robust models of the physiological changes in pregnancy are lacking and developing such medication to fruition will likely be prolonged.