New data about preeclampsia: some possibilities of prevention

Abstract

This concise report deals with the known effects of progestogen lack in early pregnancy with failure of implantation and blood supply to the placenta depending on proper trophoblast invasion, spiral artery remodeling, and vessel dilatation. The pathophysiology of preeclampsia will be outlined and the most recent data on the effect of dydrogesterone presented. Dydrogesterone appears to be able to reduce significantly the development of preeclampsia. The effect is related to begin with such prevention and this should be continued until 37th weeks of gestation which would also mean prevention of premature labor.

Chinese abstract

关于先兆子痫的新数据：预防的一些可能性

摘要

这份简要报告解决了妊娠早期孕激素缺乏导致着床失败, 胎盘血供取决于适当的滋养层侵入以及螺旋动脉重塑和血管扩张的已知影响。本文将概述先兆子痫的病理生理学和最新的地屈孕酮效应数据。 地屈孕酮似乎能够显著减少先兆子痫的发展。 这种效果与开始这种预防有关, 应该持续到妊娠第37周, 这也意味着早产的预防。

关键词: 先兆子痫; 妊娠期高血压; 螺旋动脉发育; 地屈孕酮的作用

Keywords:

• Preeclampsia
• hypertension in pregnancy
• spiral artery development
• effect of dydrogesterone

Introduction

Each year 10 million women worldwide develop preeclampsia (PE) and approximately 76,000 die due to PE and related hypertension disorders. The number of babies, who die of this pregnancy disorder, is thought to be in the order of 500,000 per year [1]. PE and its related disorders, such as hypertension in pregnancy with an incidence of 2–13% or more are responsible for nearly 40% of premature birth delivered before 35th weeks of gestation [2].

We must, therefore, continue our research efforts to understand the etiology, prediction as well as developing prevention or treatment, which is among the biggest challenges in maternity care [3]. In 2012, the medical cost of preeclampsia calculated in the USA for the 12 months after delivery in total about 2.8 billion US Dollars (1.03 billion for the mothers and 1.15 billion for the infants) [4].

It is widely accepted, that PE begins with an asymptomatic phase during the first trimester characterized by an insufficient trophoblast invasion and an incomplete spiral artery remodeling process. Both these processes contribute to an increase in oxidative stress and the development of systemic endothelial dysfunction leading to the characteristic signs of PE in the later phase of the disease [5].

Hypertension in pregnancy may affect women*s long-term cardiovascular health and that is also true for infants from mothers with PE. It was tested that vessels of women, who did have PE showed after acetylcholine application a 50% less opening compared with women who had healthy pregnancy. In contrast, angiotensin II constricts these vessels in women with preeclampsia by more than 20% compared with women, who had a normal pregnancy. Apparently, women, who have had PE, are more sensitive to angiotensin II [6]. Indeed, maternal vascular malperfusion (MVM) represents hypo-ischemic damage in the placenta and this is associated with adverse pregnancy outcome [7].

Excess gestational weight gain was associated with MVM lesions, which was related to lower birth weight (p = .002) as well as a 2-fold increase risk for the delivery of a small for gestational age infant (10.3 vs. 5.9%; p = .01). In overweight or obese women MVM lesions where associated with increased risk of preterm birth (p = .04) and hypertension disorders of pregnancy (p = .02) [7].

Action of endogenous progesterone is manifold including increased blood flow and placenta remodeling, endometrium decidualization, uterine muscle contractions, cervix closure and immunological protection of the fetus besides the increase in blood flow and spiral artery remodeling [8,9], and extensive invasion of the maternal decidua by extravillous trophoblast [10], uterine contractions, cervix closure and immunological protection of the fetus besides the increase in blood flow and spiral artery remodeling and endocrine- immune-mediated mechanisms [11–13].

There are certain conditions that significantly increase the risk of miscarriage: Higher age (>33 years) lower body mass index (BMI <20), low serum progesterone (<12 ng/ml) prior to onset of miscarriage. Also higher levels of stress or demand and reduced concentration of progesterone-induced blocking factor [13]. The relationship between stress and miscarriage has been shown. There were lower progesterone levels in early as well as in later pregnancy [14]. To correct this, it was demonstrated that with higher doses of dydrogesterone a reduced rate of miscarriages was reached [15].

The pathophysiology of preeclampsia can be divided into two stages:

Stage 1.

Alterations of placental perfusion. The reduced placental perfusion is primarily due to abnormalities of implantation and vascular remodeling.

Stage 2.

The maternal syndrome.

Blood flow to organs other than the placenta is reduced. A vasoconstriction, microthrombus formation, and reduced plasma volume can lead to the systematically reduced perfusion. An increased sensitivity of endogenous pressure agents contributes to the loss of fluid from the vascular compartment. Preeclampsia is also characterized by activation of the coagulation cascade [16].

Preeclampsia is the major cause of maternal and perinatal morbidity and mortality. It is a multisystem disorder characterized by hypertension (≥ 140 mm Hg systolic and ≥90 mm Hg diastolic) and proteinuria (≥ 300 mg/d) that occurs after 20 weeks of gestation and can be present as late as 7 weeks postpartum [17]. Although preeclampsia affects 2–13% of pregnancies, reported incidence shows great variation due to differences in definition, demographic characteristics and diagnostic criteria [18]. The ideology remains enigmatic also risk factors, such as nulliparity, previous preeclampsia, genetic factors, maternal obesity, maternal age, diabetes mellitus, and twin pregnancy contribute to preeclampsia [16].

Recent data on dydrogesterone and preeclampsia

The first randomized, prospective study about the influence of dydrogesterone on the development of preeclampsia is published in 2014 showing the data in Table 1.

Table 1. Incidence of gestational hypertension (GH)/preeclampsia (PE) [19,20].

Group	Prevention GH/PE		Control group
	N	%	N	%
Study group	2	1.7	114	98.3
Control group	15	12.9	101	87.1
	p < .001
	Incidence of fetal stress
	N	%	N	%
Study group	5	4.3	111	95.7
Control group	21	18.1	95	81.9
	p < .029

Using women with ART dydrogesterone 30 mg/d p.o. as early as day 1–5 after ovum pick-up until 16 weeks of gestation. The prevention effect was great (p < .001). Including the incidence of fetal stress (p < .029) [19,20].

A large retrospective study was done with dydrogesterone 2 × 10 mg/d p.o. or dydrogesterone 2 × 10 mg p.o. and 500 mg 17 alpha-Hydroxyprogesterone caproate/week compared to the control group had a significantly greater effect of both hormone medications compared with the control group (p < .05) [21].

Also, a case of a woman, who did have in the first pregnancy severe preeclampsia and delivery by C-section and continuous hypertension being treated with methyldopa, did have a positive outcome in the second pregnancy with dydrogesterone 30 mg/d p.o. from early pregnancy until 37th weeks of gestation. The pregnancy was uneventful and delivery was done by repeat C-section at 39th weeks of gestation with a fetal weight of 3750 g and a length of 53 cm [22].

Conclusion

Prevention of gestational hypertension/preeclampsia can be accomplished with 30–40 mg/d p.o. of dydrogesterone from early pregnancy till 37th weeks of gestation.

Disclosure statement

No potential conflict of interest was reported by the author.