Becoming More Scientific, More Rational and More Accurate In Preeclampsia

 Becoming More Scientific, More Rational and More Accurate In Preeclampsia

 

Abstract

Currently the etiopathological changes in preeclampsia are believed to begin at the fetomaternal interface and so the placenta is labeled as the main cause of these conditions. A group from George's University of London and some from other parts of the world have proposed that in mothers with an already compromised cardiovascular function, before the commencement of pregnancy, pregnancy adds to a heavy load resulting in a series of adverse manifestations. In one study, it was found that on an average in a pregnant mother the left ventricular mass increased by 52% in about 9 months. When this was compared with the increase in the left ventricular mass of athletes, it was found that they register an increase of only 25% over a long period of 24 months. This means that the mother gets a much lesser time to bring about the necessary cardiac changes than even the robustly training athletes. It has been demonstrated that hypertensive women with increased Systemic Vascular Resistance (SVR) + low Cardiac Output (CO) had a higher risk of developing preeclampsia sooner. These and similar parameters can become new tools for prediction of preeclampsia. With the new understanding of pathophysiology the choice of antihypertensives is likely to change and may become more scientific and rational. It will lead to a consistent effect of the antihypertensive drugs in contrast to the present scenario. There are many robust arguments to counteract this new theory also. As a result trying to explain only one etiology and make it a "universal-fit" for all is wrought with grave danger of error. It seems as of now there are more than one etiologies all resulting in the clinical maternal manifestations of preeclampsia.

Becoming More Scientific, More Rational and More Accurate In Preeclampsia

Introduction:

Preeclampsia manifesting at or before 34 weeks of pregnancy has been established as an obstetric vasculopathy¹. It shares its origin with many serious obstetric conditions like IUGR, stillbirths, preterm labor, recurrent missed abortions, and the like. Immunology is believed to have a big role in causing these conditions. One basic fact that emerges from all different aspects involved in these processes is that the placenta seems to be the villain. The etiopathological changes begin at the feto-maternal interface and so the placenta is labeled as the main cause of these conditions.

However, some new developments have appeared that are going to disrupt the status quo in this field. Lots of work especially from St. George’s University of London and from other parts of the world have proposed that it is not the placenta that is responsible for these conditions. It is the previously compromised maternal cardiovascular condition before pregnancy that invites these clinical conditions².

Maternal cardiovascular primacy:

This theory believes that in mothers with an already compromised cardiovascular function, before the commencement of pregnancy, pregnancy adds to a heavy load resulting in a series of adverse manifestations. There is inadequate perfusion at the placental interface leading to defective placentation and subsequent clinical results. So the placenta, as per this theory is not the villain but a victim³. This theory of maternal cardiovascular primacy has the potential to change our approach to preeclampsia in particular and most obstetric vasculopathies in general, completely.

Why does preeclampsia occur in pregnancies with an increased demand?

It is suggested that in these subjects even if the cardiovascular function is not altered, the pregnancy demand is more. This happens in conditions like multiple pregnancies, fetal macrosomia, postdate pregnancy, gestational diabetes, and excessive maternal weight gain in pregnancy. It is believed that due to increased demand of the conceptus a relative cardiovascular insufficiency is generated in the mother leading to effects on the placental circulation. This in turn leads to the clinical effects of obstetric vasculopathies.

Shared risk factors:

On careful examination, it can be found that the two – cardiovascular diseases and preeclampsia have many common risk factors. The St. George’s University group has identified these conditions as:

Physical attributes: Both conditions occur in subjects with advanced maternal age, obese subjects and are found to be more in some ethnic groups like the Afro-Caribbean mothers.

Environmental factors:  There are some distinct environmental factors common to both. This includes maternal smoking, sedentary lifestyle and psychological stress in the mother.

Autoimmune conditions: Conditions like SLE and Antiphospholipid antibody syndromes are known to cause effects on the cardiovascular system of the mother as well as obstetric vasculopathies including preeclampsia. 

Shared hormonal factors: it has been found that reproductive endocrinal conditions like Polycystic Ovarian Syndrome (PCOS) are associated with cardiovascular problems in the mother as well as preeclampsia.

Medical Disorders: Conditions like diabetes, chronic renal diseases, hypertension, abnormal lipid profile and the like are found to be strongly associated with both – cardiovascular conditions in the mother as well as obstetric vasculopathies including preeclampsia.

Examining Events before Pregnancy:

If we want to examine the validity of the theory that preeclampsia is a result of a cardiovascular compromise in the mother well before she got pregnant then we will have to examine her state before she got pregnant. In this, maternal echocardiographic studies in preeclampsia have demonstrated significant cardiac dysfunction, both before and at clinical onset of preeclampsia. Melchiorre et al showed that there was a significant abnormal cardiac geometry and diastolic dysfunction in majority of women before pregnancy who subsequently go on to develop preeclampsia once pregnant⁴. Valensise et al demonstrated that low cardiac output and high total vascular resistance before pregnancy are associated with higher risk of fetal distress or maternal complications⁵.

One interesting observation is worth discussing here: It was found that the incidence of hypertension within 10 years of delivery was significantly higher for young women (20–29 years) after preeclampsia when compared with older women (40–49 years) with a non-preeclamptic pregnancy. This is thought to be because the CV (cardiovascular) function of the younger mother was already affected. She therefore developed preeclampsia in pregnancy and hypertension later in life. Comparing this with her older counterpart who did not develop preeclampsia, such mothers did not have a compromised cardiovascular function and so did not develop hypertension after pregnancy.

Pregnancy changes in comparison with changes in athletes:

•      In one study, it was found that on an average in a pregnant mother the left ventricular mass increased by 52% in about 9 months⁶

•      When this was compared with the increase in the left ventricular mass of athletes, it was found that they register an increase of only 25% over a long period of 24 months even after an Olympic-level of  training⁷

This means that the mother gets a much lesser time to bring about the necessary cardiac changes than even the robustly training athletes. Now, if her cardiovascular function is integrally compromised, she will not be able to bring about these changes efficiently. It results in poor perfusion and therefore clinical preeclampsia (and other vasculopathies)

Primis v/s Multis:

            We have all observed in clinical practice that multiparous women develop preeclampsia less readily than the primis. The explanation that we currently have for this is based on immunology. The immunological system of a multi is well sensitized to immunological challenge in her first pregnancy so she has a less likelihood of developing preeclampsia. However, the theory of cardiovascular basis believes that as her heart is already trained and molded in previous pregnancy a multi has less likelihood of developing preeclampsia. However if the next pregnancy occurs late, say after more than five years then her heart loses the extra efficiency that it has successfully developed. Such multipara are then equally susceptible to developing preeclampsia.

Is Birth A Cure To Preeclampsia?

By asking this question what is being examined is whether delivery permanently takes care of the process of preeclampsia? Because if preeclampsia was caused by pregnancy, after delivery, the process should reverse like uterine involution. No doubt, delivery does tame down the process and fury of preeclampsia and have thus saved millions of mothers and newborns. But in many cases this process of hypertension persists subsequently long after the pregnancy and puerperium are over. The reason now given to explain this is - these pregnant mothers are already having a compromised cardiovascular function, even after delivery and puerperium this sub-optimal cardiovascular functioning continues and she continues to register hypertension.

Need for novel tools for prediction of preeclampsia:

If maternal cardiovascular changes being a prequel to obstetric vasculopathies and preeclampsia theory is accepted then that opens up a new set of predictors of these conditions. In that case, we can use tools that identify a compromised CV function to predict obstetric vasculopathies. Those tools that can measure a reduced Cardiac Output (CO), increased Systemic Vascular Resistance (SVR) and cardiac muscular size will tell preeclampsia well before a BP machine diagnoses hypertension of preeclampsia. Also, the markers, both biochemical and sonographic, that are currently in use for these predictions will be supplementary in these subjects in whom preeclampsia is a result of maternal compromised cardiovascular function.

In a study by Kalafat and others, a noninvasive ultrasonic cardiac output monitor was used to obtain cardiovascular variables of cardiac output (CO) and systemic vascular resistance (SVR) and weight-adjusted indices. It was found that women with high SVR + normal CO and high SVR + low CO cardiovascular profiles had a significantly higher risk of earlier preeclampsia compared with women with normal SVR + normal CO. The findings of this study demonstrate that hypertensive women with increased SVR + low CO had a higher risk of developing preeclampsia sooner as shown in Fig.1⁸.

 

Fig. 1: Correlation of Cardiac Output, Systemic vascular resistance and time to preeclampsia

 

Thus these parameters can become new tools for prognostication and prediction of preeclampsia in particular and other obstetric vasculopathies in general.

 

Antihypertensive use in preeclampsia:

With the new understanding of pathophysiology coming in, all aspects of obstetric vasculopathies are likely to get affected. Understandably therefore the choice of antihypertensives will also need a relook. Thankfully the choice of antihypertensives is likely to become more scientific and rational under the influence of this new understanding. Currently, this choice varies as per the national guidelines although drugs have vastly different mechanisms of action. There seems to be a policy of “uniform fit” for all preeclamptic subjects. For instance, labetalol is the first-line drug in the UK. However, beta-blockers have negative inotropic and chronotropic effects. A good cardiologist would usually not choose this drug for a hypertensive patient with low cardiac output and increased vascular resistance as found in preeclampsia.

This brings us to explore a scientific way to select an antihypertensive in pregnancy. For this, it will be important to know which component of CVS has been affected in her singly or in combination. Is it

·         The force of contraction

·         The heart rate

·         The cardiac geometry

·         The diastolic dysfunction

·         The primary or secondary vascular dysfunction

A scientific and rational selection would be a drug or a drug combination that takes these factors into account. One single drug or a drug combination may not fit all. It seems that over a period of time, the right drug or combination will be identified. It will lead to a consistent effect of the antihypertensive drugs in contrast to the present scenario. Currently, the guideline-based universal fit drugs are understandably not giving consistent results. Once the cause is accurately attacked, the consistency of the effect of antihypertensives will follow.   

Counterpoints to this theory:

Irrefutable Immunology: The fetus is surely an allograft and to explain all changes in preeclampsia on basis of a mere compromised cardiac function in the mother is too simplistic. Any immunologically active molecule is bound to create a reaction in the maternal body. To ignore all these stormy changes with a wave of the hand is like denying the existence of a very big and proven scientific fact.

Antiphospholipid antibodies: How do recurrent miscarriages get explained by a compromised cardiac function? How does the compromised cardiac function as early as 12 weeks kill the conceptus producing a fetal demise? If it is so profound so early, how does it spare other organs from any effects and only eliminate the life from the conceptus?

Hypertension after pregnancy: Proponents of the theory of maternal cardiovascular primacy state that persistence of hypertension after pregnancy is a proof that she was already cardiovascular compromised. However, explanations for this hypertension by advocates of placental primacy is that preeclampsia leaves profound changes in the maternal cardiovascular system of the mother. Consequently, her system is never restored to normotensive state. She then goes on to register hypertension later in life and her blood pressure never comes back to normal. To support their argument they state that persistence of hypertension is not found in all mothers who have preeclampsia. Also, some mothers do register hypertension subsequently after pregnancy but in them the blood pressure returns to normal after some variable period of time. If maternal cardiovascular primacy was the only cause then the hypertension should worsen in all preeclamptic subjects after pregnancy as her age advances. This is not found consistently and in many subjects in fact the pressure returns to normal.

Diuretics: This group has supported the use of diuretics for reducing the need for an additional antihypertensive. Paradoxically they criticize the use of antihypertensives that are not wise to use in low CO conditions. How wise it is then to use diuretics in subjects with preeclampsia which has a low CO?

Diabetes and Preeclampsia: It is argued that diabetics develop preeclampsia as they have fetal macrosomia. However, increased susceptibility to preeclampsia in diabetics have been demonstrated irrespective of fetal macrosomia⁹.

 The Middle Path:

Trying to explain only one etiology and make it a “universal-fit” for all is wrought with grave danger of error. It seems as of now there are more than one etiologies all resulting in the allied maternal manifestations of preeclampsia. This “middle-path” will be more comfort-giving and inclusive.

 

References:

1.             Desai P. Obstetric Vasculopathies: Ed. 1. Chapter 1 Jaypee Publishers: Delhi

2.     Melchiorre K, Sharma R, Thilaganathan B. Cardiovascular implications in preeclampsia: an overview. Circulation. 2014 Aug 19; 130(8):703-14.

3.          Melchiorre K, Giorgione V, Thilaganathan B. The placenta and preeclampsia: villain or victim? Am J Obstet Gynecol. 2021 Mar 24:S0002-9378(20)31198-4.

4.        Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension. 2011 Oct; 58(4):709-15.

5.      Valensise H, Tiralongo GM, Pisani I, Farsetti D, Lo Presti D, Gagliardi G, Basile MR, Novelli GP, Vasapollo B. Maternal hemodynamics early in labor: a possible link with obstetric risk? Ultrasound Obstet Gynecol. 2018 Apr;51(4):509-513

6.              Kametas NA, McAuliffe F, Hancock J, Chambers J, Nicolaides KH. Maternal left ventricular mass and diastolic function during pregnancy. Ultrasound Obstet Gynecol. 2001 Nov; 18(5):460-6.

7. Fagard R. Athlete's heart. Heart. 2003; 89(12):1455-1461. doi:10.1136/heart.89.12.1455

8.          Kalafat E, Thilaganathan B. Cardiovascular origins of preeclampsia. Curr Opin Obstet Gynecol. 2017 Dec; 29(6):383-389.

9.       Weissgerber TL, Mudd LM. Preeclampsia and diabetes. Curr Diab Rep. 2015 Mar; 15(3):9. 

Note:

You can watch my video explaining this new theory and aspects related to it on YouTube. Please click on: https://youtu.be/d6Atlm6iWMs