Basky Thilaganathan MD PhD FRCOG

Professor and Director, Fetal Medicine Unit, St George’s Hospital, St George’s University of London, Cranmer Terrace, London SW17 0QT, UK

 

Preeclampsia diagnosed or requiring delivery before 34 weeks’ gestation is often labeled as early-onset disease, whereas the remainder is referred to as late-onset disease. The distinction is commonly explained as a reflection of the marked importance of abnormal placentation in the development of early-onset preeclampsia. Inadequate or defective placentation has been associated with poor fetal growth restriction and a placental ‘stress’ response leading to systemic endothelial dysfunction typical of preeclampsia, especially the early-onset variety. However, there are several inconsistencies with the placental origins hypothesis, especially when considering late-onset preeclampsia. These inconsistencies have been frequently attributed to disease heterogeneity or ‘maternal’ form of preeclampsia – neither of which are adequate or actual explanations of the etiology of preeclampsia. The emerging hypothesis that preeclampsia occurs as a consequence of placental hypoperfusion from maternal cardiovascular dysfunction deserves more attention.

 

EVIDENCE FOR PLACENTAL ETIOLOGY OF PREECLAMPSIA

The long-standing belief in the primary placental origin of preeclampsia is based on placental histology, clinical features and a series of epidemiological associations. These are reviewed below in sequence here.

Placental histology

There is believed to be a fundamental association between preeclampsia and placental histological abnormality. However, a recent systematic review on placental histology in preeclampsia has demonstrated that histological lesions previously assumed to be characteristic of preeclampsia are neither sensitive nor specific markers for the disorder. [1]

Impaired fetal growth

Poor fetal growth is an expected and anticipated consequence of impaired placental development in preeclampsia. However, the majority of preeclampsia cases occur at term, where the prevalence of SGA is only 15% and there is, in fact, a relatively greater preponderance of LGA birth, even after the exclusion of diabetic pregnancy. [2]

Common risk factors

Epidemiological evidence suggests that women who develop preeclampsia have preconception risk factors that are also strong risk factors for cardiovascular disease. [3] These preconception risk factors indicate that suboptimal pre-pregnancy cardiovascular health and endothelial dysfunction may predispose to preeclampsia.

Effect of new partner

Pregnancy with a new partner is a risk factor for the development of preeclampsia. It has always been assumed that this association is causative and that it represents an immunological mechanism of impaired trophoblast development. However, epidemiological studies in both spontaneously pregnant and IVF pregnancies have demonstrated that PE is explained by maternal age and inter-birth interval, but not change in partner. [4].

IVF and ovum donation

The association of IVF conception with preeclampsia is explained by increased maternal age and other co-morbidities in these women. However, ovum donation is an independent risk factor for preeclampsia which was thought to reflect a decidual mechanism of impaired trophoblast development. A more plausible explanation is that the majority of women undergoing ovum donation are post-menopausal or have mosaic Turner’s syndrome, and are thereby at much higher risk for cardiovascular disorders [5].

Previous history of preeclampsia

Is perhaps one of the strongest risk factor for developing early-onset preeclampsia in the current pregnancy. [6] It is difficult to fathom why a placental disorder cured by birth can influence the outcome of following pregnancies. In contrast, current evidence suggests that preeclampsia is linked to permanent aberrations of the maternal endothelial and cardiovascular system. [7]

Parity

Primiparity is associated with a modest increase in risk for preeclampsia, as it is for gestational diabetes also. This association is difficult to explain on the basis of trophoblast development, especially when the immunological theories of preeclampsia are unsupported. However, several studies have demonstrated improved cardiovascular performance and adaptation to pregnancy in multiparous compared to nulliparous women. [7, 8]

Genetics of preeclampsia

There are only a few genetic loci that are consistently associated with preeclampsia in different populations. It is noteworthy that these loci explain only a small proportion of the disorder and that the vast majority of the identified loci involve known cardiovascular genes. [9]

 

MATERNAL CARDIOVASCULAR FUNCTION IN PREGNANCY

Pregnancy-mediated changes in the heart musculature include increased left ventricle muscle mass, ventricular thickness and increased cardiac output supporting the hypothesis that a hyperdynamic circulation is required to meet the increased metabolic requirements of pregnancy. [10] Melchiorre et al. followed up a large cohort of 559 healthy, non-obese pregnant women with assessments throughout all trimesters and the postpartum period. [11] An average increase in ventricular mass of 40% was observed at term compared to the non-pregnant state. The increase in cardiac output ceased after the first trimester and was accompanied by an increase in total vascular resistance index at term. Notably, the authors showed that even in normal pregnancy, 2-5% of women exhibited signs of ventricular dysfunction and approximately 1 out of every six women demonstrated mildly impaired diastolic function.

Cardiovascular function before the onset of preeclampsia

Changes in cardiac function are observable several months before the onset of preeclampsia, with the magnitude of the changes dependent on the gestation of onset. [12] Women who go on to develop early-onset preeclampsia have a lower cardiac index, markedly increased total vascular resistance index, impaired myocardial relaxation, and increased prevalence of abnormal heart geometry at mid-trimester echocardiography. These changes are present, but less marked in late-onset preeclampsia.

Cardiovascular function during the clinical phase of preeclampsia

At the time of diagnosis, women with preeclampsia demonstrate significant signs of cardiovascular compromise, the severity of which correlates with the timing of onset. During the immediate pre-clinical phase of preeclampsia total peripheral resistance index, sFlt-1 and B-type natriuretic peptide (BNP) levels are all elevated. [13,14] A combined model using these established cardiovascular parameters was successful in differentiating preeclampsia cases from controls with very high accuracy (AUC: 0.96).

Long-term cardiovascular effects of preeclampsia

The evidence for preeclampsia as a risk factor for future cardiovascular morbidity is incontrovertible and the association is staggering considering that the pregnancy sometimes precedes the index event by several decades. In fact, a substantial proportion of women never recover from the significant subclinical cardiovascular changes associated with preeclampsia [15]. There is also evidence for increased cardiovascular risk in the offspring of the preeclamptic mother. [16] The association of cardiovascular dysfunction with preeclampsia – before disease onset, at diagnosis, postpartum and across generations – supports the argument that the cardiovascular system is integral to the etiology of preeclampsia.

 

PARALLELS BETWEEN GESTATIONAL DIABETES AND PREECLAMPSIA

Causation is not so simple to determine as one would think. An often repeated mantra is ‘association is not causation’. It is why vaccines as a cause of autism are so compelling to some – vaccines are given at the same time autism starts to manifest. Concluding causation from sequential events is how the human mind works, and reality, constantly conspires to fool us into making false causal connections. Bradford Hill proposed a series of criteria for determining the likelihood of a causal association. Amongst these, analogy with another disease where causality is proven is considered to be one of the strongest causal criteria.

It is well accepted that the glucose load, or endocrine ‘stress’ of pregnancy may result in the development of gestational diabetes when maternal pancreatic function is sub-optimal. However, the cardiovascular system in preeclampsia receives no such recognition despite several parallels between these two pregnancy-specific conditions (Table 1). The role of the maternal cardiovascular system deserves further consideration, principally to further differentiate whether cardiovascular derangement in preeclampsia is a secondary effect or a primary etiological factor.

 

CONCLUSIONS

Defective placentation causes early-onset preeclampsia, a disease entity that is considered more or less distinct from late-onset preeclampsia. The latter has been attributed as “maternal” preeclampsia because of several inconsistencies with the placental origins hypothesis. An alternative explanation for preeclampsia is that placental dysfunction is secondary to maternal cardiovascular maladaptation in pregnancy. The concept that placental dysfunction is secondary to a maternal disorder is not new when one considers the clinical similarities between preeclampsia and gestational diabetes – both pregnancy-specific conditions that are cured by birth. It is accepted that gestational diabetes develops when the maternal pancreas is unable to manage the increasing glucose load of pregnancy. It is now apparent that pregnancy presents a substantial cardiovascular load on the maternal heart, and that cardiovascular dysfunction precedes the disorder, predominates in the clinical syndrome and persists for several decades postpartum. It is time consider the evidence that failure of the maternal cardiovascular system to adapt to pregnancy may well be the primary mechanism leading to secondary placental dysfunction in preeclampsia. Placental dysfunction is fundamental to the pathophysiology of pregnancy complications such as preeclampsia, but to date, the placenta has been considered in isolation without regard to the fact that it’s functioning is dependent on adequate perfusion by the maternal circulation. It may be appropriate to now consider the evidence that failure of the maternal cardiovascular system to adapt to pregnancy may well be the primary mechanism leading to secondary placental dysfunction in preeclampsia.

 

Conflicts of interests:

No conflicts of interest to declare.

 

REFERENCES

1. Falco ML, Sivanathan J, Laoreti A, Thilaganathan B, Khalil A. Placental histopathology associated with preeclampsia: A systematic review and Meta-Analysis. Ultrasound Obstet Gynecol. 2017;50:295-301.
2. Verlohren S, Melchiorre K, Khalil A, Thilaganathan B. Uterine artery Doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia. Ultrasound Obstet Gynecol. 2014;44:293-8.
3. Egeland GM, Klungsøyr K, Øyen N, Tell GS, Næss Ø, Skjærven R. Preconception Cardiovascular Risk Factor Differences Between Gestational Hypertension and Preeclampsia: Cohort Norway Study. Hypertension. 2016;67:1173-80.
4. Tandberg A, Klungsøyr K, Romundstad LB, Skjærven R. Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits. BJOG. 2015;122:915-22.
5. Nejdet S, Bergh C, Källén K, Wennerholm UB, Thurin-Kjellberg A. High risks of maternal and perinatal complications in singletons born after oocyte donation. Acta Obstet Gynecol Scand. 2016 Aug;95(8):879-86.
6. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Preeclampsia Identification Group. Clinical risk factors for preeclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ. 2016;353:i1753.
7. Weissgerber TL, Milic NM, Milin-Lazovic JS, Garovic VD. Impaired Flow-Mediated Dilation Before, During, and After Preeclampsia: A Systematic Review and Meta-Analysis. Hypertension. 2016 ;67:415-23.
8. Morris EA, Hale SA, Badger GJ, Magness RR, Bernstein IM. Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol. 2015;212:633.e1-6.
9. Buurma AJ, Turner RJ, Driessen JH, Mooyaart AL, Schoones JW, Bruijn JA, Bloemenkamp KW, Dekkers OM, Baelde HJ. Genetic variants in pre-eclampsia: a meta-analysis. Hum Reprod Update. 2013;19:289-303.
10. Gati S, Papadakis M, Papamichael ND, Zaidi A, Sheikh N, Reed M, Sharma R, Thilaganathan B, Sharma S. Reversible de novo left ventricular trabeculations in pregnant women: implications for the diagnosis of left ventricular noncompaction in low-risk populations. Circulation. 2014;1 30:475–483.
11. Melchiorre K, Sharma R, Khalil A, Thilaganathan B. Maternal Cardiovascular Function in Normal Pregnancy: Evidence of Maladaptation to Chronic Volume Overload. Hypertension. 2016 ;67:754-62.
12. K Melchiorre , G Sutherland , R Sharma , M Nanni , B Thilaganathan. Mid-Gestational Maternal Cardiovascular Profile in Preterm and Term Preeclampsia: A Prospective Study. 2012;120: 496-504.
13. Verlohren S, Perschel FH, Thilaganathan B, et al. Angiogenic Markers and Cardiovascular Indices in the Prediction of Hypertensive Disorders of Pregnancy. Hypertension. 2017;69:1192-1197.
14. Borges VTM, Zanati SG, PeraÇoli MTS, et al. Maternal hypertrophy and diastolic disfunction and brain natriuretic peptide concentration in early and late Preeclampsia. Ultrasound Obstet Gynecol. 2017. doi: 10.1002/uog.17495.
15. Melchiorre K, Sutherland GR, Baltabaeva A, Liberati M, Thilaganathan B. Maternal cardiac dysfunction and remodeling in women with preeclampsia at term. Hypertension. 2011;57:85-93.
16. Alsnes IV, Vatten LJ, Fraser A et al. Hypertension in Pregnancy and Offspring Cardiovascular Risk in Young Adulthood: Prospective and Sibling Studies in the HUNT Study (Nord-Trøndelag Health Study) in Norway. Hypertension. 2017;69 :591-598.

 

Figure: Risk of pre-eclampsia among women with and without individual clinical risk factors determined by 16 weeks’ gestation. Taken from Bartsch E et al. [6].

(IUGR=intrauterine growth restriction; SLE=systemic lupus erythematosus; ART=assisted reproductive technology; BMI=body mass index; aPL=antiphospholipid antibody syndrome; N/A=not applicable).

 

 

 

 

 

Table: Comparison of general outlines of gestational diabetes and preeclampsia as pregnancy related disorders

	Gestational Diabetes	Preeclampsia
Definition and diagnosis
Maternal organ system	Endocrine	Cardiovascular
Definition	New onset hyperglycemia after 20wks	New onset hypertension after 20wks
Diagnosis	High glucose level	High BP
Pre-pregnancy disease	Results in a more severe pregnancy phenotype	Results in a more severe pregnancy phenotype
Clinical characteristics
Predisposing factors	Same as for diabetes	Same as for cardiac disease
Screening test	GTT (measure of pancreatic function)	BP (measure of cardiac function)
Screening performance	Improves with testing in later pregnancy	Improves with testing in later pregnancy
Organ function	Relative insulin insufficiency	Relative cardiovascular insufficiency
Disease amelioration	Reduce load (lower carbs)	Reduce load (lower BP)
Disease cure	Birth	Birth
Pregnancy outcome
Fetal outcome (short term)	Macrosomia in severe/early GDM	SGA in severe/early PE
Infant outcome (long term)	Increased risk of obesity and early-onset diabetes	Increased risk of cardiovascular disease
Maternal short term outcome	Most normoglycaemic Occasional hyperglycemia	Most normotensive Occasional hypertension
Maternal long term outcome	50% risk of diabetes within 10 years	30% risk of hypertension within 10 years