The incidence of preeclampsia in the western countries is estimated to range from 2% to 6% in healthy, nulliparous women. In developing nations, the incidence of the disease is reported to be 4- 18%,with hypertensive disorders being the second most common obstetric cause of stillbirths and early neonatal deaths in these countries Etiology of the disease is multifactorial, with risk factors like ma-ternal age, oxidative stress, angiotensin T-235 homozygote having a different role in every case. Moreover, the disease its self is a multisystem expression of a complicated pathophysiology. Many attempts to explain the latter have been made with often controversial results. In the present article we explore the hypothesis of intra-abdominal pressure as possible causative factor of preeclampsia and the role ofthe maternal venous compartment and rennin-angiotensin-anldosterin system in this hypothesis.
Preeclampsia is a multisystem disorder that complicates 2-8 % of pregnancies and together with the other hypertensive disorders of pregnancy contributes significantly to perinatal mortality and morbidity1. Preeclampsia is defined as the presence of hypertension (Blood Pressu-re BP≥140/90 mm Hg) on 2 occasions, at least 6 hours apart, but without evidence of end-or-gan damage, in a woman who was normoten-sive before 20 weeks’ gestation and proteinuria (>0.3gr/24h). In a patient with preexisting es-sential hypertension, preeclampsia is diagno-sed if systolic BP (SBP) has increased by 30 mmHg or if diastolic BP (DBP) has increased by 15 mmHg. Depending on the severity, symptomatology may also include pulmonary oedema, cyanosis, visual disturbances, epigastric pain, persistent headaches, intrauterine fetal growth retardation (IUGR), e.t.c2. Pathogene-sis of the disease is multifactorial. Various risk factors have been mentioned in the literature, each with different effect: nulliparity (odds 3:1), family history(5:1), maternal age>40 (3:1), diabetes mellitus (2:1), chronic hyperten-sion (10:1), chronic renal disease (20:1), ho-mozygosity and heterozygosity for angiotensi-nogen gene T235 (odds 20:1 and 4:1 respectively), antiphospholipid syndrome (10:1), and others2. In the present article we explore the hypothesis of intra-abdominal pressure (IAP) as possible causative factor of preeclampsia and the role of the maternal venous compart-ment and rennin-angiotensin-anldosterin sy-stem in this hypothesis.
It’s almost a century ago that H. Paramore sug-gested that preeclampsia is a secondary result of intra-abdominal hypertension3. Today, there is more evidence to support this thesis.
Animal studies report that increased IAP may be a cause for systemic hypertension in central obesity and preeclampsia4. Raised IAP has al-so been measured postpartum in healthy wo-men, immediate after caesarian section; while under spinal anesthesia, intra-abdominal pres-sure in >25% of healthy term parturients was > 12 mmHg6. The two syndromes also share a lot of clinical signs like arterial hypertension, oedema, proteinuria, headaches and nausea7.
Apart from that, maternal endothelial dysfun-ction in preeclampsia is associated with increa-sed soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor (VEGF) and placental growth fa-ctor (PIGF). Angiotensin II (AT II) is a potent vasoconstrictor that increases concomitant wi-th sFlt-1 during pregnancy and may promote the expression of sFlt-1 in pregnancy. In other words, elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local rennin/angiotensin system (RAAS) 9-11. Plasma rennin activity (PRA) and concentration (PRC), and plasma AT II and aldosterone concentrate-ons (PAC) are reduced compared to normal pregnancy12. In the second case and relatively to PRC and ATII, pro-rennin is more increa-sed12-14. In preeclampsia pro-rennin remains increased13-14; that, could explain arterial hy-pertension. Recently, investigators have loca-ted Angiotensin-(1-7) which has vasodilatating and natriuretic properties related with aquapo-rin-114-16.The balance between the two- results in the expression of vasoconstrictor and vole-mic effect in every physiological function.
During an uncomplicated pregnancy, estrogen leads to increased angiotensinogen synthesis by the liver leading to increased AT II. Yet, there is concomitant reduction in vascular sen-sitivity to endogen AT II15. In fact, pregnant women require twice as much AT II by intra-venous infusion as compared with their non pregnant counterparts to achieve similar vaso-motor responses8. In preeclampsia, there seems to be an increased sensitivity to AT II admini-stration17-19. Even though concentration of AT II and Angiotensin-(1-7) are relatively low, hypertensive response could be explained by im-balance between the two subastances20,21. On the other hand, AT II vascular sensitivity may be inhibited during normal pregnancy but adrenergic response is normal; as a result pla-sma aldosterone is increased and volemic effe-ct exists (marked expansion of the extracellular volume and the plasma volume)22,23. In pree-clampsia, aldosterone levels are low, often due to defect in 18-methyl oxidase activity which leads to impaired aldosterone synthase active-ty24. Along with that, rennin and AT II levels commonly decrease toward the normal nonpre-gnant range. This means that preeclampsia- compared to normal pregnancy- is a status of increased vascular contraction with concomi-tant endovascular volume depletion. Moreo-ver: the combination of hypertension and “nor-mal” levels of rennin and AT II can be seen as an indication of a hyperactive RAAS. They are in fact what one would expect from a self-re-gulating system: if hypertension was caused by a factor outside the system, the RAAS should have turned itself down (i.e. lower AT II and rennin levels).
The aforementioned may also explain the nor-mal plasma rennin levels in chronic intra-ab-dominal hypertension4.
Some investigators have focused on other me-chanisms linked with the role of the RAS in pre-eclampsia, e.g AT II type 1 receptor agonistic auto antibodies, AT1-B2 hetrodimerization, u-teroplacental rennin secretion and a redox swi-tch in angiotensinogen 26-28. In some cases(e.g. AT II type 1 receptor agonistic auto antibody-es) the importance of local RAAS in the utero-placental unit (found in cytotrophoblast, deci-dua and placental endothelium) is also high-lighted29.
Others studied the maternal venous compart-ment. The splanchnic bed is the main blood re-servoir of the body, containing up to 25% of to-tal blood volume30. The vascular histological structure within it, contributes actively to the regulation of cardiac output, through active ve-nules’ vasoconstriction and passive “empty-ing” of venous reservoir after arterial vasocon-striction30-32. Venous hemodynamic disturban-ces cause organ injury mainly through 1) in-crease intravenous pressure which leads to ve-nous stasis at microcirculation and 2) impaired tissue perfusion due to arterial vasoconstri-ction32.
During pregnancy, it appears that venous ada-ptations favor a pro-vasodilatory state in which α-adrenergic responsiveness is decreased, cou-pled with an increase in endothelial-dependent vasodilatatory responsiveness which appears to be primarily mediated by an nitric oxide (NO)-dependent mechanism. In addition, there is downregulation of smooth muscle response to NO which is largely related to cGMP produ-ction and this is likely compensated for by lar-ge increases in NOproduction and/or availabi-lity. The increased capacitance of the venous system is necessary to accommodate the pla-sma volume increases seen in normal pregnan-cy31-35.A dilatation of the left atrium occurs already in early gestation, whereas a rise of a-trial natriuretic peptide (ANP) is observed in the second half of pregnancy. This rise of ANP originates from extension of the atrium due to expansion of the plasma volume and prevents overfilling of the cardiovascular system33-34.
Preeclampsia, on the contrary, is known as a maternal cardiovascular maladaptation syndro-me. Venous distensibility, capacitance, and compliance are reduced. In pregnant women who subsequently develop early-onset pree-clampsia, first trimester cardiac output is lower than normal, whereas this is higher than nor-mal in women destined to develop late-onset preeclampsia. Arterial hypertension and liver and/or renal dysfunction can be secondary to abnormal venous hemodynamics35-36.
Doppler ultrasonography shows promising re-sults with respect to evaluation of maternal cardiovascular maladaptation. In non-pregnant individuals, Doppler studies of renal interlobar veins are used in obstructive uropathy to dis-tinguish physiological from pathological pye-localiectasis, for non-invasive monitoring of transplant kidneys and in the work up of renal vein occlusion37-38.During pregnancy, studies are mainly focusing on hepatic (HV) and inter-lobar renal veins. During the course of normal pregnancy, the HV waveforms changed from predominantly triphasic to predominantly mo-nophasic patterns, even though inter- and intra-individual variation have also been described. Along with that impendance index of renal in-terlobar veins (RIVI) decreases during the course of pregancy and this is consistent with an increase of venous compliance38. That is: the gestational decrease in renal interlobar vein (RIV) impedance index (RIVI) and flattening of the hepatic vein (HV) waveform correlate well with the known reduction in peripheral vascular resistance and the increased intrava-scular blood volume during pregnancy37-39. RI-VI is higher in preeclampsia than in uncompli-cated pregnancies24. Moreover, RIVI is higher in early preeclampsia than in late preeclampsia pregnancies and this is associated with lower birthweight percentiles and higher protein-ria40. Higher RIVI was also associated with a sharp reduction in forward venous flow during the last 100 ms of the Doppler wave; the latter being result from venous preacceleration nadir (VPAN) mechanism, i.e backflow of atrial blo-od into the venous system during atrial contra-ction, by lack of a valve mechanism39.
Hypotheses and perspectives
If we combine the aforementioned, we reach the recent reframing of the hypothesis of the pathogenesis of preeclampsia. According the latter, raised IAP during pregnancy can cause compression of renal veins.Ultrasonographic data provide evidence for impaired drainage of venous blood from the kidneys during pree-clamptic pregnancy.This reduction in renal perfusion will activate the RAAS through the juxtaglomular apparatus41-44. Activation of RAAS will have many effects including incre-ased rennin secretion, increased reabsorption of sodium and fluid, arteriolar vasoconstriction and a rise of blood pressure7. Yet, the fact that these phenomena are not fully noticed during preeclampsia may be explained by the fact that RAAS is inhibited during clinical phase of preeclampsia but not during initiative phase42-44. The consistency of reduced renal perfusion, will lead to a constant RAAS activation in or-der to restore renal blood flow. This could pro-voke a raise in angiotensin II (ΑΤΙΙ) and alter-ations of the levels of molecules like VEGF, PIGF and fms-like tyrosιne kinase-1; changes whichcould cause maternal endothelial dys-function and give rise to many symptoms of preeclampsia41-43.
Furthermore, in certain conditions (e.g. obese women), raised IAP could induce a status of decreased cerebral venous outflow to such de-gree that it could create a raised ICP situation (pseudotumor cerebri). The latter is known to predispose for other obstetric complications, such as placental abruption46.
Yet, if the compression theory of renal veins due to raised IAP is proven to be correct, then other questions arise. For example, further re-search is needed to prove whether in the patho-physiology of preeclampsia participate other abdominal vessels (e.g. uterine veins), or whe-ther it’s the compression of one or both renal veins – and in what degree- that triggers the pathologic sequence. It would also be interest-ing to study the influence of different body po-sitions in women with preeclampsia, while lo-oking at the renal veins resistance or compres-sion, the rennin and AT II levels and the blood pressure at the same time41. Monitoring and studying local RAAS (especially in uteropla-cental unit) should also give us new informa-tion on the subject.
The acceptance of the theory may create new therapeutic approaches. Simple measures like not lying on their back when being at risk of preeclampsia should probably be advised in these patients. And if that’s not enough, electi-ve stenting of the renal veins could also be a therapy option.
Additionally, the fact that 38% of cases with seizures (eclampsia) occur before labor, 18% during labor and 44% (usually 24-48h) after labor, implies that the removal of the source of raised IAP (fetus) is not enough to stop the pa-thophysiological sequence in all cases. Is the pharmacological inhibition of RAAS–most li-kely at AT II level, but without excluding the rest of the possibilities,e.g. Angiotensin-(1-7) or Angiotensin-(1-5)–a feasible treatment opti-on in certain patients?
Effect of anesthesia and analgesia is under question too. In experimental modest epidural anesthesia seems to lower proteinuria and SBP47-48.
And if understanding of IAH in maternal care is limited, it is completely unknown whether there are subclinical effects of even modest e-levations of maternal IAP on the fetus. In ani-mal models intra-amniotic pressure (IAMNP) has been related linearly to maternal IAP49. Some investigators hypothesized that elevated IAMNP is translated to elevated fetal IAP, bo-th of which were vulnerable to elevations in maternal IAP. Through this mechanism, eleva-ted fetal IAP could result in increased urethral resistance, the chronicity of which could lead to abnormal development of the bladder detru-sor muscles, resultant dysfunctional voiding in children and possible urinary tract anomalies. But this question is still under investigation50.
The information summarised above reveals a new and tempting hypothesis: the clinical sta-ge ofpreeclampsia, a condition generally con-sidered as one of the most serious gestational complications of which background mecha-nisms are not yet fully understood, might be a systemic response to a combination of intra-abdominal hypertension with a preceding fai-lure of the venous system to regulate cardiac output appropriately. In order to accept or refu-te this hypothesis, data from more studies and observations are needed. This is why the ex-ploration of the adult’s venous compartment, RAAS and intra-abdominal pressure both in non-pregnant and pregnant conditions, is of in-terest to all and scientists involved in research and management on gestation-induced mater-nal disturbances.
- Steegers E.A., Dadelszen P., Duvecock J.,et al. Pre-eclampsia. Lancet 2010; ;376:633-44.
- Schroeder B. Practice Guidelines in diagnosis and management of pre-eclampsia. ASOG 2002; Bulletin No 33
- Paramore R.H. The Intra-abdominal Pressure in Pregnancy. Proceedings of the Royal Society of Medicine (Obstetrics and Gynaecology Section) 1913; 6:291-334.
- Bloomfield Gl., et al. Correlations between intra-abdominal pressure and obesity-related co-morbidities.Int J Obes Relat Metab Disord. 2000; ;24:819-24.
- Abdel-Razeq SS, Campbell K, Funai EF, et al. Normative postpartum intrabdominal pressure. Am J Obstet Gynecol 2010;203:149.
- Chun R, Baghirzada L, Tiruta C, et al. Measurement of intra-abdominal pressure in term pregnancy: a pilot study.Int J Obstet Anesth 2012; ;21:135-9.
- Joynt GM, Wai JK. Intra-abdominal hypertension and abdominal compartment syndrome – making progress?Anaesth Intensive Care 2012;40:11-3.
- Irani R.A., Xia Y. Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin in Nephrol 2011; 31: 47-58.
- Atlas S. The RAAS system: pathophysiology and pharmaceuticals inhibition, J Manag Care Pharm 2007;13:S9-S20.
- Varughese B, Bhatla N., Kumar N et al. Circulating angiogenic factors in pregnancies complicated by pre-eclampsia. National Medical Journal of India 2010; 23: 77-81.
- Zhou C.C., Ahmad S., Mi T. et al. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circulation Research 2007; 5: 88-95.
- Chaudhary S, Salhotra R. Sub-arachnoid block for caesarean section in severe preeclampsia.J Anaesthesiol Clin Pharmacol 2011; 27:169-173.
- Brown MA, Wang J, Whitworth JA. The rennin – angiotensin – aldosterone system in pre-eclampsia. Clin Exp Hypertens 1997;19:713–26.
- Brar HS, Do YS, Tam HB, et al. Uteroplacental unit as a source of elevated circulating prorenin levels in normal pregnancy. Am J Obstet Gynecol 1986;155 :1223 – 26.
- Hsueh WA. Renin in the female reproductive system. Cardiovasc Drugs Ther 1988 Nov;2:473-7.
- Abdul-Karim R, Assalin S. Pressor response to angiotonin in pregnant and nonpregnant women. Am J Obstet Gynecol 1961;82:246–51.
- Nicholson E, Gallery E, Brown M,et al. Renin activation in normal and hyper-tensive human pregnancy. Clin Exp Hypertens 1987;6:453–64.
- Brosnihan KB, Neves LA, Chappell MC. Does the angiotensin-converting enzyme (ACE)/ACE2 balance contri-bute to the fate of angiotensin peptides in programmed hypertension? Hyper-tension 2005;46:1097 – 9.
- Ferreira AJ, Santos RA, Bradford CN, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension 2010; 55: 207–13.
- Joyner J, Neves LA, Stovall K,et al. Angiotensin-(1–7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats. Am J Physiol Regul Integr Comp Physiol 2008;294:1073–80.
- Gant NF, Daley GL, Chand S, et al. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 1973; 52:2682–9.
- Merrill DC, Karoly M,Chen K,et al . Angiotensin-(1 – 7) in normal and preeclamptic pregnancy. Endocrine 2002; 18:239–45.
- Valdes G, Germain AM, Corthorn J, et al. Urinary vasodilator and vasocon-strictor angiotensins during menstrual cycle, pregnancy, and lactation. Endocrine 2001; 16:117–22.
- West C, Zhang Z, Ecker G, et al. Increased renal alpha-epithelial sodium channel (ENAC) protein and increased ENAC activity in normal pregnancy. Am J Physiol Regul Integr Comp Physiol 2010; 299:1326–32.
- Weinberger MH, Kramer NJ, Petersen LP,et al. Sequential changes in the renin–angiotensin–aldosterone systems and plasma progesterone concentration in normal and abnormal human pregnancy. Perspect Nephrol Hypertens 1976; 5:263–9.
- Shah D.M. Role of the renin-angiotensin system in the pathogenesis of preeclampsia. American Journal of Physiology – Renal Physiology. 2005; 288: 614-25.
- Zhou A., Carrell R.W., Murphy M.P., et al. A redox switch in angiotensinogen modulates angiotensin release. Nature 2010; 468: 108-111
- Anton L., Merrill D.C., Neves L.A., et al. Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study. Reprod Biol Endocrinol 2010 Nov 4;8:135. doi: 10.1186/1477-7827-8-135.
- Renin−angiotensin system in pre-eclampsia: everything old is new again Julia J Spaan and Mark A Brown Obstet Med2012; 5: 147-50.
- Pang CC. Measurement of body venous tone. J Pharmacol Toxicol Methods 2000; 44:341-60.
- Berne R, Levy M. Control of cardiac output: coupling of heart and blood vessels. In: Berne R, Levy M, editors. Cardiovascular physiology. London: The C.V. Mosby Company 2001:199-226.
- Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology 2008; 108:735-8.
- Krabbendam Ι, Courtar D, Janssen ΒJ et al.Βlunted autonomic response to volume expansion in formerly preeclamptic women with low plasma volume. Reprod Sci 2009; 16:105-12.
- Krabbendam Ι, Spaanderman M. Venous adjustments in healthy and hypertensive pregnancy. Expert Rev Obstet Gynecol 2007; 2:671-9.
- Gyserlayers W. Exploring the functionality of maternal venous hemodynamics. Obstet Gynecol 2010; 2: 182-6.
- Valensise H, Vasapollo b, Gagliardi G et al. Early and latepreeclampsia: two different maternal hemodynamic states in the latent phase of the disease. Hypertension 2008; 52:873-80.
- Bateman G.A., Giles W. Renal venous Doppler sonography in preeclampsia. Journal of Ultrasound in Medicine 2004; 23: 1607-11.
- Gyserlayers W. Hemodynamics of the maternal venous compartment. Ultrasound Obstet Gynecol 2008; 32: 714–8.
- Gyselaers W, Molenberghs G, Mesens T, et al. Maternal hepatic vein Doppler velocimetry during uncomplicated pregnancy and pre-eclampsia.Ultrasound Med Biol 2009; 35: 1278-83.
- Gyselaers W, Mesens T, Tomsin K,et al. Maternal renal interlobar vein impedance index is higher in early- than in late-onset preeclampsia.Ultrasound Obstet Gynecol 2010; 36: 69–75.
- Dalfsen A. Preeclampsia, intrabdomi-nal hypertention and the renal veins, medi.philica.com,2011(access 1/2014).
- Shojaati K, Causevic M, Kadereit B, et al. Evidence for compromised aldosterone synthase enzyme activity in preeclampsia. Kidney Int 2004; 66:2322 – 8.
- De Leon RG, De Melian EM, Coviello A, et al. Prorenin concentration in the hypertensive disorders in pregnancy. Hypertens Pregnancy 2001; 20:157 – 68.
- Salas SP, Marshall G, Gutierrez BL,et al. Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension 2006; 47: 203–8.
- Sugerman H. Hypothesis: preeclampsia is a venous disease secondary to an increased intra-abdominal pressure. J. Med Hypotheses 2011; 77: 841-4.
- Walid MS, Sanoufa M, Robinson JS Jr. Can pseudotumor cerebri predispose to placental abruption?South Med J 2010; 103:489-90.
- Dong YJ, Gao LL. Effect of epidural block on 24-hour urine protein in pregnant rat models with preeclampsia.Arch Gynecol Obstet 2012;286:609-11.
- Chaudhary S, Salhotra R. Subarachnoid block for caesarean section in severe preeclampsia.J Anaesthesiol Clin Pharmacol 2011; 27:169-73.
- Karnak I, Aksoz E, Ekinci S,et al.Increased maternal intraabdominal pressure alters the contractile properties of fetal rabbit bladder.J Pediatr Surg 2008; 43:1711-7.
- Chun R, Kirkpatrick AW. Intra-abdominal pressure, intra-abdominal hypertension, and pregnancy: a review. Annals of Intensive Care2012; 2(Suppl 1):S5.
Authors have no conflicts of interest or financial ties to disclose.
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