The incidence of pre-eclampsia 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 maternal 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 pre-eclampsia and the role ofthe maternal venous compartment and rennin-angiotensin-anldosterin system in this hypothesis.
Pre-eclampsia 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. Pre-eclampsia is defined as the presence of hypertension (Blood Pressure 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 normotensive before 20 weeks’ gestation and proteinuria (>0.3gr/24h). In a patient with pre-existing essential hypertension, pre-eclampsia is diagnosed 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. Pathogenesis 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 hypertension (10:1), chronic renal disease (20:1), homozygosity and heterozygosity for angiotensinogen 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 pre-eclampsia and the role of the maternal venous compartment and rennin-angiotensin-anldosterin system in this hypothesis.
It’s almost a century ago that H. Paramore suggested that pre-eclampsia 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 pre-eclampsia4. Raised IAP has also been measured postpartum in healthy women, immediate after caesarian section; while under spinal anesthesia, intra-abdominal pressure 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 dysfunction in pre-eclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Angiotensin II (AT II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy and may promote the expression of sFlt-1 in pregnancy. In other words, elevated sFlt-1 levels in pre-eclampsia 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 concentrateons (PAC) are reduced compared to normal pregnancy12. In the second case and relatively to PRC and ATII, pro-rennin is more increased12-14. In pre-eclampsia pro-rennin remains increased13-14; that, could explain arterial hypertension. Recently, investigators have located Angiotensin-(1-7) which has vasodilatating and natriuretic properties related with aquaporin-114-16.The balance between the two- results in the expression of vasoconstrictor and volemic 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 sensitivity 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 pre-eclampsia, there seems to be an increased sensitivity to AT II administration17-19. Even though concentration of AT II and Angiotensin-(1-7) are relatively low, hypertensive response could be explained by imbalance 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 plasma aldosterone is increased and volemic effect exists (marked expansion of the extracellular volume and the plasma volume)22,23. In pre-eclampsia, aldosterone levels are low, often due to defect in 18-methyl oxidase activity which leads to impaired aldosterone synthase activety24. Along with that, rennin and AT II levels commonly decrease toward the normal nonpregnant range. This means that pre-eclampsia- compared to normal pregnancy- is a status of increased vascular contraction with concomitant endovascular volume depletion. Moreover: the combination of hypertension and “normal” 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-regulating 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 normal plasma rennin levels in chronic intra-abdominal hypertension4.
Some investigators have focused on other mechanisms linked with the role of the RAS in pre-eclampsia, e.g AT II type 1 receptor agonistic auto antibodies, AT1-B2 hetrodimerization, uteroplacental rennin secretion and a redox switch in angiotensinogen 26-28. In some cases(e.g. AT II type 1 receptor agonistic auto antibodyes) the importance of local RAAS in the uteroplacental unit (found in cytotrophoblast, decidua and placental endothelium) is also high-lighted29.
Others studied the maternal venous compartment. The splanchnic bed is the main blood reservoir of the body, containing up to 25% of total blood volume30. The vascular histological structure within it, contributes actively to the regulation of cardiac output, through active venules’ vasoconstriction and passive “emptying” of venous reservoir after arterial vasoconstriction30-32. Venous hemodynamic disturbances cause organ injury mainly through 1) increase intravenous pressure which leads to venous stasis at microcirculation and 2) impaired tissue perfusion due to arterial vasoconstriction32.
During pregnancy, it appears that venous adaptations favor a pro-vasodilatory state in which α-adrenergic responsiveness is decreased, coupled 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 production and this is likely compensated for by large increases in NOproduction and/or availability. The increased capacitance of the venous system is necessary to accommodate the plasma volume increases seen in normal pregnancy31-35.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.
Pre-eclampsia, on the contrary, is known as a maternal cardiovascular maladaptation syndrome. Venous distensibility, capacitance, and compliance are reduced. In pregnant women who subsequently develop early-onset pre-eclampsia, first trimester cardiac output is lower than normal, whereas this is higher than normal in women destined to develop late-onset pre-eclampsia. Arterial hypertension and liver and/or renal dysfunction can be secondary to abnormal venous hemodynamics35-36.
Doppler ultrasonography shows promising results with respect to evaluation of maternal cardiovascular maladaptation. In non-pregnant individuals, Doppler studies of renal interlobar veins are used in obstructive uropathy to distinguish physiological from pathological pyelocaliectasis, 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 interlobar renal veins. During the course of normal pregnancy, the HV waveforms changed from predominantly triphasic to predominantly monophasic patterns, even though inter- and intra-individual variation have also been described. Along with that impendance index of renal interlobar 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 intravascular blood volume during pregnancy37-39. RI-VI is higher in pre-eclampsia than in uncomplicated pregnancies24. Moreover, RIVI is higher in early pre-eclampsia than in late pre-eclampsia pregnancies and this is associated with lower birthweight percentiles and higher proteinria40. 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 blood into the venous system during atrial contraction, 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 pre-eclampsia. 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 pre-eclamptic pregnancy.This reduction in renal perfusion will activate the RAAS through the juxtaglomular apparatus41-44. Activation of RAAS will have many effects including increased 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 pre-eclampsia may be explained by the fact that RAAS is inhibited during clinical phase of pre-eclampsia but not during initiative phase42-44. The consistency of reduced renal perfusion, will lead to a constant RAAS activation in order to restore renal blood flow. This could provoke a raise in angiotensin II (ΑΤΙΙ) and alterations of the levels of molecules like VEGF, PIGF and fms-like tyrosιne kinase-1; changes whichcould cause maternal endothelial dysfunction and give rise to many symptoms of pre-eclampsia41-43.
Furthermore, in certain conditions (e.g. obese women), raised IAP could induce a status of decreased cerebral venous outflow to such degree 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 research is needed to prove whether in the patho-physiology of pre-eclampsia participate other abdominal vessels (e.g. uterine veins), or whether it’s the compression of one or both renal veins – and in what degree- that triggers the pathologic sequence. It would also be interesting to study the influence of different body positions in women with pre-eclampsia, while looking at the renal veins resistance or compression, the rennin and AT II levels and the blood pressure at the same time41. Monitoring and studying local RAAS (especially in uteroplacental unit) should also give us new information 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, elective 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 pathophysiological sequence in all cases. Is the pharmacological inhibition of RAAS–most likely at AT II level, but without excluding the rest of the possibilities,e.g. Angiotensin-(1-7) or Angiotensin-(1-5)–a feasible treatment option 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 elevations of maternal IAP on the fetus. In animal models intra-amniotic pressure (IAMNP) has been related linearly to maternal IAP49. Some investigators hypothesized that elevated IAMNP is translated to elevated fetal IAP, both of which were vulnerable to elevations in maternal IAP. Through this mechanism, elevated fetal IAP could result in increased urethral resistance, the chronicity of which could lead to abnormal development of the bladder detrusor 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 stage ofpreeclampsia, a condition generally considered as one of the most serious gestational complications of which background mechanisms are not yet fully understood, might be a systemic response to a combination of intra-abdominal hypertension with a preceding failure of the venous system to regulate cardiac output appropriately. In order to accept or refute this hypothesis, data from more studies and observations are needed. This is why the exploration of the adult’s venous compartment, RAAS and intra-abdominal pressure both in non-pregnant and pregnant conditions, is of interest to all and scientists involved in research and management on gestation-induced maternal 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 comorbidities.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 contribute to the fate of angiotensin peptides in programmed hypertension? Hypertension 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 vasoconstrictor 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, intrabdominal 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.
Theodoros Aslanidis, 4 Doridos street, PC 54633, Thessaloniki, Greece, tel.: +306972477166, e-mail: