Eileen D. M. Gallery

Proteinuria and its assessment in normal and hypertensive pregnancy.

OBJECTIVES The purposes of this study were (1) to determine 24-hour urinary protein excretion rates in normal human pregnancy and (2) to assess the reliability of assessment of proteinuria by dipstick measurement. STUDY DESIGN At 17 to 20 and 33 to 36 weeks of pregnancy, 174 normal volunteers collected a 24-hour urine sample; the volume and the protein and creatinine concentrations were measured. The result for protein was compared with dipstick analysis of an early morning midstream urine sample collected at the conclusion of the 24-hour period. Sixty-eight consecutive inpatients admitted to the antenatal ward with hypertension and positive urine dipstick tests for protein underwent the same procedure. The interobserver variability in dipstick analyses of urine samples of known protein content was assessed with the aid of 66 volunteers from the hospital staff. RESULTS The upper 95% confidence limit of the normal population was less than 200 mg per 24 hours, at both stages of pregnancy investigated. In these women and in the hypertensive inpatients a high proportion of false-positive and false-negative results was found with dipstick analyses. Interobserver variation in assessment of proteinuria by dipstick was high, with an 18% false-positive rate and a false-negative rate approaching 40% for samples with 30 mg/dl. Even in the presence of 100 mg/dl the false-negative rate was 7%, whereas the concentration of protein was significantly underestimated in 20% of samples with 500 mg/dl. CONCLUSION Dipstick urinalysis cannot be relied on either to detect or to exclude the presence of proteinuria in pregnant women.

EXCRETION OF ANTIHYPERTENSIVE MEDICATION INTO HUMAN BREAST MILK: A SYSTEMATIC REVIEW

Objective: To establish which antihypertensive medications are safe for use while breastfeeding, by reviewing the available evidence. Methods: Reports of studies examining the transfer of antihypertensive medications to breastmilk were identified from multiple MEDLINE and EMBASE searches, manual review of bibliographies of articles and textbooks on drug use during lactation. The reports were reviewed and the results were compiled. Results: Prospective cohort studies and case reports constituted the only available evidence. Compilation of these results found that the milk to plasma (M/P) ratios varied widely across the beta-blocker family, the beta-blockers with low protein binding having the highest M/P ratios. The angiotensin-converting enzyme (ACE) inhibitors, methyldopa, and some calcium channel blockers had low M/P ratios. Conclusion: The available data to date indicate that ACE inhibitors, methyldopa, beta-blockers with high protein binding, and some calcium channel blockers all appear to be safe treatments of hypertension in a nursing mother. The data suggest that drugs to be avoided are beta-blockers with low protein binding. However, the available evidence is limited and further studies are needed to confirm these findings.

Plasma from preeclamptic women stimulates decidual endothelial cell growth and prostacyclin but not nitric oxide production: close correlation of prostacyclin and thromboxane production.

Objective: To examine the effect of plasma from preeclamptic women on production of the vasoactive substances prostacyclin, thromboxane, nitric oxide, and cyclic guanosine monophosphate (cGMP) by decidual endothelial cells; to determine any effects on cell growth and health; and to examine whether cells from preeclamptic women are activated compared with cells from normal women. Methods: Decidual endothelial cells from normal and preeclamptic women were incubated for 24 hours in media containing 10% plasma from preeclamptic women or matched normal women. Prostacyclin and thromboxane production was measured, as was nitric oxide and cGMP production after a further 45-minute generation period in 2% test plasma. Cell numbers and lactate dehydrogenase release were also determined. Results: In plasma from preeclamptic women, cells grew significantly faster (P < .05), prostacyclin production was increased (P < .05), and lactate dehydrogenase release was reduced (P < .01). Production of thromboxane, nitric oxide, and cGMP was not significantly affected. Decidual endothelial cells from preeclamptic women had increased growth (P < .0001) and produced more prostacyclin (P < .05) and nitric oxide (P < .001) than normal decidual endothelial cells. There were highly significant correlations between prostacyclin and thromboxane production for incubations in plasmas from preeclamptic women and between background levels of prostacyclin in each plasma from preeclamptic women and the prostacyclin produced in incubations containing that plasma (P < .0001). Conclusion: We found that plasma from preeclamptic women contained a factor that stimulated endothelial cell growth and regulated production of related amounts of prostacyclin and thromboxane. The plasma level of this factor appeared to be related to background levels of prostacyclin. The results also indicated that decidual endothelial cells from preeclamptic women were in a relatively activated state.

Sodium excretion in normal and hypertensive pregnancy: A prospective study

One hundred fifty-eight intravenous saline solution infusions (3 mmol Na per kilogram body weight) were performed in (1) normal primigravid women during the second and third trimesters and post partum, after 1 week of either a high, low, or ad libitum salt intake; (2) normotensive primigravid women during midpregnancy who later developed pregnancy-induced hypertension, and (3) seven proteinuric and seven nonproteinuric primigravid women with ad libitum salt intake who had established pregnancy-induced hypertension. Sodium excretion did not differ significantly between pregnancy and after pregnancy despite marked differences in plasma renin activity, aldosterone concentration, volume, and glomerular filtration rate. Sodium excretion after saline solution loading varied according to prestudy sodium intake and was reduced between the second and third trimesters, independent of dietary salt intake. Those destined to develop pregnancy-induced hypertension had sodium excretion similar to that of continuously normotensive subjects during the second trimester, but those with established proteinuric pregnancy-induced hypertension had the lowest plasma volume, plasma aldosterone concentration, and plasma renin activity and retained sodium to the same degree as salt-deplete women with normotension. These results demonstrate that the balance of sodium regulatory factors is similar between pregnancy and post partum, that prestudy salt intake and stage of gestation can alter the natriuretic response to saline solution loading, and that normal pregnant women retain more administered sodium in late pregnancy than in midpregnancy despite further increases in plasma volume and no alterations to blood pressure or glomerular filtration rate. Those with established proteinuric pregnancy-induced hypertension retain sodium avidly without stimulation of plasma renin activity or plasma aldosterone concentration, findings not apparent during midpregnancy in those who later developed this disorder.

Peripheral arterial pulse wave analysis in women with pre‐eclampsia and gestational hypertension

Objective  To compare peripheral pulse pressure waveforms in normal pregnancy, gestational hypertension (GH) and pre‐eclampsia (PE).

4 Volume homeostasis in normal pregnancy and pre-eclampsia: physiology and clinical implications

Summary The pieces of the jigsaw puzzle of volume homeostasis in human pregnancy are being put together gradually. This chapter has focused on recent advances in our understanding of factors controlling extracellular fluid volume in normal pregnancy and their disturbance in women who develop pre-eclampsia. We have explored the clinical implications of these guidelines for management of patients with pre-eclampsia. Clearly there is still much to be learned. Studies of the cellular and subcellular handling of sodium are still in their infancy and will add much to our understanding of the physiology of volume homeostasis in normal pregnancy and its disturbance in pre-eclampsia and other causes of hypertension in pregnancy.

Pregnancy-Specific Down-Regulation of NF-κB Expression in T Cells in Humans Is Essential for the Maintenance of the Cytokine Profile Required for Pregnancy Success

It is accepted that human pregnancy is associated with a shift away from Th1 type and a bias toward Th2-type immune responses. The molecular mechanisms that regulate this shift are as yet unknown. We assessed the expression and activity of NF-κB, a transcription factor that plays a central role in regulating immune responses. We isolated T cells from PBMCs from nonpregnant and pregnant females and demonstrated that the NF-κB/IκB signaling pathway is down-regulated in T cells in pregnancy. Using Western blotting, high levels of NF-κB (p65) were detected in all nuclear fractions of T cells from nonpregnant females. In contrast, low levels of p65 were detected in nuclear fractions from T cells from pregnant females. Levels of IκBα and -β were also higher in cytoplasmic fractions from T cells from nonpregnant than from pregnant females. The reduction in p65 levels in pregnancy was reflected in the activity of NF-κB in EMSA; T cells from pregnant females contain less active NF-κB than from nonpregnant females. Stimulation of T cells from nonpregnant females with PMA/ionomycin resulted in IκBα degradation, p65 translocation, and subsequent production of the Th1 cytokines IFN-γ and IL-2. In contrast, PMA stimulation had no effect on NF-κB activity in T cells from pregnant females, and this was reflected in reduced Th1 cytokine production. Using the inhibitor of NF-κB activity, SN50, we were able to show that NF-κB activity was essential for the production of Th1 cytokines, suggesting that specific down-regulation of NF-κB in T cells throughout gestation is paramount to pregnancy success through specific regulation of cytokine production.

Isolation and purification of microvascular endothelium from human decidual tissue in the late phase of pregancy

Normal pregnancy demands significant structural and physiologic adaptations of the uterine microvasculature, to facilitate adequate placentation. In pregnancies complicated by pregnancy-associated hypertension (preeclampsia), this process is defective, resulting in a high incidence of intrauterine growth retardation. The microvascular endothelium, a focal point for both initiation and inhibition of coagulation and control of vascular tone, may well contribute to development and aggravation of these abnormalities. We describe a method for isolation, purification, and culture of human decidual endothelial cells from biopsies performed at the time of cesarean section. The separation procedure is technically simple, requires only a small piece of tissue, and takes approximately 2 hours to perform. Some of the unique features of these cells in culture are outlined. This technique will permit the close examination of various aspects of the function of these cells in normal pregnancy, and their comparison with cells from pregnancies complicated by hypertension.

Sodium‐renin‐aldosterone relations in normal and hypertensive pregnancy

Summary. To examine the short‐term regulation of sodium excretion, plasma volume, and the renin‐aldosterone system in pregnancy, women in their first pregnancy received either a high‐salt (HS) (250 mmol/day) or a low‐salt (LS) (20 mmol/day) diet for 7 days during the second and third trimester and after delivery (total 213 studies). Twenty women, studied while normotensive during mid‐pregnancy, developed pregnancy‐induced hypertension (PIH) in the third trimester. There was slightly greater difficulty adapting to sodium depletion (LS diet) during normal pregnancy compared with postpartum. The final mean values for sodium excretion were 27 (SE 2), 28 (SE 3) and 14 (SE 4) mmol/day in the second and third trimester and postpartum respectively. Sodium excretion with the HS diet was similar at all stages and plasma volumes were maintained as effectively during pregnancy as after delivery following both diets. Plasma renin activity (PRA) and aldosterone concentration rose and fell significantly following the LS and HS diets but the sensitivity of renin response to changes in salt intake was blunted during normal pregnancy. Women who later developed PIH, when studied whilst normotensive, failed to stimulate plasma aldosterone after salt depletion in their second trimester and did not exhibit the ‘sodium‐independent’ component of PRA seen in continuously normotensive subjects at this stage.

The long-term effects of prematurity and intrauterine growth restriction on cardiovascular, renal, and metabolic function.

Objective. To determine relative influences of intrauterine growth restriction (IUGR) and preterm birth on risks of cardiovascular, renal, or metabolic dysfunction in adolescent children. Study Design. Retrospective cohort study. 71 periadolescent children were classified into four groups: premature small for gestational age (SGA), premature appropriate for gestational age (AGA), term SGA, and term AGA. Outcome Measures. Systolic blood pressure (SBP), augmentation index (Al), glomerular filtration rate (GFR) following protein load; plasma glucose and serum insulin levels. Results. SGA had higher SBP (average 4.6 mmHg) and lower GFR following protein load (average 28.5 mL/min/1.73 m2) than AGA. There was no effect of prematurity on SBP (P = .4) or GFR (P = .9). Both prematurity and SGA were associated with higher AI (average 9.7%) and higher serum insulin levels 2 hr after glucose load (average 15.5 mIU/L) than all other groups. Conclusion. IUGR is a more significant risk factor than preterm birth for later systolic hypertension and renal dysfunction. Among children born preterm, those who are also SGA are at increased risk of arterial stiffness and metabolic dysfunction.