Proteinuria during pregnancy: definition, pathophysiology, methodology, and clinical significance.

Qualitative and quantitative measurement of urine protein excretion is one of the most common tests performed during pregnancy. For more than 100 years, proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines recommend that proteinuria is sufficient but not necessary for the diagnosis. Still, in clinical practice, most patients with gestational hypertension will be diagnosed as having preeclampsia based on the presence of proteinuria. Although the reference standard for measuring urinary protein excretion is a 24-hour urine collection, spot urine protein-to-creatinine ratio is a reasonable "rule-out" test for proteinuria. Urine dipstick screening for proteinuria does not provide any clinical benefit and should not be used to diagnose proteinuria. The classic cutoff cited to define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3% to 8% of pregnancies. Although this threshold is widely accepted, its origin is not based on evidence on adverse pregnancy outcomes but rather on expert opinion and results of small studies. After reviewing the available data, the most important factor that influences maternal and neonatal outcome is the severity of blood pressures and presence of end organ damage, rather than the excess protein excretion. Because the management of gestational hypertension and preeclampsia without severe features is almost identical in frequency of surveillance and timing of delivery, the separation into 2 disorders is unnecessary. If the management of women with gestational hypertension with a positive assessment of proteinuria will not change, we believe that urine assessment for proteinuria is unnecessary in women who develop new-onset blood pressure at or after 20 weeks' gestation. Furthermore, we do not recommend repeated measurement of proteinuria for women with preeclampsia, the amount of proteinuria does not seem to be related to poor maternal and neonatal outcomes, and monitoring proteinuria may lead to unindicated preterm deliveries and related neonatal complications. Our current diagnosis of preeclampsia in women with chronic kidney disease may be based on a change in protein excretion, a baseline protein excretion evaluation is critical in certain conditions such as chronic hypertension, diabetes, and autoimmune or other renal disorders. The current definition of superimposed preeclampsia possesses a diagnostic dilemma, and it is unclear whether a change in the baseline proteinuria reflects another systemic disease such as preeclampsia or whether women with chronic disease such as chronic hypertension or diabetes will experience a different "normal" pattern of protein excretion during pregnancy. Finally, limited data are available regarding angiogenic and other biomarkers in women with chronic kidney disease as a potential aid in distinguishing the worsening of baseline chronic kidney disease and chronic hypertension from superimposed preeclampsia.

Angiogenic dysfunction in molar pregnancy.

OBJECTIVE: Molar pregnancy is associated with very early-onset preeclampsia. Since excessive circulating antiangiogenic factors may play a pathogenic role in preeclampsia, we hypothesized that molar placentas produce more antiangiogenic proteins than normal placentas. STUDY DESIGN: This retrospective case-control study used a semiquantitative immunohistochemical technique to compare histologic sections of molar placentas to normal controls. Tissue slides were treated with 2 antisera: one recognized the antiangiogenic markers fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), while the other recognized vascular endothelial marker CD31. Stain intensity was graded from 1+ (strong focal staining) to 4+ (91-100% staining). RESULTS: Molar placentas (n = 19) showed significantly more staining than controls (n = 16) for Flt/sFlt1 (P < .0001). CONCLUSION: There was a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This supports a hypothesis that the phenotype of preeclampsia in molar pregnancy may result from trophoblasts overproducing at least 1 antiangiogenic protein.

Effects of calcium supplementation on uteroplacental and fetoplacental blood flow in low-calcium-intake mothers: a randomized controlled trial.

OBJECTIVE: We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations. STUDY DESIGN: Pulsatility index (PI) and resistance index (RI) (uterine and umbilical arteries) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20-36 weeks' gestation in 510 healthy, nulliparous Argentinean women with deficient calcium intake in a randomized, placebo-controlled, double-blinded trial. RESULTS: Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week. Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks, respectively. Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women. CONCLUSION: Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation.

Influence of maternal asthma and asthma severity on newborn morphometry.

OBJECTIVE: To determine if maternal asthma or asthma severity affects newborn morphometry. STUDY DESIGN: A secondary analysis was performed on data collected in a multicenter prospective observational cohort study of asthma in pregnancy. Patients enrolled included women with asthma stratified by severity of disease and controls. Asthma severity was defined according to the classification proposed by the National Asthma Education Program (NAEP) Report of the Working Group on Asthma and Pregnancy, modified to include medication requirements. Newborn morphometry measurements included birth weight (BW) and multiples of the median birth weight (BW-MOM), head circumference (HC), length (L), HC:BW ratio, and ponderal index (PI). RESULTS: Of 2480 patients there were 828 nonasthmatic controls, 828 with mild, 775 with moderate, and 49 with severe disease. Comparing all groups, there were statistically significant differences in maternal age (p < .001), race (p = .005), parity (p = .006), prepregnancy weight (p = .028), and medical care source (p = .001), with the severe asthma group having the highest mean maternal age (25.7 years), and proportion of African Americans (71.4%), proportion of multiparous patients (63.3%), and proportion of patients receiving government assistance (85.7%). When the control group was excluded from the comparisons, differences in prepregnancy weight and medical care source were no longer significant. BW-MOM and L did not differ between groups. The HC:BW ratio increased with asthma severity (p = .029) and was increased compared to controls (p = .010). This remained significant after controlling for confounding variables (both p <.001). HC was statistically significantly different between all groups (p = .032), as well as among women with varying degrees of asthma severity (p = .013), which was not clinically significant. After covariates adjustment, HC was not significantly different among all groups (p = .228), nor the asthma groups (p = .144). CONCLUSION: Asthma severity is associated with an increased HC:BW ratio. Severity was not found to impact HC, BW-MOM, L, or PI independently. However, the magnitudes of the effects were too small to suggest a clinically significant effect of asthma on neonatal morphometry in this large prospectively studied sample.

Maternal plasma concentrations of the soluble tumor necrosis factor receptor 2 are increased prior to the diagnosis of preeclampsia.

OBJECTIVE: Soluble receptor levels of tumor necrosis factor (sTNF-R)-1 and -2 are increased during preeclampsia. We postulated the increase preceded overt disease. STUDY DESIGN: Archived plasma from the Eunice Kennedy Shriver National Institute of Child Health and Human Development aspirin to prevent preeclampsia in high risk women trial were used to measure serial sTNF-R1 and sTNF-R2 (enrollment, 24-28 week's gestation) in 986 women (577 also sampled at 34-38 weeks). RESULTS: Preeclampsia incidence was 21.2%. sTNF-R2 levels were higher at enrollment (P = .02) and weeks 24-28 (P = .01) in women who eventually developed preeclampsia. The magnitude of increase from baseline of both receptors was significantly greater in women who developed preeclampsia in the future. Women with week 24-28 sTNF-R2 levels in the highest quartile had significantly increased odds to develop preeclampsia (P = .03 vs quartile 1). This association was observed in the placebo but not the aspirin arm (P

Maternal infection and risk of preeclampsia: systematic review and metaanalysis.

There are lingering questions regarding the association between maternal infection and preeclampsia. Systematic review and metaanalysis was conducted of observational studies that examined the relationship between maternal infection and preeclampsia. Forty-nine studies met the inclusion criteria. The risk of preeclampsia was increased in pregnant women with urinary tract infection (pooled odds ratio, 1.57; 95% CI, 1.45-1.70) and periodontal disease (pooled odds ratio, 1.76; 95% CI, 1.43-2.18). There were no associations between preeclampsia and presence of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus, treated and nontreated HIV infection, and malaria. Individual studies did not find a relationship between herpes simplex virus type 2, bacterial vaginosis, and Mycoplasma hominis and preeclampsia. Urinary tract infection and periodontal disease during pregnancy are associated with an increased risk of preeclampsia. More studies are required to verify this as well as to explore whether or not such relationships are causal and, if so, the mechanisms involved.

Advances in the understanding of eclampsia.

Preeclampsia, a serious hypertensive complication of pregnancy characterized by new-onset hypertension and proteinuria after midpregnancy, is a multisystem disorder that often involves the central nervous system. Neurologic signs and symptoms include hyperreflexia, headaches, visual disturbance, seizures, and cerebral hemorrhage. Eclampsia-new-onset seizures in the setting of preeclampsia-usually occurs before or within 48 hours of delivery, but can present as late as 1 month postpartum (late postpartum eclampsia). Magnesium sulfate is the drug of choice to prevent and treat eclampsia, a recommendation validated through large, randomized, and placebo-controlled trials. This review describes the pathogenesis, clinical features, and treatment of eclampsia, focusing on recent observations regarding roles of circulating antiangiogenic factors in the pathogenesis of the neurologic complications of eclampsia.

Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review.

OBJECTIVE: To evaluate claims that elevated soluble fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased placental growth factor predict preeclampsia. DATA SOURCES: MEDLINE (1966-March 2006), EMBASE (1980-June 2006), POPLINE (1980-June 2006), CINAHL (1982-June 2006), and LILACS (1982-June 2006) were searched, and experts contacted. METHODS OF STUDY SELECTION: Studies identified and included were those reporting blood and urine levels of sFlt-1 or placental growth factor obtained before gestational week 30 or overt preeclampsia. TABULATION, INTEGRATION, AND RESULTS: Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing placental growth factor were included in this review. There was considerable interreport heterogeneity in methodology and results for sFlt-1 measured before gestational week 25. After week 25 placental growth factor and sFlt-1 levels varied consistently between the normal pregnancy group and women destined to develop preeclampsia, achieving significance in women who developed severe preeclampsia. CONCLUSION: Third-trimester increases in sFlt-1 and decreases in placental growth factor levels are associated with preeclampsia, specifically severe disease, based on retrospective data. The evidence is insufficient to recommend these markers to be used for screening, and prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests.

Blood pressure dynamics during pregnancy and spontaneous preterm birth.

OBJECTIVE: The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. STUDY DESIGN: We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). RESULTS: Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. CONCLUSION: An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern.

Reference intervals for anion gap and strong ion difference in pregnancy: a pilot study.

OBJECTIVE: Acid-base status and electrolyte levels change in normal pregnancy. We hypothesized that these physiological changes affect both anion gap and strong ion difference (SID). METHODS: A cross-sectional study of normal pregnant women (6 in the first trimester, 47 in the second trimester, 59 in the third trimester, and 13 postpartum). RESULTS: The anion gap in pregnancy (8.5 +/- 2.9 mEq/L) was less, compared to postpartum values (10.7 +/- 2.5 mEq/L), (p < 0.005). The SID, too, was lower (pregnancy, 38.3 +/- 2.9 mEq/L, postpartum 43.5 +/- 2.3 mEq/L, p < 0.001), reflecting the combined influence of changes in albumin, SID, and PCO(2). CONCLUSION: Anion gap and SID both decrease in pregnancy, events which must be taken into account when managing acid-base disorders in gestation.

Neuropsychological performance in normal pregnancy and preeclampsia.

OBJECTIVE: The objective of the study was to evaluate neurocognitive function in preeclampsia and normal pregnancy. STUDY DESIGN: Three groups (each n = 15) were studied before and after delivery using standard neurocognitive test techniques. Group A consisted of normal laboring patients; group B, preeclamptics receiving magnesium; and group C, women in preterm labor receiving MgSO4 tocolysis (Mg control). The tests, examining attention, working memory, explicit memory, auditory comprehension, and measures for emotional distress, pain, and fatigue were analyzed via 4-way multivariate analysis of variance and multiple t tests. RESULTS: Preeclamptics receiving MgSO4 had better attention and working memory (P = .05), compared with normal laboring women and the preterm patients. Explicit memory was impaired in all groups, and this could not be accounted for by pain or emotional distress. CONCLUSION: We could detect no cognitive defects in preeclamptics, compared with normotensive gravidas, at least while the cerebral vasodilator MgSO4 is being infused.

World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women.

OBJECTIVE: The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery. STUDY DESIGN: Randomized placebo-controlled, double-blinded trial in nulliparous normotensive women from populations with dietary calcium < 600 mg/d. Women who were recruited before gestational week 20 received supplements (1.5 g calcium/d or placebo) throughout pregnancy. Primary outcomes were preeclampsia and preterm delivery; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates. RESULTS: The groups comprised 8325 women who were assigned randomly. Both groups had similar gestational ages, demographic characteristics, and blood pressure levels at entry. Compliance were both 85% and follow-up losses (calcium, 3.4%; placebo, 3.7%). Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia (4.1% vs 4.5%) that was evident by 35 weeks of gestation (1.2% vs 2.8%; P = .04). Eclampsia (risk ratio, 0.68: 95% CI, 0.48-0.97) and severe gestational hypertension (risk ratio, 0.71; 95% CI, 0.61-0.82) were significantly lower in the calcium group. Overall, there was a reduction in the severe preeclamptic complications index (risk ratio, 0.76; 95% CI, 0.66-0.89; life-table analysis, log rank test; P = .04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (risk ratio, 0.80; 95% CI, 0.70-0.91). Preterm delivery (the neonatal primary outcome) and early preterm delivery tended to be reduced among women who were < or = 20 years of age (risk ratio, 0.82; 95% CI, 0.67-1.01; risk ratio, 0.64; 95% CI, 0.42-0.98, respectively). The neonatal mortality rate was lower (risk ratio, 0.70; 95% CI, 0.56-0.88) in the calcium group. CONCLUSION: A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality, albeit these were secondary outcomes.

Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?

OBJECTIVE: Preeclampsia, gestational hypertension, and unexplained intrauterine growth restriction may have similar determinants and consequences. In this study, we compared determinants and perinatal outcomes associated with these obstetric conditions. STUDY DESIGN: We analyzed 39,615 pregnancies (data from the WHO Antenatal Care Trial), of which 2.2% were complicated by preeclampsia, 7.0% by gestational hypertension, and 8.1% by unexplained intrauterine growth restriction (ie, not associated with maternal smoking, maternal undernutrition, preeclampsia, gestational hypertension, or congenital malformations). We compared the risk factors associated with these groups. Fetal death, preterm delivery, and severe neonatal morbidity and mortality were the primary outcomes. Logistic regression analyses were adjusted for study site, socioeconomic status, and (if appropriate) birth weight and gestational age. RESULTS: Diabetes, renal or cardiac disease, previous preeclampsia, urinary tract infection, high maternal age, twin pregnancy, and obesity increased the risk of both hypertensive conditions. Previous large-for-age birth, reproductive tract surgery, antepartum hemorrhage and reproductive tract infection increased the risk for gestational hypertension only. Independent of maternal age, primiparity was a risk factor only for preeclampsia. Both preeclampsia and gestational hypertension were associated with increased risk for fetal death and severe neonatal morbidity and mortality. Mothers with preeclampsia compared with those with unexplained intrauterine growth restriction were more likely to have a history of diabetes, renal or cardiac disease, chronic hypertension, previous preeclampsia, body mass index more than 30 kg/cm2, urinary tract infection and extremes of maternal age. Conversely, unexplained intrauterine growth restriction was associated with higher risk of low birth weight in previous pregnancies, but not with previous preeclampsia. Both conditions increased the risk for perinatal outcomes independently but preeclampsia was associated with considerable higher risk. CONCLUSION: Preeclampsia and gestational hypertension shared many risk factors, although there are differences that need further evaluation. Both conditions significantly increased morbidity and mortality. Conversely, preeclampsia and unexplained intrauterine growth restriction, often assumed to be related to placental insufficiency, seem to be independent biologic entities.

Spirometry is related to perinatal outcomes in pregnant women with asthma.

OBJECTIVE: The purpose of this study was to test the hypothesis that maternal asthma symptoms and pulmonary function are related to adverse perinatal outcomes. STUDY DESIGN: Asthmatic patients were recruited from the 16 centers of the Maternal Fetal Medicine Units. Forced expiratory volume in 1 second was obtained at enrollment and at monthly study visits, and the frequency of asthma symptoms was assessed from enrollment to delivery. Perinatal data were obtained at postpartum chart reviews. RESULTS: The final cohort included 2123 participants with asthma. After adjustment for demographic characteristics, smoking, acute asthmatic episodes, and oral corticosteroid use, significant relationships were demonstrated between gestational hypertension and preterm birth and lower maternal gestational forced expiratory volume in 1 second. The data did not show any significant independent relationship between asthma symptom frequency and perinatal outcomes. CONCLUSION: Lower pulmonary function during pregnancy is associated with increased gestational hypertension and prematurity in the pregnancies of women with asthma, which may be due to inadequate asthma control or factors that are associated with increased asthma severity.

Late postpartum eclampsia: examples and review.

Eclampsia, defined as the occurrence of seizures in pregnant women, usually in the setting of preeclampsia and in the absence of other neurologic disorders, occurs mainly before, during , or within 48 hours after delivery. When convulsions occur later postpartum, diagnosis is difficult and treatment disputed. We review the entity of late postpartum eclampsia and report 2 examples in which the serum levels of antiangiogenic and angiogenic proteins were measured.