Isolated gestational proteinuria preceding the diagnosis of preeclampsia - an observational study.

INTRODUCTION: Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. MATERIAL AND METHODS: This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. RESULTS: IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2-18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. CONCLUSIONS: IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE.

Perinatal outcomes of abnormal umbilical coiling according to a modified umbilical coiling index.

AIM: The aim of this study was to determine the relation between perinatal outcomes and umbilical cord coiling as evaluated by a modified umbilical coiling index. METHODS: In this retrospective study, 200 consecutive umbilical cords were examined. An umbilical venous and arterial coiling index was calculated by dividing the total number of umbilical venous and arterial coils by the length of cord individually. Umbilical cords with umbilical venous coiling indices in the lowest decile, the highest decile, and the remaining deciles were defined as hypocoiled, hypercoiled, and normocoiled, respectively. The perinatal outcomes of the subjects with hypocoiled and hypercoiled umbilical cords were compared with those with normocoiled umbilical cords. RESULTS: In 69.5% of subjects, a difference in the degree of coiling was detected between the umbilical veins and arteries. While all umbilical venous twisting demonstrated the same direction, the direction of the arterial twisting reversed at a certain point along the umbilical cord in 19.0% of the subjects. The arteriovenous coiling difference was small in the hypercoiled group and large in the hypocoiled group. A hypocoiled umbilical cord evaluated by umbilical venous coiling index was found to be associated with prolonged deceleration (odds ratio [OR], 4.18; 95% confidence interval [CI], 1.54-11.38), operative delivery (OR, 2.67; 95%CI, 1.01-7.09), and nuchal cord entanglement (OR, 3.21; 95%CI, 1.23-8.33). CONCLUSION: Umbilical coiling abnormalities were investigated using a novel umbilical venous coiling index. A hypocoiled umbilical cord evaluated by umbilical venous coiling index was found to be associated with fetal heart rate abnormalities, operative delivery, and nuchal cord entanglement.

Urinary protein-to-creatinine ratio in pregnant women after dipstick testing: prospective observational study.

BACKGROUND: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP. METHODS: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr > 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP. RESULTS: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and ≥ 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 + . CONCLUSIONS: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with ≥ 1+ as well as normotensive women with ≥ 2+ on dipstick test should be advised to undergo the P/Cr test.

Factors contributing to mortality and morbidity in pregnancy-associated intracerebral hemorrhage in Japan.

AIM: The aim of this study was to analyze the causes and outcomes for intracerebral hemorrhage (ICH) occurring during pregnancy and postnatally. MATERIAL AND METHODS: A nationwide study of pregnancy-related ICH in Japan was performed. We contacted 1582 facilities to identify women with ICH in pregnancy or postnatally between 1 January 2006 and 31 December 2006. A total of 1012 facilities (70%) responded with completed questionnaires. Risk factors for ICH, neurological features, onset to diagnosis time (O-D time), and obstetric data were recorded. RESULTS: Thirty-eight cases of pregnancy-associated ICH were identified, corresponding to 3.5 per 100 000 deliveries. There were seven maternal deaths, giving a case mortality rate of 18.4%. Pre-eclampsia was identified in 10 cases (26.3%) and hemolysis elevated liver enzymes and low platelet count (HELLP) syndrome was present in five. There were four cases (10.5%) with Moyamoya disease and seven (18.4%) with arteriovenous malformation. HELLP syndrome and moderately or severely disturbed consciousness at disease onset were significantly associated with a poor outcome (modified Rankin Scale ≥3). Pre-eclampsia, HELLP syndrome and O-D time >3 h were significantly associated with maternal mortality. CONCLUSION: Early diagnosis may prevent maternal death, even in severe cases of pregnancy-related ICH. However, maternal-fetal care centers do not always have full-time neurosurgeons or diagnostic imaging tools suitable for diagnosis of ICH. Thus, a network should be established between maternity centers and neurosurgery departments with computed tomography or magnetic resonance imaging available at all times. We recommend transferal of pregnant women with neurological symptoms to a regional facility that is equipped to treat such patients.

Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2014 edition.

The 'Clinical Guidelines for Obstetrical Practice, 2011 edition' were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding. Each answer with a recommendation level of A, B or C was prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' was weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 104 Clinical Questions and Answers items, with the omission of the Discussion, List of References, and Tables and Figures, are presented herein to promote a better understanding among English readers of the current standard care practices for pregnant women in Japan.

The risk factors for labor onset hypertension.

Our aim was to clarify the perinatal outcomes of and risk factors for hypertension that is first detected after labor onset (labor onset hypertension, LOH), which may be a risk factor for eclampsia and stroke during labor. A total of 1349 parturient women who did not exhibit preeclampsia or gestational hypertension prior to labor were examined. The patients were classified into four groups: the normotensive (n=1023) (whose systolic blood pressure (SBP) remained below 140 mm Hg throughout labor), mild LOH (n=241) (whose maximum SBP during labor ranged from 140 to 159 mm Hg), severe LOH (n=66) (whose maximum SBP during labor ranged from 160 to 179 mm Hg) and emergent LOH groups (n=19) (whose maximum SBP during labor was greater than 180 mm Hg). The perinatal outcomes and patient characteristics of the four groups were compared. Twenty-four percent of the pregnant women who remained normotensive throughout pregnancy developed hypertension during labor. One of the patients in the emergent LOH group developed eclampsia. The blood pressure at delivery and frequencies of hypotensor use, interventional delivery and low Apgar scores differed significantly among the four groups. The following risk factors for severe/emergent LOH were extracted: being over 35 years old, a body mass index at delivery of >30, an SBP at 36 weeks' gestation of 130-134 mm Hg, an SBP at admission of 130-139 mm Hg, proteinuria (a score of 2+ on the dipstick test) and severe edema. The risk factors for severe/emergent LOH were identified in this study. In high risk cases, repeatedly measuring maternal blood pressure during delivery might help detect critical hypertension early.

Possible activation of the renin-angiotensin system in the feto-placental unit in preeclampsia.

The purpose of this study was to elucidate the mechanisms underlying the regulation of feto-placental circulation mediated by the renin-angiotensin system under preeclamptic conditions. We measured angiotensin-converting enzyme (ACE) activity, protein expression, and mRNA expression in uncomplicated and preeclamptic placentas and examined the localization of ACE. In addition, ACE activity and mRNA expression in human umbilical venous endothelial cells (HUVECs) under hypoxic conditions were analyzed. ACE activity, protein expression, and mRNA expression in placental tissues from preeclampsia were all significantly higher than those from uncomplicated pregnancies. ACE activity in vessel fractions was extensively higher than that in trophoblast-rich or macrophage-rich fractions. Additionally, ACE activity in HUVECs was significantly higher than that in human arterial endothelial cells, and ACE mRNA was primarily localized to venous endothelial cells of stem villous in placentas. Furthermore, hypoxic condition induced both ACE activity and mRNA expression in HUVECs. These results suggested that venous endothelial cells within placental stem villous tissues and umbilicus play an important role in the regulation of the feto-placental renin-angiotensin system, and in response to hypoxic conditions the feto-placental unit seemed to induce ACE activity in the placenta; such an effect would be likely to lead to regulation of the fetal circulation.

Possible involvement of aminopeptidase A in hypertension in spontaneously hypertensive rats (SHRs) and change of refractoriness in response to angiotensin II in pregnant SHRs.

BACKGROUND: Hypertension complicated with pregnancy is a major cause of maternal and fetal mortality, but its pathophysiology is unclear. OBJECTIVE: To investigate the pressor response to angiotensin II (Ang II) and the involvement of the Ang II degrading protease, aminopeptidase A, in spontaneously hypertensive rats (SHRs). DESIGN: Pregnant SHRs and Wistar-Kyoto (WKY) rats were studied. Angiotensin II (200 ng/kg per min) or saline was infused by osmotic pump from day of 15 gestation, and caesarean section was performed at day 20 of gestation. Blood pressure during pregnancy, weight of placentas and pups at caesarean section, and aminopeptidase A activity in placenta and renal cortex were measured. RESULTS: Ang II treatment induced increases in blood pressure that were greater in non-pregnant WKY rats than those in pregnant WKY rats, pregnant SHRs, and non-pregnant SHRs. Renal aminopeptidase A activity in SHRs was significantly lower than that in WKY rats. Renal aminopeptidase A activity in pregnant SHRs was significantly greater than that in non-pregnant SHRs, but there was no significant increase in pregnant WKY rats. Placental aminopeptidase A activity in SHRs was greater than that in WKY rats. Placental aminopeptidase A activity in WKY rats was increased by Ang II, but was not increased in SHRs. Weights of placentas and pups were significantly lower in SHRs than in WKY rats. CONCLUSIONS: Renal aminopeptidase A may be involved in the development of hypertension and the regulation of blood pressure in SHRs. Placental aminopeptidase A may be upregulated in response to fetal stress in pregnant SHRs.

Tissue distribution of placental leucine aminopeptidase/oxytocinase during mouse pregnancy.

Placental leucine aminopeptidase (P-LAP), also called oxytocinase, is an enzyme responsible for hydrolyzing oxytocin. This enzyme is identical to cystine aminopeptidase. We examined the tissue distribution of P-LAP in normal adult mice and also in mothers and fetuses during mouse pregnancy using immunohistochemical (IHC) analysis. P-LAP-immunoreactive protein was expressed in various organs in a cell- and gestational stage-dependent manner. In the kidney, P-LAP was located in distal and collecting tubules but not in proximal tubules. The islet of Langerhans in the maternal pancreas stained positively for P-LAP in the periphery in early gestation. This staining pattern changed so that both the periphery and inner cells were positive during mid-gestation and finally only inner cells were positive in late gestation. Among the hematopoietic cells in the fetal liver, only megakaryocytes showed strong expression of P-LAP. The staining intensity increased with gestation on the apical surface of trophoblasts in the placental labyrinth. These data demonstrate that P-LAP is present in a variety of tissues, and its presence is affected by pregnancy and fetal development. Therefore, P-LAP may play a significant role in various physiological processes in non-pregnant, pregnant, and fetal mice.

Increased intracranial blood flow volume in a preeclamptic woman with postpartum photophobia.

BACKGROUND: Cerebral circulatory changes in preeclampsia are unclear. We studied the changes in intracranial blood flow volume using a new color Doppler ultrasonographic assessment in a preeclamptic woman with photophobia. CASE: A 39-year-old preeclamptic primigravida was admitted and delivered by cesarean at 36 weeks' gestation. She developed bilateral photophobia with blood pressure elevation at 2 days postpartum. Blood flow volume index [mean velocity x pid(2)/4] (d = luminal diameter at systolic phase) was established. The sum of blood flow volume indexes of the bilateral internal carotid arteries and vertebral arteries increased at the onset of photophobia and blood pressure elevation. The blood flow volume index increased above 120 mm Hg of mean arterial blood pressure. CONCLUSION: These data represent the increased cerebral hemodynamic changes in preeclampsia with photophobia.

Effects of estradiol administration on feto-placental growth in rat.

BACKGROUND: To clarify the effect of estradiol benzoate on placental structure and its consequences for fetal survival and fetoplacental growth. STUDY DESIGN: Estradiol benzoate (0, 0.1, 1, 10, 100 microg/day) was infused intraperitoneally into pregnant Wistar rats from 12 to 19 days' gestation. Survival rate, weight of pups and placentas at 20 days' gestation, and plasma levels of estrogen and progesterone were measured. Pathological changes in the placenta were also examined. RESULTS: Estradiol benzoate reduced fetal survival (1 microg/day: 100%, 10 microg/day: 70%, 100 microg/day: 14.6%) and the weights of the pups and placentas in a dose-dependent manner. Maternal estradiol concentration was raised 23-fold with 100microg/day of estradiol benzoate. Trophoblast degeneration, including apoptosis and destruction of placental labyrinth was induced but the structures of the maternal kidney and liver were not affected. CONCLUSIONS: In pregnant rats, estradiol benzoate causes fetal mortality at a pharmacological dose (more than 10 microg/day) and fetoplacental growth retardation via trophoblastic degeneration and destruction of the placental labyrinth even at a physiological dose (1 microg/day).

Management of eclampsia and stroke during pregnancy.

To establish the etiologies and therapeutic strategies for the treatment of eclampsia and stroke during pregnancy, we performed a questionnaire-based study of stroke during pregnancy in Aichi prefecture (2005-2009). This study revealed the following findings: 66% of deliveries were managed in primary medical institutions, 40% of eclampsia episodes and 31% of strokes occurred at primary medical institutions, and 19% of strokes occurred at home. Home-onset strokes displayed a mortality rate of 40%. Using the results of this questionnaire, we investigated cases of eclampsia and/or stroke during pregnancy and revealed important issues regarding their management. In pregnant women with eclampsia or stroke, accurate antihypertensive and anticonvulsive treatment are necessary. Discriminating between eclampsia and stroke during labor is difficult. However, when facial or arm muscle weakness or a facial deficit is detected, stroke should be strongly suspected. Brain computed tomography can usually detect most cases of hemorrhagic stroke. When a stroke is detected, collaborative treatment with a neurosurgeon should be started as soon as possible. If stroke is suspected at a primary medical institution, rapid maternal transport to an intensive medical institution is necessary. In patients whose blood pressure is greater than 180/120 mmHg, the use of MgSO4 to decrease the risk of convulsions and reduce blood pressure is recommended. These findings might aid the development of therapeutic strategies for pregnant women with eclampsia or stroke.

Pure red cell aplasia and acute hepatitis during pregnancy.

Pure red cell aplasia during pregnancy is rare. We present a case in a 26-year-old pregnant woman, referred to our hospital at 31 weeks' gestation because of severe anemia caused by acute hepatitis. She was treated with repeated blood transfusions and the pure red cell aplasia gradually remitted during the pregnancy. A live infant was delivered by cesarean section at 34 weeks' gestation. Postpartum, the pure red cell aplasia and hemolytic anemia remitted completely. Our case illustrates that pure red cell aplasia may occur late in pregnancy associated with acute viral hepatitis and is reversible during pregnancy without any necessity for steroid therapy.

Effect of prostaglandin E1 on ophthalmic artery velocimetry in a pre-eclamptic woman with visual disturbance caused by retinal arterial narrowing.

We reported the ophthalmic arterial velocimetry and the effect of prostaglandin E1 on that using color Doppler ultrasonography in a 29-year-old pre-eclamptic woman with postpartum weakness of vision due to retinal arterial narrowing. In this case, we found higher pulsatility index and lower mean velocity than that in normal pregnancy. The 30.8% reduction of ophthalmic artery pulsatility index and 53.9% acceleration of mean velocity were observed at 25 min after intravenous administration of prostaglandin E1. Normalization of these values preceded the recovery of vision. These findings suggest a vasodilated effect of prostaglandin E1 on orbital circulation in a pre-eclamptic woman with weakness of vision due to retinal arterial narrowing.

Expression of glucose transporter 4 in the human pancreatic islet of Langerhans.

Glucose transporter 4 (GLUT4) is the main insulin-responsive glucose transporter in skeletal muscle and adipose tissue of human and rodent, and is translocated to the plasma membrane in response to insulin. GLUT2 is well known as the main glucose transporter in pancreatic islets and could highly regulate glucose-stimulated insulin secretion by B-cells as a glucose sensor. We confirmed the presence of GLUT4 mRNA and GLUT4 protein in pancreas in the human. Indirect immunohistochemistry showed that the pancreatic islets of human and rat were conspicuously labeled by anti-GLUT4 antibody. The presence of placental leucine aminopeptidase (P-LAP), a homologue of insulin-regulated aminopeptidase (IRAP), was also shown in the human pancreatic islet. IRAP/P-LAP is thought to be involved in glucose metabolism. This study provides the first evidence that GLUT4 is present in human and rat pancreatic islets and may suggest its specific role in glucose homeostasis in conjunction with IRAP/P-LAP.

Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice.

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.