Low placental growth factor levels and high soluble endoglin levels at 26-31 weeks of gestation precede light placenta with and without relatively heavy infant, respectively: A retrospective cohort study.

AIM: Our aim was to examine whether serum levels of placental growth factor (PlGF) and soluble endoglin (sEng) at 19-25 and 26-31 weeks of gestation were associated with the occurrence of the 9-block categorization of placenta weight (PW) and fetal/placenta ratio (F/P ratio). METHODS: We performed a retrospective cohort study in 1391 women with singleton pregnancy. Serum levels of PlGF and sEng were measured by enzyme immunosorbent assay. A light placenta was defined as PW ZS < -1.28 SD. Based on the PW (light, normal, and heavy) and F/P ratio (relatively heavy, balanced growth, and relatively small), 9-block categorization were performed. Multivariable logistic regression analyses were performed. RESULTS: Low PlGF at 26-31 weeks was an independent risk factor for the birth of infants belonging to Block A (light placenta and relatively heavy infant), after adjusting for prepregnancy body mass index and serum levels of sEng. High sEng at 26-31 weeks was an independent risk factor for the birth of infants belonging to Block D (light placenta and balanced growth of infant), after adjusting for past history of either preeclampsia or gestational hypertension, high pulsatility index of uterine artery flow velocity waveforms in the second trimester, and serum level of PlGF. CONCLUSIONS: Low PlGF levels at 26-31 weeks of gestation may precede a light placenta and relatively heavy infant (Block A), and high sEng levels at 26-31 weeks of gestation may precede a light placenta and balanced growth of infant (Block D).

Markedly higher sFlt-1/PlGF ratio in a woman with acute fatty liver of pregnancy compared with HELLP syndrome.

AIM: To compare serum levels of angiogenesis-related factors between 14 women with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome and a woman with acute fatty liver of pregnancy (AFLP). METHODS: Serum samples were collected in 2004-2008 and 2013-2016. The levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured by an automated electrochemiluminescence immunoassay using Elecsys sFlt-1 and Elecsys PlGF. After logarithmic transformation, levels of sFlt-1, PlGF and the sFlt-1/PlGF ratio in a woman with AFLP were compared with those in women with HELLP syndrome, using the one-sample t-test. RESULTS: At 37 weeks of gestation, a patient was diagnosed with AFLP based on Swansea criteria (showing six features including elevated transaminases), and she also showed a duodenal ulcer with active bleeding, thrombocytopenia and hypertension. Her serum levels of sFlt-1 and sFlt-1/PlGF ratio were significantly higher than in those with HELLP syndrome (273 040 pg/mL vs 15 135 [mean], P < 0.001; 4236 vs 224, P < 0.001; respectively). However, her serum level of PlGF was not significantly different from those with HELLP syndrome. CONCLUSION: Serum levels of sFlt-1 and the sFlt-1/PlGF ratio, but not PlGF, in a woman with AFLP were markedly higher than those in women with HELLP syndrome. AFLP may be a different clinical entity from HELLP syndrome based on angiogenesis-related factors. Clinically, the sFlt-1/PlGF ratio may be used to rapidly distinguish AFLP from HELLP syndrome.

Vaginal Ureaplasma species increase chorioamnionitis in very preterm infants with preterm premature rupture of the membranes at < 28 weeks of gestation.

Our aim was to investigate the association between vaginal Ureaplasma species (spp.) and the subsequent occurrence of chorioamnionitis (CAM), perinatal death, neonatal morbidity, and long-term neurodevelopmental impairments (NDIs) at 3 years of age. We analyzed 55 pregnant women with singleton pregnancy who had preterm premature rupture of the membranes (pPROM) at < 28+0 weeks of gestation, and delivered between 22+0 and 31+6 weeks at our tertiary hospital in 2007-2016. NDIs were defined as either cerebral palsy or developmental delay evaluated at 1.5 and/or 3 years old. The presence of Ureaplasma spp. and Mycoplasma hominis were evaluated using urea-arginine broth and Mycoplasma PPLO Agar. The presence of Ureaplasma spp. in the vagina was positive in 41%. Vaginal Ureaplasma spp. was a significant risk factor for CAM; however, it was not significantly associated with the occurrence of perinatal death, pulmonary hypoplasia, respiratory distress syndrome, transient tachypnea of the newborn, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia defined as oxygen required and occasional ventilatory assistance required at week 36 as modified (BPD36), or NDIs. The crude odds ratio (95% confidence interval) of Ureaplasma spp. for the occurrence of CAM was 9.5 (1.10-82) (p = 0.041). In very preterm birth infants with pPROM, CAM, BPD36, and NDIs occurred in 78, 60, and 36%, respectively. Vaginal Ureaplasma spp. was a significant risk factor for CAM in very preterm birth infants with pPROM. The incidences of BPD36 and NDIs in such infants were very high, nearing 3/5 and 1/3, respectively.

Independent risk factors for a small placenta and a small-for-gestational-age infant at 35-41 weeks of gestation: An association with circulating angiogenesis-related factor levels at 19-31 weeks of gestation.

AIM: Our aim was to investigate the effects of angiogenesis-related factor levels at 19-25 and 26-31 weeks of gestation (WG) on the later occurrence of a small-for-gestational-age (SGA) placenta (small placenta) or an SGA infant delivered at 35-41 WG. METHODS: We measured plasma levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), and the serum level of soluble endoglin (sEng) in 679 pregnant women with blood sampling at both 19-25 and 26-31 WG in a prospective study. A small placenta and an SGA infant were defined as <10th percentile, respectively. Multivariate logistic regression analyses were performed using maternal factors, a high mean pulsatility index (high mPI) of the uterine artery in the second trimester, and angiogenesis-related factor levels. RESULTS: Regarding the occurrence of a small placenta, low PlGF at 19-25 WG (adjusted odds ratio [95% confidence interval]: 2.4 [1.01-5.7]) and a high mPI (2.5 [1.4-4.3]) were independent risk factors. Moreover, low PlGF at 26-31 WG (3.3 [1.5-7.0]) was also an independent risk factor after adjusting for the effect of mPI. Concerning the occurrence of an SGA infant, a high mPI (2.8 [1.6-5.2]) and high sEng at 26-31 WG (2.3 [1.2-4.5]) were independent risk factors. CONCLUSION: Low levels of PlGF at 19-25 and 26-31 WG were independent risk factors for a small placenta at ≥35 WG; and a high sEng at 26-31 WG was an independent risk factor for an SGA infant at ≥35 WG.

Automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation predicts preterm preeclampsia: a retrospective cohort study.

Our aims were to obtain the gestational-age-specific median of common logarithmic placental growth factor (PlGF) values in the first trimester in women with a singleton pregnancy in order to generate the gestational-age-specific multiple of the median (MoM) of log10PlGF at 9-13 weeks of gestation, to evaluate screening parameters of MoM of log10PlGF at 9-13 weeks of gestation to predict preterm preeclampsia (PE), and to construct an appropriate prediction model for preterm PE using minimum risk factors in multivariable logistic regression analyses in a retrospective sub-cohort study. Preterm PE occurred in 2.9% (20/700), and PE in 5.1% (36/700). Serum PlGF levels were measured using Elecsys PlGF®. MoMs of log10PlGF at 9-13 weeks of gestation in Japanese women with a singleton pregnancy followed a normal distribution. We determined the appropriate cut-off value of MoM of log10PlGF to predict preterm PE at around a10% false-positive rate (0.854). The MoM of log10PlGF < 0.854 yielded sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (95% confidence interval [CI]), and negative likelihood ratio (95% CI) of 55.0%, 91.9%, 17.5%, 98.5%, 6.79 (4.22-10.91), and 0.49 (0.30-0.80), respectively. The combination of MoM of log10PlGF and presence of either chronic hypertension or history of PE/gestational hypertension (GH) yielded sensitivity and specificity of 80.0 and 85.7%, respectively, to predict preterm PE. In conclusion, the automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation may be useful to predict preterm PE.

Establishing reference values for mean notch depth index, pulsatility index and resistance index in the uterine artery at 16-23 weeks' gestation.

AIM: Our aim was to determine the reference values of indices of impedance to flow in uterine arteries at 16-23 weeks, and to evaluate the effects of these indices for predicting early-onset pre-eclampsia (EO-PE), which was defined as PE with onset at <32 weeks. METHODS: During 2004 to 2008, 1536 women with a singleton pregnancy were recruited into a prospective cohort study at 16-23 weeks. The mean notch depth index (mNDI), mean pulsatility index (mPI) and mean resistance index (mRI) were calculated. RESULTS: Early-onset pre-eclampsia occurred in 16 (1.0%). The 80th, 90th, 95th and 97.5th percentiles of the mNDI at 16-23 weeks were determined. Normal reference ranges of the mPI and mRI were constructed, and individual standard deviation scores (SDS) of the mPI and mRI were calculated. The area under the receiver-operating characteristics curves (AROC) of the mNDI, mPI, mRI and bilateral notching (BN) for predicting EO-PE were 0.807, 0.809, 0.782 and 0.798, respectively. For predicting EO-PE, a mNDI of the 90th percentile, mPI-SDS of 1.383, mRI-SDS of 0.975 and BN yielded sensitivities (specificities) of 0.688 (0.886), 0.750 (0.889), 0.813 (0.809) and 0.750 (0.845) with positive likelihood ratios and 95% confidence intervals of 6.0 (4.2-8.6), 6.8 (4.9-9.3), 4.3 (3.3-5.5) and 4.9 (3.6-6.6), respectively. CONCLUSIONS: We established the reference values for mNDI, mRI and mPI at 16-23 weeks. The positive likelihood ratios of mNDI and mPI for predicting EO-PE showed moderate screening performances, indicating mNDI or mPI in the second trimester could assist to find high risk women with the subsequent onset of EO-PE.

C-reactive protein levels at pre-/post-indicated cervical cerclage predict very preterm birth.

AIMS: To investigate the relation between serum levels of C-reactive protein (CRP) at pre-/post-cerclage points and preterm birth at <33 weeks of gestation in women with indicated cervical cerclage (CC). METHODS: Fifty-eight women with CC indicated for a short or soft cervix, but no visible or protruding fetal membranes into the vagina, between 17 and 26 weeks of gestation, were reviewed. Serum CRP levels were examined three times: just before cerclage, and on day 1 and day 2 post-cerclage. RESULTS: Serum CRP levels on day 1 and day 2, but not just before cerclage, predicted the occurrence of very preterm birth. In women with cervical dilatation of <3.0 cm, serum CRP levels on post-cerclage day 1 were associated with the increase of very preterm birth [CRP ≥1.5 mg/dL vs. <1.5 mg/dL: 4/5 (80%) vs. 8/31 (26%), P=0.033]. In women with cervical dilatation of <3.0 cm, serum CRP ≥3.0 mg/dL on post-cerclage day 2 was also associated with the increase of very preterm birth. CONCLUSION: In women with indicated CC between 17 and 26 weeks of gestation, increased levels of serum CRP on post-cerclage day 1 or 2 might be ominous signs for very preterm birth.

Difficulty of predicting early-onset super-imposed preeclampsia in pregnant women with hemodialysis due to diabetic nephropathy by serum levels of sFlt-1, PlGF, and sEng.

There are few case reports in which circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured before the onset of super-imposed preeclampsia in women with hemodialysis. A 40-year-old Japanese nulliparous women with hemodialysis due to diabetic nephropathy became pregnant by frozen embryo transfer. Intensive hemodialysis was started at 5 weeks of gestation. Her blood pressure (BP) in the first trimester was around 130/80 mmHg. At 20+3 weeks, she was admitted for close monitoring; her BP was 137/75 mmHg. Her BP increased to 157/88 mmHg at 31+2 weeks, and nifedipine at 20 mg/day was started at 31+6 weeks. However, the serial longitudinal measurements of sFlt-1, PlGF, and sEng did not predict the onset of super-imposed preeclampsia. Cesarean section was performed at 33+6 weeks due to uncontrollable hypertension. A healthy female infant weighing 2138 g was delivered. As for the changes of biomarkers between just before and just after hemodialysis, sFlt-1 was significantly higher just after compared with just before hemodialysis (5774 ± 1875 pg/mL vs. 2960 ± 905 pg/mL, respectively, p < 0.001). PlGF was also significantly higher just after compared with just before hemodialysis (2227 ± 1038 pg/mL vs. 1377 ± 614 pg/mL, respectively, p < 0.001). However, the sFlt-1/PlGF ratio and sEng levels were not significantly different between just before and just after hemodialysis (p = 0.115, p = 0.672, respectively). In conclusion, prediction of early-onset super-imposed preeclampsia using angiogenic and anti-angiogenic markers in pregnant women with hemodialysis might be difficult.

Clinical usefulness of serum levels of soluble fms-like tyrosine kinase 1/placental growth factor ratio to rule out preeclampsia in women with new-onset lupus nephritis during pregnancy.

Measurement of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio may be clinically useful to discriminate systemic lupus erythematosus (SLE) from preeclampsia. Here, we present a pregnant woman with new-onset SLE with hypertension, with the measurement of the sFlt-1/PlGF ratio during pregnancy. A 31-year-old Japanese nulliparous woman, who had been diagnosed with idiopathic thrombocytopenic purpura at 10 years, had a systolic blood pressure of 120 mmHg and was negative for proteinuria at 12+1 weeks. Since her blood pressure increased to 159/86 mmHg with 3+ proteinuria at 25+4 weeks, preeclampsia was suspected. Deterioration of the kidney function (creatinine: 0.58 mg/dL at 24+6 weeks to 0.83 mg/dL at 33+6 weeks) necessitated cesarean section at 33+6 weeks. After delivery, she still showed increased creatinine and proteinuria. Therefore, she was transferred to a nephrology specialist in a tertiary center and was finally diagnosed with SLE with lupus nephritis class IV-G(A) (diffuse lupus nephritis). The serum levels of sFlt-1 and the sFlt-1/PlGF ratio, which are usually elevated in preeclampsia, were within normal reference ranges at 27+6, 28+1, and 28+6 weeks of gestation, although the serum levels of PlGF were slightly lower than the normal reference range. In conclusion, measurement of the sFlt-1/PlGF ratio may be clinically useful to discriminate lupus nephritis from preeclampsia.

Preeclamptic patient-derived circulating cell-free DNA activates the production of inflammatory cytokines via toll-like receptor 9 signalling in the human placenta.

OBJECTIVES: Preeclampsia, a pregnancy-specific syndrome, is associated with maternal systemic and placental inflammatory responses. Cell-free DNA (cfDNA) and cf-foetal DNA (cffDNA) in the blood are elevated in patients with preeclampsia and act as danger signals. Placenta-derived foetal DNA induces inflammatory responses and pregnancy complications in mice. However, whether extracellular DNA from the placenta really causes inflammatory responses remains unclear. Therefore, we investigated the effect of serum cfDNA and placental cffDNA on inflammatory responses using normal pregnant women and preeclampsia patients. METHODS: Sera were taken from normal pregnant women and preeclampsia patients, and human trophoblast cell line Sw.71 cells were treated with serum with or without toll-like receptor 9 (TLR9; a sensor of exogenous DNA) inhibitor and genome elimination reagent. For cffDNA collection, placental tissue from the participants was cultured, and the released cffDNA was administrated to Sw.71 cells. RESULTS: The amount of serum cfDNA was higher in preeclampsia patients than in normal pregnant women. Treatment of preeclampsia serum stimulated inflammatory cytokine secretion, which was inhibited by a genome elimination reagent. Expression levels of TLR9 and amount of cffDNA from the placenta were higher in preeclampsia patients than of normal pregnant women. Preeclampsia-derived cffDNA increased inflammatory cytokine levels compared with normal pregnant derived cffDNA. CONCLUSION: In human trophoblast cells, preeclampsia patient-derived cfDNA increased inflammatory cytokine levels via TLR9. Preeclampsia placenta released more cffDNA, which stimulated inflammatory cytokine. We suggest that elevated circulating cfDNA and cffDNA induces placental inflammatory responses, resulting in accelerated pathological features of preeclampsia.

Temporary hypertension and white coat hypertension in the first trimester as risk factors for preeclampsia.

We compared the risk of preeclampsia (PE) among women with normal blood pressure (BP), high-normal BP, high BP, temporary hypertension (THT), white coat hypertension (WCH), and chronic hypertension (CH) in the first trimester. This was a retrospective cohort study involving 2858 pregnant women, who received regular maternal checkups at <12 weeks. BP levels were evaluated using the average of the second and third BP readings. When patients showed HT in the first trimester that later normalized during 14-19 weeks, we called this condition THT. BP levels were classified as normal BP, high-normal BP, high BP, THT, WCH, and CH. PE was defined as a new onset of HT after 20 weeks accompanied by either proteinuria or other organ dysfunctions. Gestational hypertension (GH) was defined as the new onset of HT after 20 weeks. The proportion of WCH in women with newly diagnosed HT was 47%. PE occurred in 1.3, 4.3, 8.1, 8.2, 14.3, and 25.0% of women with normal BP, high-normal BP, high BP, THT, WCH, and CH, respectively. GH occurred in 0.3, 1.8, 9.9, 2.0, and 28.6% of women with normal BP, high-normal BP, high BP, THT, and WCH, respectively. After adjusting for possible confounding variables, high-normal BP, high BP, THT, WCH, and CH were independent risk factors for PE vs. normal BP; in addition, high-normal BP, high BP/THT, and WCH were independent risk factors for GH vs. normal BP. In conclusion, THT and WCH in the first trimester were risk factors for PE, and WCH was a risk factor for GH.

Alteration of serum soluble endoglin levels after the onset of preeclampsia is more pronounced in women with early-onset.

It has been established that serum soluble endoglin (sEng) increases in women with preeclampsia. However, sEng levels have not been evaluated using a normal reference value specific to each gestational age. First, we established the normal reference value for sEng using 85 pregnant controls without preeclampsia, from whom serum samples were collected three times at 20-23, 27-30, and 36-38 weeks of gestation. Second, we evaluated the serum sEng levels after the onset of preeclampsia in 56 preeclamptic patients. In three women (3.5%) with normal pregnancies, sustained high sEng levels (>15 ng/mL) were observed. We calculated the reference value for sEng using the remaining 82 normal controls. The log10sEng was almost normally distributed at each gestational week during 20-38 weeks, and the mean log10sEng was represented as a quadratic curve of gestational week. The SD of log10sEng was represented as a linear equation of gestational week. The mean log10sEng significantly and gradually increased from 20-23 weeks to 27-30 weeks of gestation and then rapidly increased at 36-38 weeks of gestation. Ninety-three percent of preeclamptic women showed sEng>or=95th percentile of the reference value. The log10sEng levels and the SD score (SDS) of log10sEng in women with early-onset preeclampsia (onset<32 weeks of gestation) were significantly higher than those in women with late-onset preeclampsia (onset>or=32 weeks of gestation) (1.97+/-0.23 vs. 1.78+/-0.28, 9.94+/-2.61 vs. 4.47+/-2.06, respectively). In conclusion, alteration of serum sEng levels after the onset of preeclampsia was more pronounced in women with early-onset preeclampsia compared to those with late onset.

Increased serum levels of sFlt-1/PlGF ratio in preeclamptic women with onset at <32 weeks compared with ≥32 weeks.

OBJECTIVE: Our first aim was to construct gestational-age-specific reference ranges of serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1/PlGF ratio at 19-38 weeks of gestation. Our second aim was to compare the serum levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in 81 women with PE which occurred at <32, 32-33, 34-35, and ≥36 weeks. METHOD: Serum levels of sFlt-1 and PlGF were measured by automated immunoassays (Elecsys sFlt-1 and Elecsys PlGF). We constructed the normal reference ranges of log10sFlt-1, log10PlGF, and the log10(sFlt-1/PlGF) between 19 and 38 weeks using 309 samples, which could be represented by a quadratic curve. The cut-off levels were defined as the 5th and 95th percentiles of their gestational-age-specific reference ranges. RESULTS: The frequencies of high sFlt-1, low PlGF, and a high sFlt-1/PlGF ratio in women with an onset at <32 weeks were all 100%, whereas there were no groups showing 100% abnormalities of sFlt-1, PlGF or the sFlt-1/PlGF ratio in women with an onset at 32-33, 34-35, and ≥36 weeks. The levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at <32 weeks were significantly different from those in women with an onset at ≥32-33 weeks, although the levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at 32-33, 34-35, and ≥36 weeks were almost the same. CONCLUSION: The appropriate threshold weeks for defining early-onset PE might be 32+0 weeks rather than 34+0 or 36+0 weeks.

Galectin-1 as a novel risk factor for both gestational hypertension and preeclampsia, specifially its expression at a low level in the second trimester and a high level after onset.

Our aim was to evaluate whether the serum level of galectin-1 (Gal-1) at 18-24 and 27-31 weeks of gestation is a risk factor for predicting the later occurrence of not only preeclampsia (PE) but also gestational hypertension (GH). We measured serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and Gal-1 using an enzyme-linked immunosorbent assay in 81 and 73 normal pregnant women, 22 and 16 women with a later onset of GH, and 37 and 29 women with a later onset of PE at 18-24 and 27-31 weeks, respectively. We also measured Gal-1 in 33 women with GH and 78 women with PE after the onset. The levels of Gal-1 after the onset of GH, late-onset PE (onset at ⩾34 weeks), and early-onset PE (onset at <34 weeks) were significantly higher than those in normal pregnant women at 27-31 weeks. However, the low levels of Gal-1 (<8.1 ng ml-1) at 18-24 weeks, but not at 27-31 weeks, predicted the later occurrence of not only early-onset PE and late-onset PE but also GH. The low level of Gal-1 at 18-24 weeks was an independent risk factor for the later occurrence of GH and PE, after adjusting for the effects of a high BP and increased sFlt-1/PlGF ratio at 18-24 weeks. In conclusion, the serum level of Gal-1 is a novel risk factor for both GH and PE, specifically its expression at a low level in the second trimester and a high level after onset.

Serum soluble LIGHT in the early third trimester as a novel biomarker for predicting late-onset preeclampsia.

Our aim was to evaluate whether serum levels of soluble LIGHT (sLIGHT) at 27-31 weeks can predict the later occurrence of gestational hypertension (GH), late-onset preeclampsia (PE), and early-onset PE. Mean blood pressure (MBP), soluble fma-like tyrosine kinase 1/placental growth factor (sFlt-1/PlGF) ratio at 27-31 weeks, and sLIGHT at 27-31 weeks were independent risk factors for late-onset PE. The combination of the three risk factors improved sensitivity with a false-positive rate of 10% (MBP: 60%, log10(sFlt-1/PlGF): 45%, sLIGHT: 35%, combination: 75%). Serum sLIGHT in the early third trimester may be a novel biomarker for predicting late-onset PE.

Alterations in placental growth factor levels before and after the onset of preeclampsia are more pronounced in women with early onset severe preeclampsia.

It has been established that the serum placental growth factor (PlGF) decreases and the soluble fms-like tyrosine kinase-1 (sFlt-1) increases in women with preeclampsia. However, there have been no studies on the relation between preeclampsia onset time and the changes in PlGF and sFlt-1. Furthermore, the PlGF and sFlt-1 levels have not been evaluated using their reference values specific to each gestational age. In this study we reevaluated the serum PlGF and sFlt-1 levels before and after the clinical manifestation of early and late onset severe preeclampsia using the new reference values developed in our recent longitudinal study. Blood specimens were obtained immediately after the clinical manifestation of severe preeclampsia in 34 referred women, and both before and after the clinical manifestation in 8 women receiving a routine checkup at our institute. Both women with early and those with late preeclampsia showed decreased PlGF and increased sFlt-1 levels compared to normotensive controls at 28 and 37 weeks (n=68). However, those with early onset preeclampsia had a higher incidence of low PlGF (<5th percentile on the reference values) and high sFlt-1 (>or=95th percentile) than those with late onset (low PlGF: 93% vs. 55%; high sFlt-1: 100% vs. 60%). log10PlGF (r=0.574, p<0.001) and log10(sFlt-1/PlGF) (r=-0.556, p<0.001) were correlated with the week of onset of preeclampsia. Before the onset of preeclampsia, the incidence rate of low PlGF in the women with early onset preeclampsia was 100% (5/5), whereas that in the women with late onset preeclampsia was 0% (0/2) (p=0.048). Therefore, alterations in the PlGF levels both before and after the onset of preeclampsia may be more pronounced in women with early onset than those with late onset severe preeclampsia.

Prediction and prevention of hypertensive disorders of pregnancy.

The most common classifications of hypertensive disorders of pregnancy consist of chronic hypertension, gestational hypertension, preeclampsia (PE) and superimposed PE. A common final pathophysiology of PE is endothelial dysfunction. The most successful translational research model for explaining the cause-effect relationship in the genesis of PE is the angiogenic/angiostatic balance theory, involving soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng). In a systematic review of articles on the prediction of early-onset PE using angiogenesis-related factors, we revealed that the prediction of early-onset PE in the first trimester is clinically possible, but the prediction of early-onset PE in the early third trimester might be ideal. In addition, an onset threshold or a serial approach appeared to be clinically useful for predicting the imminent onset of PE, with onset at <4 weeks after blood sampling in the second and early third trimesters, because the positive likelihood ratio was >10 and the positive predictive value was >20%. The National Institute for Health and Care Excellence guidelines state that the Triage PlGF testing and Elecsys immunoassay for the sFlt-1/PlGF ratio could help to exclude PE in women with suspected PE at 20-34 weeks of gestation. Until now, we have not found any effective therapies to prevent PE. However, low-dose aspirin treatment starting at ⩽16 weeks of gestation might be associated with a marked reduction in PE. In addition, early statin treatment might prevent the occurrence of PE. Currently, a clinical trial using pravastatin for the prevention of PE is ongoing.

Normal and high-normal blood pressures, but not body mass index, are risk factors for the subsequent occurrence of both preeclampsia and gestational hypertension: a retrospective cohort study.

Blood pressure (BP) levels and body mass index (BMI) are known as risk factors for preeclampsia and gestational hypertension. However, there have been few investigations regarding the effects of BP and BMI levels on preeclampsia and gestational hypertension in the same cohort. In the present study, we conducted a retrospective cohort study using multiple logistic regression analysis. The cohort included 1,518 patients without nephritis. The unadjusted odds ratios (ORs) of preeclampsia and gestational hypertension were increased in pregnant women with normal BP (120-129 mmHg systolic or 80-84 mmHg diastolic), high-normal BP and hypertension in the second trimester compared to those with optimal BP. The unadjusted ORs of preeclampsia and gestational hypertension were also increased in obese women in the pre-pregnancy period compared to women with normal range BMI. When adjustment was made for both the BP levels and pre-pregnancy BMI levels, the ORs (95% confidence intervals) of normal BP, high-normal BP, hypertension and obesity for the subsequent occurrence of preeclampsia were 5.1 (2.2-12), 8.3 (3.1-22), 16 (5.0-50) and 2.0 (0.67-5.9), and those for the subsequent occurrence of gestational hypertension were 7.0 (2.6-19), 7.4 (2.1-25), 22 (6.1-83) and 1.3 (0.33-4.8), respectively. For the subsequent occurrence of preeclampsia or gestational hypertension, normal BP, high-normal BP and hypertension in the second trimester may be independent risk factors. Obesity in the pre-pregnancy period, however, may not be an independent risk factor.

Hydrocephalus after intraventricular hemorrhage in eclamptic woman with HELLP syndrome.

We report the first case of an obstructive hydrocephalus after intraventricular hemorrhage in a woman with HELLP syndrome and eclampsia. A 25-year-old primiparaous woman had severe preeclampsia at 36 weeks of gestation. She complained of epigastric pain and nausea. The levels of AST, ALT, and LDH were 539, 560, and 1051 IU/L, respectively; the platelet count was 101 x 109/L. Cesarean section was promptly performed. Intraoperatively, she had a first convulsion. The CT scan revealed only mild brain edema. The platelet count deteriorated to 30 x 109/L at 5 hour after the operation, and she had a second convulsion with an intraventricular hemorrhage. On the 6th post-cesarean day, she complained severe headache followed by coma. The CT scan revealed the enlargement of both lateral ventricles, indicating the occurrence of obstructive hydrocephalus. Drainage into cerebral ventricle was performed, resulting in the recovery of consciousness to a normal level.

Establishing reference values for both total soluble Fms-like tyrosine kinase 1 and free placental growth factor in pregnant women.

It has been reported that the concentration of free placental growth factor (PIGF) is decreased and that of soluble fms-like tyrosine kinase 1 (sFlt-1) is increased before the onset of preeclampsia. However, no study has determined the reference values for sFlt-1 and free PIGF during pregnancy using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. This longitudinal cohort study was undertaken to address this issue. Serum samples were collected from 148 women at 10, 18, 28, and 37 weeks of gestation. Preeclampsia occurred in 6 women: 4 women who delivered at <37 weeks of gestation, and 2 women who delivered at > or =37 weeks. The average and 90% confidence interval (90% CI) of the serum concentration of both sFIt-1 and free PIGF were determined in a total of 433 specimens from 148 subjects with 1 to 4 collections at 7 to 39 weeks of gestation, and were represented as quadric curves. The mean values (90% CI) of sFlt-1 (pg/ml) at 10, 18, 28, and 37 weeks of gestation were 413 (174-981), 296 (125-704), 413 (174-982), and 1,130 (477-2,690), respectively. The mean values (90% CI) of free PIGF (pg/ml) were 36 (14-89), 206 (83-515), 518 (207-1,290), and 354 (142-884), respectively. We also established the reference values for the ratio of sFlt-1/PIGF. These values may be useful for predicting the subsequent occurrence of preeclampsia.