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1.  Preeclampsia and the risk of large for gestational age infants 
Objective
To compare the risk of giving birth to large for gestational age infants in women with and without preeclampsia, after adjustment for obesity and glucose intolerance.
Study Design
Prospective cohort study of pregnant women with and without preeclampsia who delivered infants between 1998 and 2006 at Massachusetts General Hospital.
Results
The risk of LGA was similar in women with and without preeclampsia (OR 0.81 95% CI 0.59–1.14). After adjustment for body mass index, glucose intolerance, and other factors, the risk of LGA was significantly lower in women with preeclampsia compared to those without preeclampsia (OR 0.69 95% CI 0.49–0.96). Stratified analysis in groups with a higher risk of LGA revealed that preeclampsia has a similar effect on the risk of LGA regardless of maternal obesity, glucose intolerance, parity, and race
Conclusion
Preeclampsia appears to be characterized by reduced, and not increased, fetal growth.
doi:10.1016/j.ajog.2010.12.030
PMCID: PMC4104476  PMID: 21371687
fetal growth; gestational diabetes; large for gestational age; preeclampsia
2.  How does smoking reduce the risk of preeclampsia? 
Hypertension  2010;55(5):1100-1101.
doi:10.1161/HYPERTENSIONAHA.109.148973
PMCID: PMC2855389  PMID: 20231524
3.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
OBJECTIVE
To test the hypothesis that high circulating concentrations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS).
STUDY DESIGN
This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hypertension and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor [PlGF] and soluble endoglin [sEng] in maternal serum were measured at 21–32 weeks of gestation.
RESULTS
Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5 % versus 20.9%, P=0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% C.I. 1.08, 4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during mid-pregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL versus 7,000 pg/mL, P = 0.01).
CONCLUSIONS
Preterm preeclampsia and gestational hypertension, characterized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during mid-pregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension
4.  Angiogenic Factors and the Risk of Adverse Outcomes in Women with Suspected Preeclampsia 
Circulation  2012;125(7):911-919.
Background
An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia.
Methods and Results
We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation, and examined for an association between sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks.
The median [25th–75th centile] sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared to those who did not (47.0 [15.5–112.2] versus 10.8 [4.1–28.6], p<0.0001). Among those presenting <34 weeks (N=167), the results were more striking (226.6 [50.4–547.3] versus 4.5 [2.0–13.5], p<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared to the lowest (OR 47.8, 95% CI 14.6–156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (AUC=0.93 for hypertension, proteinuria, and sFlt1/PlGF versus AUC=0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within two weeks of presentation in 86.0% of women with sFlt1/PlGF ratio ≥ 85 compared with 15.8% of women with sFlt1/PlGF ratio <85 (HR 15.2, 95% CI 8.0–28.7).
Conclusions
In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within two weeks. The accuracy of this test is substantially better than current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings.
doi:10.1161/CIRCULATIONAHA.111.054361
PMCID: PMC3319742  PMID: 22261192
Preeclampsia; adverse maternal and perinatal outcomes; angiogenic factors; triage; hypertension; proteinuria
5.  Folate and vitamin B12 in idiopathic male infertility 
Asian Journal of Andrology  2011;13(6):856-861.
Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case–control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P = 0.01 and P = 0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l−1; P = 0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.
doi:10.1038/aja.2011.96
PMCID: PMC3372894  PMID: 21857689
folate; idiopathic male infertility; semen quality; vitamin B12
6.  CIRCULATING SOLUBLE ENDOGLIN AND PLACENTAL ABRUPTION 
Prenatal diagnosis  2008;28(9):852-858.
Objective
Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption.
Methods
In a nested case control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (<20 weeks), mid- (21–32 weeks), and late (≥33 weeks) pregnancy.
Results
There was no significant difference in sEng between abruption cases and controls in early pregnancy. sEng was significantly elevated among abruption cases at 21–32 weeks (10.7 versus 5.9 ng/mL, P<0.01). Subgroup analyses revealed no differences in sEng concentrations at any gestational age interval between cases with abruption without hypertension and healthy controls. Among women who developed hypertension and placental abruption, sEng was not significantly increased in early pregnancy, but was in mid-pregnancy (19.3 versus 5.5 ng/mL, P=0.002) and in late pregnancy (15.6 versus 9.5 ng/mL, P=0.04).
Conclusion
Serum levels of the anti-angiogenic factor sEng are elevated prior to the development of hypertension and placental abruption. These elevations are not apparent until the late second trimester (26 – 27 weeks, on average), but they persist from this time in gestation onward. sEng may be useful for identifying pregnant women at risk for abruption and hypertension.
doi:10.1002/pd.2065
PMCID: PMC2574843  PMID: 18702104
Abruptio placentae; preeclampsia; gestational hypertension; endoglin; angiogenic factors
8.  Folate and vitamin B12 in idiopathic male infertility 
Asian Journal of Andrology  2011;13(6):856-861.
Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case–control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l−1; P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.
doi:10.1038/aja.2011.96
PMCID: PMC3372894  PMID: 21857689
folate; idiopathic male infertility; semen quality; vitamin B12
9.  The use of angiogenic biomarkers to differentiate non-HELLP related thrombocytopenia from HELLP syndrome 
Objective
Preeclampsia is diagnosed using clinical criteria and in atypical cases the diagnosis may be inaccurate as there are no specific tests to confirm or exclude preeclampsia. This study sought to evaluate the utility of angiogenic biomarkers, sFlt1, sEng and PlGF to distinguish patients with gestational thrombocytopenia and immune thrombocytopenic purpura (ITP) from patients with thrombocytopenia resulting from the HELLP syndrome, a complication of severe preeclampsia.
Methods
Serum was collected and the angiogenic biomarkers of patients with ITP and gestational thrombocytopenia (N=9) were compared to patients with HELLP (N=11) and preeclampsia (N=11). Circulating levels of these angiogenic biomarkers were also compared by gestational age to 1564 randomly selected normotensive women from the Calcium for Preeclampsia Prevention study.
Results
Patients with non-HELLP thrombocytopenia had lower sFlt1 (7.3 +/- 3.8 ng/mL vs 15.5 +/- 5 ng/mL, p<0.001), lower sEng (8.7 +/- 3.6 vs 34 +/- 17, p <0.001) and higher PlGF (484 +/- 412 vs 66.3 +/- 44, p= 0.003) than patients with HELLP syndrome. Angiogenic factor abnormalities in patients with preeclampsia were similar to patients with HELLP syndrome, suggesting a common pathogenesis. Patients with non-HELLP thrombocytopenia had angiogenic profiles similar to normotensive controls, whereas patients with HELLP syndrome had levels higher than the 90th percentile for sFlt1 and sEng and lower than the 10th percentile for PLGF.
Conclusion
Angiogenic biomarkers may be useful in excluding conditions, which mimic preeclampsia.
doi:10.1080/14767050903184207
PMCID: PMC3132879  PMID: 19701867
preeclampsia; angiogenic factors; thrombocytopenia
10.  First Trimester Prediction of Early Preeclampsia - a Possibility at Last! 
Hypertension  2009;53(5):747-748.
doi:10.1161/HYPERTENSIONAHA.109.129379
PMCID: PMC2679993  PMID: 19273735
11.  Circulating Angiogenic Factors in Gestational Proteinuria without Hypertension 
Objectives
Our goal was to determine whether obstetrical outcomes and serum angiogenic factors are altered in women with gestational proteinuria without hypertension.
Methods
We performed a nested case-control study of 108 women with gestational proteinuria, comparing them to 1564 randomly selected normotensive women without proteinuria during pregnancy (controls) and to 319 women who developed pre-eclampsia.
Results
Women with gestational proteinuria had greater body-mass index and higher blood pressure at study enrollment. Adverse obstetrical outcomes were infrequent. Levels of PlGF were lower than controls beginning early in gestation. Compared to gestational-age matched controls, PlGF was reduced beginning 6 to 8 weeks before proteinuria. Although sFlt-1 and soluble endoglin concentrations were elevated 1 to 2 weeks before proteinuria, these elevations were modest and transient. After onset of proteinuria, angiogenic factor levels generally did not differ significantly from controls.
Conclusion
Gestational proteinuria in healthy nulliparous women appears to be a mild variant of pre-eclampsia.
doi:10.1016/j.ajog.2008.10.033
PMCID: PMC2679962  PMID: 19168169
gestational proteinuria; pre-eclampsia; angiogenic factor; soluble fms-like tyrosine kinase 1; soluble endoglin; placental growth factor
12.  Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study 
Objective To determine if pre-eclampsia is associated with reduced thyroid function during and after pregnancy.
Design Nested case-control study during pregnancy and population based follow-up study after pregnancy.
Setting Calcium for Pre-eclampsia Prevention trial of healthy pregnant nulliparous women in the United States during 1992-5, and a Norwegian population based study (Nord-Trondelag Health Study or HUNT-2) during 1995-7 with linkage to the medical birth registry of Norway.
Participants All 141 women (cases) in the Calcium for Pre-eclampsia Prevention trial with serum measurements before 21 weeks’ gestation (baseline) and after onset of pre-eclampsia (before delivery), 141 normotensive controls with serum measurements at similar gestational ages, and 7121 women in the Nord-Trondelag Health Study whose first birth had occurred in 1967 or later and in whom serum levels of thyroid stimulating hormone had been subsequently measured.
Main outcome measures Thyroid function tests and human chorionic gonadotrophin and soluble fms-like tyrosine kinase 1 concentrations in the Calcium for Pre-eclampsia Prevention cohort and odds ratios for levels of thyroid stimulating hormone above the reference range, according to pre-eclampsia status in singleton pregnancies before the Nord-Trondelag Health Study.
Results In predelivery specimens of the Calcium for Pre-eclampsia Prevention cohort after the onset of pre-eclampsia, thyroid stimulating hormone levels increased 2.42 times above baseline compared with a 1.48 times increase in controls. The ratio of the predelivery to baseline ratio of cases to that of the controls was 1.64 (95% confidence interval 1.29 to 2.08). Free triiodothyronine decreased more in the women with pre-eclampsia than in the controls (case ratio to control ratio 0.96, 95% confidence interval 0.92 to 0.99). The predelivery specimens but not baseline samples from women with pre-eclampsia were significantly more likely than those from controls to have concentrations of thyroid stimulating hormone above the reference range (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4). Both in women who developed pre-eclampsia and in normotensive controls the increase in thyroid stimulating hormone concentration between baseline and predelivery specimens was strongly associated with increasing quarters of predelivery soluble fms-like tyrosine kinase 1 (P for trend 0.002 and <0.001, respectively). In the Nord-Trondelag Health Study, women with a history of pre-eclampsia in their first pregnancy were more likely than other women (adjusted odds ratio 1.7, 95% confidence interval 1.1 to 2.5) to have concentrations of thyroid stimulating hormone above the reference range (>3.5 mIU/l). In particular, they were more likely to have high concentrations of thyroid stimulating hormone without thyroid peroxidase antibodies (adjusted odds ratio 2.6, 95% confidence interval 1.3 to 5.0), suggesting hypothyroid function in the absence of an autoimmune process. This association was especially strong (5.8, 1.3 to 25.5) if pre-eclampsia had occurred in both the first and the second pregnancies.
Conclusion Increased serum concentration of soluble fms-like tyrosine kinase 1 during pre-eclampsia is associated with subclinical hypothyroidism during pregnancy. Pre-eclampsia may also predispose to reduced thyroid function in later years.
doi:10.1136/bmj.b4336
PMCID: PMC2778749  PMID: 19920004
13.  A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble VEGF receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small-for-gestational-age neonate 
Introduction
Accumulating evidence suggests that an imbalance between pro-angiogenic [i.e. vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)] and anti-angiogenic factors [i.e. soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor β, and its soluble form has been recently implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies, and those destined to develop PE (preterm and term) or to deliver an SGA neonate.
Methods
This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: 1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n=46); 2) patients who delivered an SGA neonate but did not develop PE (n=56); and 3) patients who developed PE (n=42). Longitudinal samples were collected at each prenatal visit, which was scheduled at four-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1 and PlGF were determined by specific and sensitive ELISA.
Results
1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; 2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p<0.036 and for term PE: 0=0.002); 3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; 4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; 5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p=0.009 and p=0.0199, respectively); and 6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p=0.147 at 25 weeks and p=0.8285 at 40 weeks).
Conclusions
1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1 and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and 2) differences in the profile of pro-angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.
doi:10.1080/14767050701830480
PMCID: PMC2587364  PMID: 18175241
intrauterine growth restriction; placental disease; SGA; IUGR; preterm birth; soluble Flt-1; longitudinal; growth curve model; pregnancy
14.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
Anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension

Results 1-14 (14)