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1.  Preeclampsia as a Risk Factor for Diabetes: A Population-Based Cohort Study 
PLoS Medicine  2013;10(4):e1001425.
Denice Feig and colleagues assess the association between gestational diabetes, gestational hypertension, and preeclampsia and the development of future diabetes in a database analysis of pregnant women in Ontario, Canada.
Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes.
Methods and Findings
We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n = 22,933), GH alone (n = 27,605), GDM alone (n = 30,852), GDM+PEC (n = 1,476), GDM+GH (n = 2,100), or none of these conditions (n = 925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR] = 2.08; 95% CI 1.97–2.19) and GH alone (HR = 1.95; 95% CI 1.83–2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR = 12.77; 95% CI 12.44–13.10); however, the co–presence of PEC or GH in addition to GDM further elevated this risk (HR = 15.75; 95% CI 14.52–17.07, and HR = 18.49; 95% CI 17.12–19.96, respectively). Data on obesity were not available.
Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes.
Please see later in the article for the Editors' Summary
Editors' Summary
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar), known as type 1 diabetes, or when the body cannot effectively use the insulin it produces—type 2 diabetes. Raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious complications and even death. Worryingly, the global burden of type 2 diabetes is increasing worldwide, and the World Health Organization estimates that 90% of the 347 million people with diabetes currently have type 2 diabetes. Previous studies have shown that type 2 diabetes can be prevented or delayed in high risk groups by a range of lifestyle and treatment interventions and so it is important to identify potential high risk groups to screen for type 2 diabetes.
Why Was This Study Done?
Gestational diabetes (a form of diabetes that is related to pregnancy) is a major risk factor for developing type 2 diabetes. Therefore, diabetes prevention strategies should target women with gestational diabetes. Likewise, other common disorders of pregnancy possibly associated with insulin resistance, such as preeclampsia (a condition in which affected women have high blood pressure, fluid retention, and protein in their urine) and gestational hypertension (high blood pressure associated with pregnancy), may lead to the future development of type 2 diabetes. So women with these conditions may also benefit from diabetes prevention strategies. Therefore, in this large database study from Ontario, Canada, the researchers examined whether pregnant women with preeclampsia or gestational hypertension had an increased risk of developing diabetes in the years following pregnancy even if they did not have gestational diabetes.
What Did the Researchers Do and Find?
The researchers used a comprehensive Canadian health database to identify all women age 15 to 50 years of age who delivered in an Ontario hospital between April 1994 and March 2008. They then identified women who had preeclampsia, gestational hypertension, or gestational diabetes through hospital records and outpatient information. The researchers then used records from the Ontario Diabetes Database to record whether these women went on to develop diabetes in the period from 180 days after delivery until March 2011.
Using these methods, the researchers identified 1,010,068 pregnant women suitable for analysis, of whom 22,933 had only preeclampsia, 27,605 had only gestational hypertension, and 30,852 had only gestational diabetes: 2,100 women had both gestational diabetes and gestational hypertension and 1,476 women had gestational diabetes and preeclampsia. Overall, 35,077 women developed diabetes (3.5%) in the follow-up period (median of 8.5 years) at a median age of 37 years. In a modeling analysis, the researchers found that women with gestational diabetes had a 15-fold increased rate of developing diabetes compared to women without gestational diabetes, gestational hypertension, and preeclampsia, while women with gestational diabetes plus either preeclampsia or gestational hypertension had a 20- to 21-fold increased rate. These results were slightly reduced after adjusting for age, income quintile, hypertension prior to pregnancy, and co-morbidity, giving a hazard ratio (HR) of 1.95 for gestational hypertension alone, an HR of 2.08 for preeclampsia alone, an HR of 12.77 for gestational diabetes alone, an HR of 18.49 for gestational diabetes plus gestational hypertension and finally, an HR of 15.75 for gestational diabetes plus preeclampsia.
These Findings Mean?
These findings suggest that both preeclampsia and gestational hypertension without gestational diabetes are associated with a 2-fold increased incidence of diabetes in the years following pregnancy after controlling for several important variables. When combined with gestational diabetes, these conditions were associated with a further elevation in diabetes incidence additional to the 13-fold increased incidence resulting from gestational diabetes alone. A limitation of this study was the lack of information on obesity and body mass index, factors which are also associated with increased risk of developing diabetes. Nevertheless, these findings highlight a possible new risk factor for diabetes, and suggest that clinicians should be aware of the need for preventative measures and vigilant screening for diabetes in women with a history of preeclampsia or gestational hypertension.
Additional Information
Please access these Web sites via the online version of this summary at
NHS Choices has information about preeclampsia, gestational diabetes, and gestational hypertension
Living with diabetes is a useful resource for patients with diabetes
The Preeclampsia Foundation has more information about preeclampsia
PMCID: PMC3627640  PMID: 23610560
2.  First Trimester Exposure to Ambient Air Pollution, Pregnancy Complications and Adverse Birth Outcomes in Allegheny County, PA 
Maternal and child health journal  2013;17(3):545-555.
Despite numerous studies of air pollution and adverse birth outcomes, few studies have investigated preeclampsia and gestational hypertension, two pregnancy disorders with serious consequences for both mother and infant. Relying on hospital birth records, we conducted a cohort study identifying 34,705 singleton births delivered at Magee-Women’s Hospital in Pittsburgh, PA between 1997 and 2002. Particle (<10 μm-PM10; <2.5 μm-PM2.5) and ozone (O3) exposure concentrations in the first trimester of pregnancy were estimated using the space–time ordinary Kriging interpolation method. We employed multiple logistic regression estimate associations between first trimester exposures and preeclampsia, gestational hypertension, preterm delivery, and small for gestational age (SGA) infants. PM2.5 and O3 exposures were associated with preeclampsia (adjusted OR = 1.15, 95 % CI = 0.96–1.39 per 4.0 μg/m3 increase in PM2.5; adjusted OR = 1.12, 95 % CI = 0.89–1.42 per 16.8 ppb increase in O3), gestational hypertension (for PM2.5 OR = 1.11, 95 % CI = 1.00–1.23; for O3 OR = 1.12, 95 % CI = 0.97–1.29), and preterm delivery (for PM2.5 ORs = 1.10, 95 % CI = 1.01–1.20; for O3 ORs = 1.23, 95 % CI = 1.01–1.50). Smaller 5–8 % increases in risk were also observed for PM10 with gestational hypertension and SGA, but not preeclampsia. Our data suggest that first trimester exposure to particles, mostly PM2.5, and ozone, may increase the risk of developing preeclampsia and gestational hypertension, as well as preterm delivery and SGA.
PMCID: PMC3636771  PMID: 22544506
Air pollution; Particulate; Preeclampsia; Gestational hypertension; Preterm; Small for gestational; age (SGA)
3.  Elevated first-trimester uric acid concentrations are associated with the development of gestational diabetes 
To demonstrate that elevated first trimester uric acid is associated with development of gestational diabetes mellitus (GDM).
Study Design:
Uric acid was measured in 1570 plasma samples collected at mean gestational age of 8.9 ± 2.5 weeks. The primary outcome was GDM, diagnosed by three hour glucose tolerance test using Carpenter and Coustan criteria or by a one hour value of ≥ 200 mg/dl. Logistic regression was performed, adjusting for relevant covariates.
Almost half (46.6%) of the women with GDM had first trimester uric acid concentrations in the highest quartile (>3.57-8.30 mg/dl). Women with uric acid in the highest quartile had a 3.25-fold increased risk (95%CI: 1.35, 7.83) of developing GDM after adjustment for BMI and age. This effect was concentration dependent as risk increased with increasing uric acid quartiles (p=0.003).
First trimester hyperuricemia is associated with an increased risk of developing GDM, independent of BMI.
PMCID: PMC2774120  PMID: 19788971
gestational diabetes; hyperuricemia; uric acid
An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascual endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of preeclampsia and/or delivery of an SGA neonate.
This longitudinal case-control study included 402 singleton pregnancies in the following groups: 1) normal pregnancies with appropiate for gestational age (AGA) neonates (n=201); 2) patients who delivered an SGA neonate (n=145); and 3) patients who developed PE (n=56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: 1) first sample obtained between 6 and 15 weeks of gestation (“first trimester” sample); and 2) second sample obtained between 20 and 25 weeks of gestation (“second trimester” sample). Plasma concentrations of s-Eng, sVEGFR-1 and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity and body mass index (BMI). General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of delivery of an SGA neonate.
1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0, and OR 2.9, 95% CI 1.5-5.6, respectively); 2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6); 3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4.3, 95% CI 1.2-15.5, and OR 2.7, 95% CI 1.2-5.9, respectively); 4) In addition, the combination of the three analytes into a pro-angiogenic versus anti-angiogenic ratio [PlGF/(sEng x VEGFR-1)] conferred risk for the subsequent development of preterm preeclampsia (OR 3.7, 95% CI 1.1-12.1); 5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.38 (95% CI 3.18-33.84) for the development of preterm PE and 1.62 (95% CI 1.01-2.60) for the development of SGA.
Changes in the maternal plasma concentrations of s-Eng, sVEGFR-1, PlGF or their ratios between the first and second trimesters of pregnancy confer an increased risk to deliver a SGA neonate and/or develop PE.
PMCID: PMC2846114  PMID: 18446652
SGA; longitudinal; PlGF; endoglin; sVEGFR-1
5.  Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort 
PLoS Medicine  2011;8(3):e1001013.
Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease.
Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)—autoimmune conditions characterized by complement-mediated injury—is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency.
Methods and Findings
We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins—membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)—in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations.
The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.
Study Registration NCT00198068
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies culminate in the birth of a healthy baby but, sadly, about a quarter of women lose their babies during pregnancy. A common pregnancy-related medical problem that threatens the life of both baby and mother is preeclampsia. Mild and severe preeclampsia affects up to 10% and 1%–2% of pregnancies, respectively. Preeclampsia occurs because of a problem with the function of the placenta, the organ that transfers nutrients and oxygen from mother to baby and removes waste products from the baby. Although preeclampsia begins early in pregnancy, it is diagnosed by the onset of high blood pressure (hypertension) and the appearance of protein in the urine (proteinuria) after 20 weeks of pregnancy. Other warning signs include headaches and swelling of the hands and face. The only cure for preeclampsia is delivery, and labor is usually induced early to prevent eclampsia (seizures), stroke, liver and kidney failure, and breathing and blood vessel problems developing in the mother. Although delivery before 37 weeks of pregnancy is not generally recommended, in cases of preeclampsia it may be too dangerous for both the baby and the mother to allow the pregnancy to continue. Unfortunately when severe preeclampsia occurs in the second trimester, babies weighing only 500 grams may be delivered and they may not survive.
Why Was This Study Done?
Because the exact cause of preeclampsia is unknown, it is difficult to develop treatments for the condition or to find ways to prevent it. Many experts think that immune system problems—in particular, perturbations in complement activation—may be involved in preeclampsia. The complement system is a set of blood proteins that attacks invading bacteria and viruses. The activation of complement proteins is usually tightly regulated (overactivation of the complement system causes tissue damage) and, because preeclampsia may run in families, one hypothesis is that mutations (genetic changes) in complement regulatory proteins might predispose women to preeclampsia. In this study, the researchers test this hypothesis by sequencing genes encoding complement regulatory proteins in pregnant women with the autoimmune diseases systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL Ab) who developed preeclampsia. In autoimmune diseases, the immune system attacks healthy human cells instead of harmful invaders. Both SLE and APL Ab are characterized by complement-mediated tissue injury and are associated with an increased risk of preeclampsia and miscarriage.
What Did the Researchers Do and Find?
Two hundred fifty women with SLE and/or APL Ab were enrolled into the PROMISSE study (a multi-center observational study to identify predictors of pregnancy outcome in women with SLE and/or APL Ab) when they were 12 weeks pregnant and followed through pregnancy. Thirty patients developed preeclampsia during the study and ten more had had preeclampsia during a previous pregnancy. The researchers sequenced the genes for complement regulatory proteins: membrane cofactor protein (MCP), factor I, and factor H in these 40 patients. Seven women (18%) had mutations in one copy of one of these genes (there are two copies of most genes in human cells). Five mutations were alterations in MCP or factor I that are gene variants that increase the risk of hemolytic uremic syndrome, a disease characterized by blood vessel damage. The sixth mutation was a new MCP mutation that impaired MCP's ability to regulate complement component C4b. The final mutation was a factor H mutation that did not have any obvious functional effect. No mutations in complement regulatory proteins were found in 34 matched participants in PROMISSE without preeclampsia but, among a group of non-autoimmune women who developed preeclampsia during pregnancy, 10% had mutations in MCP or factor I.
What Do These Findings Mean?
These findings identify MCP and factor I mutations as genetic defects associated with preeclampsia in pregnant women with SLE and/or APL Ab. Importantly, they also reveal an association between similar mutations and preeclampsia in women without any underlying autoimmune disease. Taken together with evidence from previous animal experiments, these findings suggest that dysregulation of complement activation is involved in the development of preeclampsia. Although further studies are needed to confirm and extend these findings, these results suggest that proteins involved in the regulation of complement activation could be new targets for the treatment of preeclampsia and raise the possibility that tests could be developed to identify women at risk of developing preeclampsia.
Additional Information
Please access these Web sites via the online version of this summary at
Tommy's, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on preeclampsia
The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, has information on preeclampsia
The UK National Health Services Choices website also has information about preeclampsia
Wikipedia has pages on the complement system, on autoimmune disease, and on preeclampsia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information on the PROMISSE study is available
PMCID: PMC3062534  PMID: 21445332
6.  Identification of Patients at Risk for Early Onset and/or Severe Preeclampsia With the Use of Uterine Artery Doppler Velocimetry and Placental Growth Factor 
Preeclampsia has been proposed to be an anti-angiogenic state that may be detected by the determination of the concentrations of the soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and placental growth factor (PlGF) in maternal blood even before the clinical development of the disease. The purpose of this study was to determine the role of the combined use of uterine artery Doppler velocimetry (UADV) and maternal plasma PlGF and sVEGFR-1 concentrations in the second trimester for the identification of patients at risk for severe and/or early onset preeclampsia.
A prospective cohort study was designed to examine the relationship between abnormal UADV and plasma concentrations of PlGF and sVEGFR-1 in 3348 pregnant women. Plasma samples were obtained between 22 and 26 weeks of gestation at the time of ultrasound examination. Abnormal UADV was defined as the presence of bilateral uterine artery notches and/or a mean pulsatility index above the 95th percentile for the gestational age. Maternal plasma PlGF and sVEGFR-1 concentrations were determined with the use of sensitive and specific immunoassays. The primary outcome was the development of early onset preeclampsia (≤34 weeks of gestation) and/or severe preeclampsia. Secondary outcomes included preeclampsia, the delivery of a small for gestational age (SGA) neonate without preeclampsia, spontaneous preterm birth at ≤32 and ≤35 weeks of gestation, and a composite of severe neonatal morbidity. Contingency tables, chi-square test, receiver operating characteristic curve, and multivariate logistic regression were used for statistical analyses. A probability value of <.05 was considered significant.
(1) The prevalence of preeclampsia, severe preeclampsia, and early onset preeclampsia were 3.4% (113/3296), 1.0% (33/3296), and 0.8% (25/3208), respectively. UADV was performed in 95.4% (3146/3296) and maternal plasma PlGF concentrations were determined in 93.5% (3081/3296) of the study population. (2) Abnormal UADV and a maternal plasma PlGF <280 pg/mL were independent risk factors for the occurrence of preeclampsia, severe preeclampsia, early onset preeclampsia, and SGA without preeclampsia. (3) Among patients with abnormal UADV, maternal plasma PlGF concentration contributed significantly in the identification of patients destined to develop early onset preeclampsia (area under the curve, 0.80; P<.001) and severe preeclampsia (area under the curve, 0.77; P<.001). (4) In contrast, maternal plasma sVEGFR-1 concentration was of limited use in the prediction of early onset and/or severe preeclampsia. (5) The combination of abnormal UADV and maternal plasma PlGF of <280 pg/mL was associated with an odds ratio (OR) of 43.8 (95% CI, 18.48-103.89) for the development of early onset preeclampsia, an OR of 37.4 (95% CI, 17.64-79.07) for the development of severe preeclampsia, an OR of 8.6 (95% CI, 5.35-13.74) for the development of preeclampsia, and an OR of 2.7 (95% CI, 1.73-4.26) for the delivery of a SGA neonate in the absence of preeclampsia.
The combination of abnormal UADV and maternal plasma PlGF concentration of <280 pg/mL in the second trimester is associated with a high risk for preeclampsia and early onset and/or severe preeclampsia in a low-risk population. Among those with abnormal UADV, a maternal plasma concentration of PlGF of <280 pg/mL identifies most patients who will experience early onset and/or severe preeclampsia.
PMCID: PMC2190731  PMID: 17403407
gestational hypertension; placental growth factor (PlGF); preeclampsia small for gestational age; soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); uterine artery Doppler velocimetry; vascular endothelial growth factor (VEGF)
7.  Uric Acid Inhibits Placental System A Amino Acid Uptake☆ 
Placenta  2008;30(2):195-200.
Hyperuricemia, a common clinical characteristic of preeclamptic pregnancies, has historically been considered a marker of reduced renal function in preeclamptic women. More recently it has been suggested that uric acid may directly contribute to pathological cell signaling events involved in disease progression as well as maternal and fetal pregnancy outcomes including fetal growth restriction. We hypothesize that the increased frequency of restricted fetal growth seen in relation to increasing uric acid concentrations in preeclamptic women is in part the result of uric acid-induced reductions in amino acid transport across the placenta. The objective of the current study was to examine the effects of uric acid on human placental System A amino acid transport using a primary placental villous explant model. Further, we examined the necessity of uric acid uptake and the role of redox signaling as a potential mechanism through which uric acid may attenuate System A activity. Placental uptake of a radiolabeled amino acid analogue, specific to the System A transporter, was reduced in a concentration-dependent fashion with increasing uric acid (0−7 mg/dL), corresponding to uric acid concentrations measured in healthy pregnant and preeclamptic women in the third trimester. Uric acid-induced reduction in System A activity was partially reversed by NADPH oxidase inhibition and completely eliminated by antioxidant treatment. This study demonstrates inhibition of placental System A amino acid transport with uric acid treatment, as a result of uric acid-induced stimulation of intracellular redox signaling cascades. These findings may be relevant to the increased frequency of fetal growth restriction observed in hyperuricemic preeclampsia. Additionally the results of this study, indicating a detrimental effect of hyperuricemia on amino acid transport in the placenta, at concentrations present in women with preeclampsia, also suggest a role for uric acid in the pathophysiology of preeclampsia.
PMCID: PMC2677697  PMID: 19058847
Uric acid; Amino acid transport; System A; Antioxidants; Redox signaling; Placenta; Preeclampsia; Fetal growth restriction; Hyperuricemia; NADPH oxidase; Probenecid; Explants
8.  Hyperuricemia and its association with carotid intima-media thickness in hypertensive and non hypertensive patients 
Carotid intima-media thickness (C-IMT) measured noninvasively by ultrasonography is widely used as a marker for increased risk of cardiovascular disease. Also hyperuricemia (HU) is a well recognized risk factor for cardiovascular diseases. The study was designed to assess the relation between hyperuricemia and carotid intima-media thickness C-IMT in patients with and without hypertension (HTN).
This study included 126 patients divided into four groups: (1) Group A, included 59 hypertensive patients with hyperuricemia. (2) Group B, included 29 hypertensive patients without hyperuricemia. (3) Group C, included 17 patients with hyperuricemia and normal blood pressure without history of hypertension. (4) Group D, included 21 control subjects.
We measured carotid intima-media thickness by B-mode ultrasound in the common carotid and internal carotid artery. Routine echocardiography and uric acid level was assessed for all patients.
We found that C-IMT was significantly higher in group A, B and C than group D; and it was significantly higher in group A than B. This means that C-IMT is significantly higher in all hypertensive groups than control group but it was significantly higher in hypertensive hyperuricemia (group A) than those hypertensives without hyperuricemia. We also observed a higher C-IMT in hyperuricemic non hypertensive patients than control group this means that hyperuricemia per se could be a risk factor for atherosclerosis.
Uric acid levels among the whole number of patients included in the study and among the groups with hyperuricemia (group A and C) were positively correlated with the intimal-media thickness (IMT) while there were no correlations in the other two groups without hyperuricemia.
We found that left ventricular hypertrophy (LVH) was significantly higher in hypertensive patients (group A&B) than normotensives (group C&D) either with or without hyperuricemia and this was evident in the hypertensive hyperuricemic patients (group A); but unexpectedly we observed the presence of LVH in the hyperuricemic non hypertensive patients (group C) which was significantly higher than the control group (group D). This means that hyperuricemia is a risk factor for development of LVH hypertrophy independently of hypertension.
Therefore, higher serum uric acid levels are associated with increased C-IMT and left ventricular hypertrophy in hypertensive and even non hypertensive patients. So, early screening for hyperuricemia and lowering serum uric acid levels might be beneficial in slowing progression of atherogenesis.
PMCID: PMC3727469  PMID: 23960588
Hyperuricemia; Hypertension; Left ventricular hypertrophy; Caroid intima mediathickness
9.  Uric acid and chronic kidney disease: which is chasing which? 
Nephrology Dialysis Transplantation  2013;28(9):2221-2228.
Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD.
Gout was considered a cause of CKD in the mid-nineteenth century [1], and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis) [2]. Additional studies showed that during life impaired renal function occurred in half of these subjects [3]. As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se [4]. Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls.
Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD [5]. The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney [6]. Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.
PMCID: PMC4318947  PMID: 23543594
uric acid; gout; allopurinol; hyperuricemia; chronic kidney disease
10.  Nonesterified Fatty Acids and Spontaneous Preterm Birth: A Factor Analysis for Identification of Risk Patterns 
American Journal of Epidemiology  2014;179(10):1208-1215.
We considered that accumulation of nonesterified (free) fatty acids (NEFAs) in the first trimester of pregnancy would mark women at excess risk of spontaneous preterm birth (sPTB) and examined the interplay between NEFAs, lipids, and other markers to explore pathways to sPTB. In a case-control study nested in the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997–2001), we assayed NEFA levels in nonfasting serum collected at a mean gestational week of 9.4 (range, 4–20 weeks) in 115 women with sPTB (<37 weeks) and 222 women with births occurring at ≥37 weeks. C-reactive protein, total cholesterol, low-density lipoprotein and high-density lipoprotein (HDL) cholesterol, triglycerides, and uric acid were also measured. Polytomous logistic regression models were used to evaluate tertiles of NEFA levels and sPTB at <34 weeks and 34–36 weeks; factor analysis was used to characterize patterns of biomarkers. Women with NEFA levels in the highest tertile versus the lowest were 2.02 (95% confidence interval: 1.13, 3.48) times more likely to have sPTB, after adjustment for covariates. Risk of sPTB before 34 weeks was particularly high among women with high NEFA levels (odds ratio = 3.73, 95% confidence interval: 1.33, 10.44). Six biomarker patterns were identified, and 2 were associated with sPTB: 1) increasing NEFA and HDL cholesterol levels and 2) family history of gestational hypertension. NEFA levels early in pregnancy were independently associated with sPTB, particularly before 34 weeks. We also detected a novel risk pattern suggesting that NEFAs together with HDL cholesterol may be related to sPTB.
PMCID: PMC4010188  PMID: 24714724
factor analysis; inflammation; nonesterified fatty acids; pregnancy; prematurity; preterm birth; risk factors
11.  Association of Elevated first Trimester Serum Uric Acid Levels with Development of GDM 
Background: Early intervention and appropriate treatment in patients with GDM will help in preventing the adverse maternal and fetal outcome and protect them from long term complications. Several studies have shown the association of hyperuricemia with GDM. This study was undertaken to find out the association of elevated first trimester uric acid with development of GDM.
Materials and Methods: This prospective observational study was conducted in Mahatma Gandhi Medical Collage and Research Institute, Pondicherry, India, between November 2010 and May 2012. A total of 70 pregnant women were included and parameters like age, parity, BMI, history of DM, serum uric acid at <15 weeks and at 24 to 28 weeks and one step test at 24 to 28 weeks were noted and compared.
Results: There was no significant correlation between the demographic variables and GDM, but a moderate significance noted between the family history of DM and one step test (p=0.048). Though there is a proportional increase in the serum uric acid with increase in the BMI, it was not statistically significant. A significant correlation was seen between BMI and risk of development of GDM (p= 0.001). Though there is a significant correlation between serum uric acid at <15 weeks and at 24 to 28 weeks, serum uric acid at <15 weeks of gestation is a better predictor of GGI and GDM (Pearson’s correlation = 0.735).
Conclusion: There is increase in the risk of development of GDM with increased levels of serum uric acid in the first trimester. Uric acid levels at <15 weeks of gestation is more significantly associated with risk of development of GDM than it’s levels at 24 to 28 weeks of gestation.
PMCID: PMC4316298  PMID: 25653992
Gestational diabetes mellitus; Hyperuricemia; Serum uric acid
12.  Evidence of Endothelial Dysfunction in Preeclampsia and Risk of Adverse Pregnancy Outcome 
The purpose of this study is to investigate whether endothelial dysfunction, as assessed by elevated cellular fibronectin (cFN), in women with preeclampsia is associated with an increased risk of preterm and/or small-for-gestational-age (SGA) births. Maternal plasma cFN was measured by enzyme-linked immunosorbent assay in samples collected at admission to delivery in 605 normotensive women, 171 women with transient hypertension, and 187 women with preeclampsia. Logistic regression was used to estimate the risk for preterm delivery, SGA, or both. Elevated cFN in women with preeclampsia was associated with an increased risk of both preterm and SGA births (odds ratio, 3.0; confidence interval [CI], 1.0-8.7) compared with women with preeclampsia without elevated cFN. The risk of preterm birth was 14.7-fold higher (CI, 8.1-26.7) and the risk of SGA was 6.8-fold higher (CI, 3.5-13.1) in women with preeclampsia, hyperuricemia, and elevated cFN compared with normotensive women. Elevated cFN is prevalent among women with preeclampsia and identifies women at increased risk of preterm delivery and SGA.
PMCID: PMC2676568  PMID: 18187406
Preeclampsia; pregnancy; cellular fibronectin; small for gestational age; preterm delivery
13.  Association of early-onset preeclampsia in first pregnancy with normotensive second pregnancy outcomes: A population-based study 
To evaluate pregnancy outcomes in normotensive second pregnancy following preeclampsia in first pregnancy.
Population-based retrospective cohort study.
State of Missouri in the United States.
White European origin or African American women who delivered their first 2 non-anomalous singleton pregnancies between 20 and 44 weeks of gestation in Missouri, 1989–2005, without chronic hypertension, renal disease, or diabetes mellitus (n = 12,835).
Preeclampsia and delivery <= 34 weeks gestational age in first pregnancy was defined as early-onset preeclampsia whereas late-onset preeclampsia was preeclampsia with delivery > 34 weeks. Multivariate regression models were fit to estimate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI).
Main outcome measures
Preterm delivery, large and small for gestational age infant, Apgar scores at 5 minutes, fetal death, cesarean section, placental abruption
Women with early-onset preeclampsia in first pregnancy were more likely to be younger, African American, recipients of Medicaid, unmarried, smokers. Despite a second normotensive pregnancy, women with early-onset preeclampsia in first pregnancy had greater odds of SGA, preterm births, fetal death, cesarean section and placental abruption in 2nd pregnancy, relative to women with late-onset preeclampsia after controlling for confounders. Moreover, maternal ethnic origin modified the association between early-onset preeclampsia in first pregnancy and preterm births in 2nd pregnancy. Having a history of early-onset preeclampsia reduces the odds of having a large for gestation infant in 2nd pregnancy.
A history of early-onset preeclampsia is associated with increased odds of adverse pregnancy outcomes despite a normotensive second pregnancy.
PMCID: PMC2884050  PMID: 20497414
Preeclampsia; Early-onset preeclampsia; Preterm birth; Small for gestational age; Fetal death; Cesarean section; Placental abruption
14.  Serum lipid profile and uric acid levels in preeclampsia in University of Benin Teaching Hospital 
Preeclampsia is a pregnancy-specific disease associated with significant maternal and perinatal mortality and morbidity. Lipid abnormality and elevated serum uric acid have been reported as early features of the disease. We aimed to detect the level of serum lipid profile and uric acid abnormalities in severe preeclamptics in Benin City and to measure their clinical significance.
Materials and Methods:
A prospective case-control study was conducted with subjects presenting with severe preeclampsia to the Obstetric Unit of the UBTH, Benin City. Fasting serum lipid profile and uric acid levels of 40 severe preeclamptic subjects and 80 gestation-matched normotensive controls were done at recruitment. The preeclamptic subjects were managed according to our departmental protocol which included stabilisation and delivery. Their sociodemographic and clinical characteristics were used to generate a database for analysis.
The mean serum uric acid level was 28% higher in severe preeclamptics than normotensive women (5.96 ± 2.54 mg/dl versus 4.30 ± 0.85; P = 0.005). There were statistically significant differences in levels of triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) between the preeclamptics and their normotensive controls (P = 0.006, P = 0.000, P = 0.000, respectively). Abnormal serum uric acid was associated with advanced maternal age (P = 0.000), early-onset preeclampsia (P = 0.000) and abnormal body mass index (BMI; P = 0.000). Low birth weight was more likely in preeclamptics with elevated serum uric acid levels (P = 0.041).
Abnormality of serum uric acid in preeclampsia was significantly associated with increased frequency of complications but lipid profile abnormalities were not shown in the subjects studied. We recommend a larger scale study to determine lipid profile in normal and complicated pregnancies in our environment.
PMCID: PMC4178341  PMID: 25298609
Lipid profile; serum uric acid; severe preeclampsia; University of Benin Teaching Hospital
15.  Mid-Trimester Maternal Serum hCG and Alpha Fetal Protein Levels: Clinical Significance and Prediction of Adverse Pregnancy Outcome 
Maternal serum human Chorionic Gonadotropin (hCG) and Alpha Fetal Protein (AFP) were originally introduced to detect trisomy 21 and neural tube defects. However, in the absence of aneuploidy or neural tube defects, mid-trimester maternal serum hCG and/or maternal serum AFP associated with adverse pregnancy outcomes. Pregnancies with unexplained mid-trimester elevation in maternal serum hCG and/or maternal serum AFP, are at increased risk for pregnancy complications resulting from placental insufficiency.
Evidence Acquisition
Mid-trimester maternal serum hCG>2.5 MoM associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, intrauterine growth restriction (IUGR), preterm delivery and intrauterine fetal death(IUFD). Mid-trimester maternal serum AFP levels >2.5 MoM are thought to reflect a defect in placentation and associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD.
Combined mid-trimester elevation in maternal serum hCG and AFP levels suggest a more complex type of placental pathology. They have stronger association with pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD.
Mid-trimester maternal serum hCG or AFP levels alone cannot detect all pregnant women with increased risk to develop pregnancy complications. Multiparameter testing of placental function in mid-trimester (maternal serum hCG and AFP screening, uterine artery Doppler and placental morphology) may allow us to identify women with increased risk to develop severe placental insufficiency and pregnancy complications. However, future prospective studies are needed to confirm the prognostic significance of multiparameter testing of placental function in mid-trimester.
PMCID: PMC3693663  PMID: 23825981
Maternal Serum Screening Tests; Chorionic Gonadotropin; AFP; Adverse Pregnancy Outcome
16.  Uric Acid as a Pathogenic Factor in Preeclampsia 
Placenta  2008;29(Suppl A):S67-S72.
Hyperuricemia is a common finding in preeclamptic pregnancies evident from early pregnancy. Despite the fact that elevated uric acid often pre-dates the onset of clinical manifestations of preeclampsia, hyperuricemia is usually considered secondary to altered kidney function. Increased serum uric acid is associated with hypertension, renal disease and adverse cardiovascular events in the non-pregnant population and with adverse fetal outcomes in hypertensive pregnancies. We hypothesize that an elevated concentration of uric acid in preeclamptic women is not simply a marker of disease severity but rather contributes directly to the pathogenesis of the disorder. Using epidemiological and experimental evidence, gained largely outside of pregnancy, we will propose pathogenic roles for uric acid in preeclamptic pregnancies. Uric acid's ability to promote inflammation, oxidative stress and endothelial dysfunction will be highlighted with discussions of the potential impact on placental development and function and maternal vascular health.
PMCID: PMC3319018  PMID: 18093648
17.  Maternal hyperuricemia in normotensive singleton pregnancy, a prenatal finding with continuous perinatal and postnatal effects, a prospective cohort study 
To assess the association of maternal hyperuricemia with adverse pregnancy outcome and neonatal metabolic, neurologic and respiratory disturbances in normotensive singleton pregnant women.
This prospective multicentric cohort study was conducted on 404 normotensive singleton pregnant women who were admitted for delivery in Vali-Asr and Akbar-Abadi teaching hospitals of Tehran University of Medical Sciences, Tehran, Iran. Upon enrollment maternal and umbilical sera were obtained for determining uric acid levels. 1 and 5 minutes Apgar scores, the need for neonatal resuscitation and neonatal intensive care unit (NICU) admission were recorded. In case of NICU admission a neonatal blood sample was drawn for determining uric acid, blood sugar and bilirubin levels. An intracranial ultrasound imaging was also carried out for the admittd neonates for detecting intraventricular hemorrhage.
Maternal hyperuricemia (uric acid one standard deviation greater than the appropriate gestational age) was independently associated with preterm birth (odds ratio (OR), 3.17; 95% confidence interval (CI), 2.1 – 4.79), small for gestational age delivery (OR, 1.28; 95% CI, 1.04 – 2.57), NICU admission (OR, 1.65; 95% CI, 1.12 – 2.94) and neonatal IVH (OR, 8.14; 95% CI, 1.11 – 87.1).
Maternal hyperuricemia in normotensive singleton pregnant women is significantly associated with preterm and SGA delivery and the development of neonatal IVH.
PMCID: PMC3995428  PMID: 24636149
Hyperuricemia; Uric acid; Neonatal; Pregnancy; IVH
18.  Maternal selenium status during early gestation and risk for preterm birth 
Preterm birth occurs in 5%–13% of pregnancies. It is a leading cause of perinatal mortality and morbidity and has adverse long-term consequences for the health of the child. Because of the role selenium plays in attenuating inflammation, and because low concentrations of selenium have been found in women with preeclampsia, we hypothesized that low maternal selenium status during early gestation would increase the risk of preterm birth.
White Dutch women with a singleton pregnancy (n = 1197) were followed prospectively from 12 weeks’ gestation. Women with thyroid disease or type 1 diabetes were excluded. At delivery, 1129 women had complete birth-outcome data. Serum concentrations of selenium were measured during the 12th week of pregnancy. Deliveries were classified as preterm or term, and preterm births were subcategorized as iatrogenic, spontaneous or the result of premature rupture of the membranes.
Of the 60 women (5.3%) who had a preterm birth, 21 had premature rupture of the membranes and 13 had preeclampsia. The serum selenium concentration at 12 weeks’ gestation was significantly lower among women who had a preterm birth than among those who delivered at term (mean 0.96 [standard deviation (SD) 0.14] μmol/L v. 1.02 [SD 0.13] μmol/L; t = 2.9, p = 0.001). Women were grouped by quartile of serum selenium concentration at 12 weeks’ gestation. The number of women who had a preterm birth significantly differed by quartile (χ2 = 8.01, 3 degrees of freedom], p < 0.05). Women in the lowest quartile of serum selenium had twice the risk of preterm birth as women in the upper three quartiles, even after adjustment for the occurrence of preeclampsia (adjusted odds ratio 2.18, 95% confidence interval 1.25–3.77).
Having low serum selenium at the end of the first trimester was related to preterm birth and was independent of the mother having preeclampsia. Low maternal selenium status during early gestation may increase the risk of preterm premature rupture of the membranes, which is a major cause of preterm birth.
PMCID: PMC3060183  PMID: 21324870
19.  Maternal Active and Passive Smoking and Hypertensive Disorders of Pregnancy 
Epidemiology (Cambridge, Mass.)  2013;24(3):379-386.
The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking.
We conducted an analysis of 74,439 singleton pregnancies with completed second- and third- trimester questionnaires. Active and passive smoke exposure by trimester were determined by maternal self-report, and covered the period of preconception through approximately 30 weeks’ gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
Rates of active smoking declined dramatically during pregnancy: for trimester 1, 23%; trimester 2, 9%; and trimester 3, 8%. Active smoking in the third trimester was associated with reduced odds of preeclampsia and gestational hypertension, with the strongest association among continuous smokers (for preeclampsia, OR = 0.57 [95% CI = 0.46–0.70]). Women who quit smoking before the third trimester had approximately the same risk of preeclampsia and gestational hypertension as nonsmokers. There was some evidence of dose-response, with the heaviest smokers (more than eight cigarettes per day) having the lowest risks of preeclampsia (0.48 [0.32–0.73]) and gestational hypertension (0.51 [0.28–0.95]). There was little evidence of an association with passive smoking exposure.
The association between smoking and preeclampsia varies substantially according to the timing and intensity of exposure. A better understanding of the biologic pathways that underlie these associations may provide important clues to the etiology of preeclampsia and the development of effective clinical interventions.
PMCID: PMC4137974  PMID: 23429405
20.  Implications of Sleep Disordered Breathing in Pregnancy 
To examine the relationship between sleep disordered breathing (SDB) and adverse pregnancy outcomes in a high-risk cohort
Study Design
This was a planned analysis of a prospective cohort designed to estimate the prevalence and trends of SDB in a high-risk pregnant women. We recruited women with a BMI ≥ 30 kg/m2, chronic hypertension, pre-gestational diabetes, prior preeclampsia, and/or a twin gestation. Objective assessment of SDB was completed between 6–20 weeks and again in the third trimester. SDB was defined as an apnea hypopnea index ≥5, and further grouped into severity categories: mild SDB (5–14.9), moderate SDB (15–29.9) and severe SDB (≥30). Pregnancy outcomes (preeclampsia, gestational diabetes, preterm birth, infant weight) were abstracted by physicians blinded to the SDB results.
Of the 188 women with a valid early pregnancy sleep study, 182 had complete delivery records. There was no relationship demonstrated between SDB exposure in early or late pregnancy and preeclampsia, preterm birth < 34 weeks, and small for gestational age (<5%) or large for gestational age (>95%) neonates. Conversely, SDB severity in early pregnancy was associated with the risk of developing gestational diabetes (no SDB 25%, mild SDB 43%, moderate/severe SDB 63%, p=.03). The adjusted OR for developing gestational diabetes for moderate/severe SDB was 3.6 (0.6, 21.8).
This study suggests a dose-dependent relationship between SDB in early pregnancy and the subsequent development of gestational diabetes. In contrast, no relationships between SDB during pregnancy and preeclampsia, preterm birth, and extremes of birthweight were demonstrated.
PMCID: PMC4511595  PMID: 24373947
sleep disordered breathing; sleep apnea; pregnancy; gestational diabetes; adverse pregnancy outcomes
21.  HbA1c as screening for gestational diabetes mellitus in women with polycystic ovary syndrome 
Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes such as preeclampsia and macrosomia. Women with polycystic ovary syndrome (PCOS) are at increased risk of developing GDM. Today, GDM is diagnosed by oral glucose tolerance test (OGTT), a rather cumbersome test for the women and health care system. The objectives of this study were to investigate whether HbA1c in first trimester of pregnancy could be used as a screening test for GDM in first trimester and throughout pregnancy in order to reduce the number of OGTTs, and whether it could predict preeclampsia and macrosomia in women with PCOS.
Post hoc analyses of data from 228 women from a prospective, randomised, multicenter study comparing metformin to placebo from first trimester to delivery. Fasting and 2-h plasma glucose were measured during a 75 g OGTT in first trimester, gestational week 19 and 32 as well as fasting plasma glucose in gestational week 36. GDM was diagnosed by WHO criteria from 1999 in first trimester and throughout pregnancy and by modified IADPSG criteria (i.e. lacking the 1-h plasma glucose value) in first trimester. The diagnostic accuracy was assessed by logistic regression and ROC curve analysis.
The area under the ROC curve for first trimester HbA1c for screening of GDM diagnosed by WHO criteria in first trimester was 0.60 (95 % CI 0.44-0.75) and 0.56 (95 % CI 0.47-0.65) for GDM diagnosed throughout pregnancy. Only 2.2 % (95 % CI 0.7-5.1 %) of the participants could have avoided OGTT. HbA1c was not statistically significantly associated with GDM diagnosed by modified IADPSG criteria in first trimester. However, first trimester HbA1c was statistically significantly associated with preeclampsia. Both HbA1c and GDM by WHO criteria in first trimester, but not by IADPSG, were negatively associated with birth weight.
First trimester HbA1c can not be used to exclude or predict GDM in women with PCOS, but it might be better to predict preeclampsia than the GDM diagnosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12902-015-0039-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4527320  PMID: 26245653
Gestational diabetes mellitus; Polycystic ovary syndrome; HbA1c; Preeclampsia; Birth weight
22.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
PMCID: PMC2740823  PMID: 19771156
23.  Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease 
Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD).
Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit.
Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6–8.9; P < 0.001) and 2.9 (1.6–5.3; P < 0.001)].
Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.
PMCID: PMC3616764  PMID: 23222419
autosomal-dominant polycystic kidney disease; end-stage renal disease; hypertension; kidney volume; uric acid
24.  Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study 
PLoS Medicine  2009;6(5):e1000061.
In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth.
Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.
Methods and Findings
In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics.
Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.
Editors' Summary
Most pregnancies last about 40 weeks, but sometimes the new family member arrives early. Every year, half a million babies in the United States (12.5% of all babies) are born prematurely (before 37 completed weeks of pregnancy). Sadly, premature babies are more likely to die than full-term babies and many have short- and/or long-term health problems. Premature babies often have breathing problems, they are susceptible to life-threatening infections, and they are more likely to have learning and developmental disabilities than those born on time. The severity of these health problems depends on the degree of prematurity—preterm babies born between 34 and 36 weeks of pregnancy rarely develop severe disabilities, but a quarter of babies born before 28 weeks of pregnancy develop serious lasting disabilities and half have learning and behavioral problems. Although doctors have identified some risk factors for early delivery (for example, smoking), it is impossible to predict who will have an early birth and there is no effective way to prevent preterm births.
Why Was This Study Done?
Some researchers think that folate supplements may prevent preterm births. Folate (folic acid), a vitamin found in leafy green vegetables, fruits, and dried beans, helps to prevent neural tube birth defects. Consequently, women are encouraged to take folic acid supplements throughout (and preferably before) pregnancy and many governments now mandate that bread, pasta, and other grain products be fortified with folic acid to help women get sufficient folate. There is some evidence that women who deliver early have less folate in their blood than women who deliver at term. Furthermore, folate supplementation during pregnancy has increased the length of pregnancy in some but not all clinical trials. A possible explanation for these mixed results is that the duration of pregnancy reflects conditions in the earliest stages of pregnancy or before conception and that folate supplementation needs to start before conception to reduce the risk of preterm birth. In this study, the researchers test this idea by analyzing data collected from nearly 35,000 pregnant women enrolled in a study that was originally designed to investigate screening for Down's syndrome.
What Did the Researchers Do and Find?
During the first three months of their pregnancy, the women were asked whether they had taken folate supplements before conception. The duration of each pregnancy was estimated from ultrasound measurements taken early in the pregnancy and from the time of delivery. During the study, 1,658 women had spontaneous preterm deliveries before 37 weeks and 160 delivered before 32 weeks. After allowing for other maternal characteristics that might have affected the likelihood of preterm delivery, the risk of spontaneous preterm delivery between 20 and 28 weeks was 70% lower in women who took folate supplements for more than a year before becoming pregnant than in women who didn't take a supplement. Long-term folate supplementation also reduced the risk of preterm delivery between 28 and 32 weeks by 50% but did not affect the risk of preterm birth beyond 32 weeks. Folate supplementation for less than a year before conception did not reduce the risk of preterm birth, and folate supplementation was not associated with any other complications of pregnancy.
What Do These Findings Mean?
These findings show that folate supplementation for a year or more before conception is associated with a 50%–70% decrease in early (but not late) spontaneous preterm births and that the longer a woman takes folate supplements before becoming pregnant, the lower her risk of a preterm birth. Although the researchers allowed for maternal characteristics that might have affected the duration of pregnancy, it is possible that folate supplementation may not be responsible for the reduction in preterm birth risk seen in this study. For example, taking folate supplements may be a marker of healthy behavior and the women taking the supplements might have been doing something else that was reducing their risk of preterm birth. However, despite this and other limitations of this study, these findings suggest that long-term folate supplementation before conception is worth investigating further as a potential way to prevent preterm births.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Nicholas Fisk
The MedlinePlus encyclopedia contains a page on premature babies (in English and Spanish); MedlinePlus provides links to other information on premature babies (in English and Spanish)
The US National Institute of Child Health and Human Development provides information on preterm labor and birth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth and on folic acid (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Office of Dietary Supplements has a fact sheet on folate
PMCID: PMC2671168  PMID: 19434228
25.  Relationship of serum uric acid, serum creatinine and serum cystatin C with maternal and fetal outcomes in rural Indian pregnant women 
Hypertensive disorders are the most common in pregnancy. Several studies showed a positive correlation between elevated maternal serum uric acid (UA), serum creatinine and adverse maternal and fetal outcomes, but only a few studies are available on serum cystatin C and maternal and fetal outcomes. The present study was undertaken to study the association of serum UA, creatinine and cystatin C with maternal and fetal outcomes.
Out of 116 pregnant women 69 women had no hypertension and 47 had hypertension with or without proteinuria. Serum UA, creatinine and cystatin C was measured by modified Uricase method, modified kinetic Jaffe’s reaction and particle-enhanced immunonephelometric assay respectively. Multivariate logistic regression was performed to determine the independent effects of serum UA, creatinine and cystatin C on maternal and fetal outcomes using stata 13.1.
The adjusted odds ratio (OR) was 3.73 (95% CI: 1.18-11.75; P=0.024) for UA; 15.79 (95% CI: 3.04-81.94; P=0.001) for creatinine and 2.03 (95% CI: 0.70-5.87; P=0.192) for cystatin C in hypertensive disorders of pregnancy. All the three renal parameters were not significantly associated with birth weight, gestational age of delivery and mode of delivery after adjusting for the confounding factors.
Serum creatinine and uric acid are independent risk factors for hypertensive disorders of pregnancy. High serum uric acid is associated with low birth weight and delivery by caesarian section whereas high serum creatinine with preterm delivery only before adjustment for confounding factors and not after adjustment. Serum cystatin C was not significantly associated with the maternal and fetal outcomes.
PMCID: PMC4646224  PMID: 26583159
Uric acid; Creatinine; Cystatin C; Gestational Hypertension; Preeclampsia; Gestational age; Birth weight; Caesarian section; Logistic regression

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