High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Vertically transferred maternal immune cells promote neonatal immunity against early life infections.

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.

In-depth characterization of monocyte subsets during the course of healthy pregnancy.

Pregnancy represents an immunological challenge for the maternal immune system. Pregnancy augments innate immune responses, and particularly monocytes contribute to maintaining the balance between pro- and anti-inflammatory immune responses required for the successful sequence of distinct immunological phases throughout pregnancy. Nonetheless, studies that focus on the heterogeneity of monocytes and analyze the alteration of monocyte subsets in a longitudinal approach throughout healthy pregnancies have remained scarce. In this study, we characterized the gradual phenotypic changes of monocyte subsets and the secretory potential of bulk monocytes in peripheral blood mononuclear cells of healthy pregnant women from a population-based prospective birth cohort study. Blood samples at predefined time points were analyzed using flow cytometry for in-depth characterization of monocyte subsets, which confirmed a shift from classical towards intermediate monocytes throughout pregnancy. Principal component analysis revealed characteristic phenotypic changes on monocyte subsets, especially on the intermediate monocyte subset, throughout pregnancy. Pregnancy-related hormones were measured in serum and ß-human chorionic gonadotropin levels were significantly associated with expression of CD11b, CD116 and CCR2 on monocyte subsets. TLR4 and TLR7/8 stimulation of monocytes furthermore showed reduced polycytokine production towards the end of pregnancy. These data provide a comprehensive overview of phenotypic changes and secretory potential of monocytes in healthy pregnant women and establish a selective contribution of different monocyte subsets to healthy pregnancy. The results from this study therefore build a basis for future comparisons and evaluation of women with adverse pregnancy outcomes.

Long-term outcomes for monochorionic twins after laser therapy in twin-to-twin transfusion syndrome.

Twin-to-twin transfusion syndrome typically occurs in the second trimester in 10-15% of monochorionic twin pregnancies. Vascular anastomoses of monochorionic placentae are the underlying cause of the development of the syndrome. If a blood flow imbalance occurs, one fetus becomes the so-called donor twin and the other the recipient. If untreated, perinatal mortality is 80-90%. Fetoscopic laser coagulation of the vascular anastomoses destroys the cause of the syndrome and leads to dual twin survival rates of around 70% and more than 90% of pregnancies with at least one survivor. However, unequal placental sharing, intrauterine death, and severe prematurity are still limiting factors for further improvement of survival rates and decreases in long-term morbidity. Prematurity and neurodevelopmental impairment affect the donor and recipient twins, whereas cardiovascular failure and obstruction of the right ventricular outflow tract are typical complications of recipients, which can lead to long-term morbidity. In this Review, we summarise the literature on follow-up data for survivors of twin-to-twin-transfusion syndrome after laser therapy, including neurodevelopmental outcomes, cardiovascular outcomes, growth, renal function, and ischaemic events, as well as the potential effects of intrauterine programming on later life.

Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy.

During pregnancy the maternal immune system has to develop tolerance towards the developing fetus. These changes in maternal immunity can result in increased severity of certain infections, but also in amelioration of autoimmune diseases. Pregnancy-related hormones have been suggested to play a central role in the adaptation of the maternal immune system, but their specific effects on innate immune function is not well understood. In a longitudinal study of pregnant women, we investigated innate immune cell function in response to toll-like receptors (TLR) 4 and 7 stimulation, two TLR pathways playing a critical role in early innate immune recognition of bacteria and viruses. IFNα production by TLR7-stimulated pDCs was decreased in early pregnancy, and increased towards the end of pregnancy. In contrast, pro-inflammatory TLR4-induced TNFα production by monocytes was increased during early pregnancy, but declined after the first trimester. Changes in cytokine production were associated with changes in pregnancy-related hormones and monocyte subpopulations over the course of pregnancy. These data demonstrating a significant association between pregnancy-related hormones and modulation of innate immune responses mediated by TLRs provide novel insights into the immunological adaptations occurring during pregnancy.

Paracetamol Medication During Pregnancy: Insights on Intake Frequencies, Dosages and Effects on Hematopoietic Stem Cell Populations in Cord Blood From a Longitudinal Prospective Pregnancy Cohort.

BACKGROUND: Paracetamol is the first choice for antipyretic or analgesic treatment throughout pregnancy. Products with Paracetamol are readily available over the counter and therefore easily accessible for self-medication. Epidemiological data on Paracetamol intake pattern during pregnancy and its potential immunological effects are sparse. We aimed to analyze a possible association between Paracetamol medication and numbers of hematopoietic stem cells (HSC) in cord blood. METHODS: The objective was addressed in the PRINCE (PRENATAL DETERMINANTS OF CHILDREN'S HEALTH) study, a population-based prospective pregnancy cohort study initiated in 2011 at the University Medical Center in Hamburg, Germany. 518 healthy pregnant women with singleton pregnancies were recruited during the first trimester. Three examinations were scheduled at the end of the 1st (gestational week 12-14), the 2nd (gestational week 22-24) and the 3rd trimester (gestational week 34-36). For 146 of these women, cord blood flow cytometry data were available. Paracetamol intake was assessed for each trimester of pregnancy. FINDINGS: Among the 518 enrolled women, 40% took Paracetamol as main analgesic treatment during pregnancy. The intake frequency and dosage of Paracetamol varied between the women and was overall low with a tendency towards higher frequencies and higher dosages in the third trimester. Paracetamol intake, particularly during the third trimester, resulted in decreased relative numbers of HSCs in cord blood, independent of maternal age, first-trimester BMI, parity, gestational age and birth weight (-0.286 (95% CI -0.592, 0.021), p=0.068). INTERPRETATION: Prenatal Paracetamol intake, especially during the third trimester, may be causally involved in decreasing HSCs in cord blood.

Maternal progesterone levels are modulated by maternal BMI and predict birth weight sex-specifically in human pregnancies.

OBJECTIVE: Successful pregnancy outcome is the result of a tailored adaptation of the maternal endocrine and immune system throughout gestation. We aimed to investigate if maternal endocrine, anthropometric and life style factors assessed longitudinally throughout pregnancy allow prediction of birth weight. STUDY DESIGN: Data on maternal factors and obstetrical characteristics from 220 pregnancies from a German prospective pregnancy cohort were analyzed using univariate and multivariate regression models. The association between maternal progesterone levels at the end of the 1st (gw 12-14), the 2nd (gw 22-24) and the 3rd trimester (gw 34-36) and birth weight of children born at term was examined. Interaction terms were included to identify possible sex-specific associations. Furthermore, associations between maternal and obstetric characteristics and progesterone levels were tested. RESULTS: After controlling for possible confounders, progesterone in the 2nd trimester emerged as an independent predictor for birth weight in pregnancies with female (p=0.01), but not male fetuses (p=0.6). In female fetuses each increase of progesterone by 1ng/ml in the 2nd trimester was associated with an increase of birth weight by 6.8g (95%-CI=1.44-12.24). Maternal 1st trimester BMI showed a significant inverse correlation to progesterone levels throughout gestation (p<0.0001 in the 1st and 2nd, p=0.01 in the 3rd trimester). This inverse association between maternal BMI and progesterone levels was confined to overweight women. CONCLUSION: Our data support that maternal progesterone levels have the potential to serve as early biomarker for reduced birth weight and underpins the importance of normal weight when entering the reproductive phase.

EVERREST prospective study: a 6-year prospective study to define the clinical and biological characteristics of pregnancies affected by severe early onset fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is a serious obstetric condition for which there is currently no treatment. The EVERREST Prospective Study has been designed to characterise the natural history of pregnancies affected by severe early onset FGR and establish a well phenotyped bio-bank. The findings will provide up-to-date information for clinicians and patients and inform the design and conduct of the EVERREST Clinical Trial: a phase I/IIa trial to assess the safety and efficacy of maternal vascular endothelial growth factor (VEGF) gene therapy in severe early onset FGR. Data and samples from the EVERREST Prospective Study will be used to identify ultrasound and/or biochemical markers of prognosis in pregnancies with an estimated fetal weight (EFW) <3rd centile between 20+0 and 26+6 weeks of gestation. METHODS: This is a 6 year European multicentre prospective cohort study, recruiting women with a singleton pregnancy where the EFW is <3rd centile for gestational age and <600 g at 20+0 to 26+6 weeks of gestation. Detailed data are collected on: maternal history; antenatal, peripartum, and postnatal maternal complications; health economic impact; psychological impact; neonatal condition, progress and complications; and infant growth and neurodevelopment to 2 years of corrected age in surviving infants. Standardised longitudinal ultrasound measurements are performed, including: fetal biometry; uterine artery, umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry; and uterine artery and umbilical vein volume blood flow. Samples of maternal blood and urine, amniotic fluid (if amniocentesis performed), placenta, umbilical cord blood, and placental bed (if caesarean delivery performed) are collected for bio-banking. An initial analysis of maternal blood samples at enrolment is planned to identify biochemical markers that are predictors for fetal or neonatal death. DISCUSSION: The findings of the EVERREST Prospective Study will support the development of a novel therapy for severe early onset FGR by describing in detail the natural history of the disease and by identifying women whose pregnancies have the poorest outcomes, in whom a therapy might be most advantageous. The findings will also enable better counselling of couples with affected pregnancies, and provide a valuable resource for future research into the causes of FGR. TRIAL REGISTRATION: NCT02097667 registered 31st October 2013.

The Impact of Entry Technique and Access Diameter on Prelabour Rupture of Membranes Following Primary Fetoscopic Laser Treatment for Twin-Twin Transfusion Syndrome.

OBJECTIVE: To evaluate the impact of entry method and access diameter at fetoscopic surgery for twin-twin transfusion syndrome in twin pregnancies with at least one survivor. The outcomes evaluated were prelabour rupture of membranes (PROM) and birth <4 weeks, preterm birth (PTB) <28 weeks, and latency to birth. METHODS: A retrospective analysis of prospectively collected data of consecutive laser procedures from 6 centers was performed. Three entry methods (sheath + trocar; cannula + trocar; cannula + Seldinger) and 6 access diameters (2.3, 3.0, 3.3, 3.5, 3.8, 4.0 mm) were used. Exclusion criteria were subsequent invasive interventions, termination of pregnancy or double fetal death after laser. Multivariate analysis was performed to determine risk factors for the study outcomes. RESULTS: Six hundred seventy three fetoscopic laser cases were analyzed. The use of different entry methods and access diameters did not affect PROM or birth <4 weeks, or latency from laser to birth. Access diameter was associated with PTB <28 weeks. Cervical length was associated with PROM and birth <4 weeks, and latency from laser to birth. CONCLUSION: Instrument choice at fetoscopic laser procedures did not affect outcomes <4 weeks. Access diameter may affect the likelihood for PTB <28 weeks. Cervical length is critically associated with obstetrical outcomes following laser surgery.

WHO multicentre study for the development of growth standards from fetal life to childhood: the fetal component.

BACKGROUND: In 2006 WHO presented the infant and child growth charts suggested for universal application. However, major determinants for perinatal outcomes and postnatal growth are laid down during antenatal development. Accordingly, monitoring fetal growth in utero by ultrasonography is important both for clinical and scientific reasons. The currently used fetal growth references are derived mainly from North American and European population and may be inappropriate for international use, given possible variances in the growth rates of fetuses from different ethnic population groups. WHO has, therefore, made it a high priority to establish charts of optimal fetal growth that can be recommended worldwide. METHODS: This is a multi-national study for the development of fetal growth standards for international application by assessing fetal growth in populations of different ethnic and geographic backgrounds. The study will select pregnant women of high-middle socioeconomic status with no obvious environmental constraints on growth (adequate nutritional status, non-smoking), and normal pregnancy history with no complications likely to affect fetal growth. The study will be conducted in centres from ten developing and industrialized countries: Argentina, Brazil, Democratic Republic of Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand. At each centre, 140 pregnant women will be recruited between 8 + 0 and 12 + 6 weeks of gestation. Subsequently, visits for fetal biometry will be scheduled at 14, 18, 24, 28, 32, 36, and 40 weeks (+/- 1 week) to be performed by trained ultrasonographers.The main outcome of the proposed study will be the development of fetal growth standards (either global or population specific) for international applications. DISCUSSION: The data from this study will be incorporated into obstetric practice and national health policies at country level in coordination with the activities presently conducted by WHO to implement the use of the Child Growth Standards.

Twin-twin transfusion syndrome: treatment and outcome.

Twin-twin transfusion syndrome complicates up to 15% of monochorionic pregnancies in the mid-trimester, and results in high perinatal mortality and morbidity if left untreated. Although some humoral factors play a role in the pathogenesis of the disease, an unequal placental sharing and the presence of placental vascular anastomoses at the chorionic plate, allowing blood volume shifts between the twins, are the anatomic prerequisite for this complication unique to monochorionic twins. Within monochorionic pregnancies, it is possible to identify a subgroup of twin pairs at high risk of developing twin-twin transfusion syndrome or selective intrauterine growth restriction during the course of pregnancy as early as in the first or early second trimester. If progressive amniotic fluid discrepancy advances to moderate twin-twin transfusion syndrome, and finally reaches the stages of severe twin-twin transfusion syndrome, accurate classification of the clinical picture and diagnosis of the individual fetal haemodynamic status are crucial for counselling parents on treatment options and possible outcomes. Clear criteria have been established for fetoscopic laser coagulation of placental vascular anastomoses, which is the treatment of choice for severe twin-twin transfusion syndrome, interrupting blood flow between the twins, and relieving uterine over-distension related to severe polyhydramnios.

Sex-specific effect of first-trimester maternal progesterone on birthweight.

STUDY QUESTION: Are maternal progesterone levels in early pregnancy associated with fetal birthweight? SUMMARY ANSWER: Low levels of first-trimester maternal progesterone are significantly associated with a reduction in birthweight in girls, but not boys. WHAT IS ALREADY KNOWN: Progesterone in the third trimester of pregnancy has previously been related to birthweight in humans. STUDY DESIGN, SIZE, DURATION: Pregnant women between gestational weeks 4 and 12 were recruited by 99 obstetricians in private practice and enrolled in a prospective cohort study. A follow-up took place at birth. Women younger than 18 years, who had undergone fertility treatments or were diagnosed with infectious diseases, were excluded from the study. A subgroup of 906 participants in whom progesterone had been measured was then selected retrospectively based on the following criteria: no miscarriages, elective abortions or pregnancy complications, infections or multiple births. Data from the follow-up were available for 623 women, who were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was coordinated at the Charité University Medicine in Berlin, Germany. Anthropometric, medical and psychosocial information were collected and serum progesterone and estradiol levels were measured in women during the first trimester of pregnancy, followed by the documentation of the pregnancy outcome at birth. Univariable and multivariable regression analyses were performed to identify maternal markers, among them progesterone, affecting birthweight and to determine environmental and maternal factors that are associated with maternal progesterone levels during pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariable regression model, each increase in maternal progesterone by 1 ng/ml during the first trimester increased girls' birthweight by 10.17 g (95% CI: 2.03-18.31 g). If the mother carried a boy, maternal smoking and perceived worries during early pregnancy predicted a reduced birthweight, irrespective of progesterone levels. Maternal body mass index over 25 and maternal age <21 years significantly correlated with the reduced levels of progesterone. Correlations between environmental challenges and maternal progesterone did not reach levels of significance. Since the analyses were exploratory, the likelihood that results may be due to chance is increased. LIMITATIONS, REASONS FOR CAUTION: Due to the exploratory nature of the analyses, results need to be independently confirmed in a larger sample. Furthermore, our findings pertain to pregnant women without pregnancy complications or fertility treatments. WIDER IMPLICATIONS OF THE FINDINGS: Maternal progesterone during early pregnancy is an indicator of subsequent fetal development in female children. Future studies should confirm this relationship and determine whether maternal progesterone is a useful tool in predicting pregnancies at risk resulting in the birth of a girl with low birthweight. Detailed identification of environmental factors modulating maternal progesterone levels should be addressed in future studies. STUDY FUNDING/POTENTIAL COMPETING INTERESTS: Financial support was provided by the Alexander von Humboldt Foundation, Excellence Initiative of the Hamburg Foundation for Research and the Association for Prevention and Information for Allergy and Asthma (Pina e.V.). The authors have no conflict of interest.

Intrauterine surgery--choices and limitations.

BACKGROUND: The past decade has seen much progress in intrauterine surgery. Randomized trials have documented the benefit of some procedures of this type for the unborn child. METHOD: Selective literature review RESULTS: Randomized trials have demonstrated the benefit of fetoscopic laser coagulation of placental anastomoses in twin-to-twin transfusion syndrome (TTTS) and of intrauterine surgery via hysterotomy for the repair of spina bifida. Other fetoscopic procedures have yielded promising initial results but are not yet supported by findings from randomized trials. Some intrauterine surgical procedures must still be considered experimental in view of the lack of randomized trials and the rarity of the conditions they are designed to treat. Fetoscopic laser coagulation for TTTS is by far the most common procedure in fetal surgery; TTTS arises in roughly 1 in 2500 pregnancies. The other procedures discussed in this article are performed much less often and for rarer indications. In general, intrauterine surgery is indicated only to treat conditions that would otherwise lead to intrauterine death or irreversible prenatal damage. CONCLUSION: Intrauterine surgery is a rapidly developing field. Prenatal intervention by laser coagulation is indicated to treat severe TTTS, as its benefit has been shown in a randomized trial. Not enough evidence is yet available for the possible benefit of intrauterine surgery to treat myelomeningocele and congenital diaphragmatic hernia. Other indications are experimental. When an indication for intrauterine surgery exists, the parents should be informed and, depending on their wishes, referred to a center where it can be performed.

Long-term outcome after intrauterine laser treatment for twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) is a severe complication occurring in about 10% of monochorionic twin pregnancies. The chronic unbalanced transfusion of blood across placental vascular communications from the donor to the recipient twin may lead to impairment of various organ systems in the affected twins. In Hamburg, Germany, since 1995 patients with TTTS were treated with fetoscopic laser coagulation as the first causal therapeutic strategy. All survivors after laser surgery were followed up in the University Children's Hospital in Bonn, Germany. In this article, we summarize long-term follow-up studies from our German study population and compare our results with data from the literature.