Preterm Fetal Growth Restriction Research Articles

Homeobox gene ESX1L expression is decreased in human pre-term idiopathic fetal growth restriction

Fetal growth restriction (FGR) is a clinically significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. This study involved idiopathic FGR, which is frequently associated with placental dysfunction. Here, we investigated mRNA levels of the human placental homeobox gene ESX1L in pre-term and term idiopathic FGR pregnancies compared with gestation-matched controls. Real-time PCR quantitation showed ESX1L levels in control placentae decreased between pre-term and term [0.7 +/- 0.20 (27-35 weeks, n = 13) versus 0.2 +/- 0.06 (36-41 weeks, n = 12), t-test, P < 0.005]. ESX1L levels in FGR-affected placentae were significantly lower than in gestation-matched controls, and there was no significant change between pre-term FGR and term FGR [0.32 +/- 0.04 (27-36 weeks, n = 11) versus 0.31 +/- 0.02 (36-41 weeks, n = 14), t-test, P = 0.82]. Multiple linear regression analysis revealed a rapid decline in ESX1L expression in control placentae [0.075-fold of the calibrator for each week of gestation (95% CI = -0.105 to -0.045, P < 0.0005)]. In FGR-affected placentae, ESX1L levels were lower than in gestation-matched controls, and the decline in ESX1L levels with gestation was not significant [0.001-fold of the calibrator for each week of gestation (95% CI = -0.030 to 0.010, P < 0.3]. The linear relationship between ESX1L mRNA levels in FGR-affected placentae and gestation-matched controls during gestation was significantly different (likelihood ratio test for interaction, P = 0.0005). Our findings were consistent with a potential role for the ESX1L gene within the growth control mechanism of the fetus, through its effect on placental function.

Collagen fibril diameters in the umbilical arteries of preterm growth restricted fetuses

RESTRICTED FETUSES WENDY KINZLER, JOHN SMULIAN, CANDE ANANTH, DONALD GERECKE, RITAHAHN, GEORGE LAMBERT, MARIONGORDON, University of Medicine and Dentistry of New Jersey, Obstetrics, Gynecology and Reproductive Sciences, New Brunswick, New Jersey, Rutgers, The State University of New Jersey, Pharmacology and Toxicology, Rutgers College of Pharmacy, Piscataway, New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey OBJECTIVE: Our previous work has demonstrated that fetal growth restriction (FGR) in preterm gestations is associated with changes in extracellular matrix (ECM) components which control fibril diameter. Our objective was to determine if actual collagen fibril diameters within the umbilical arterial wall are altered in FGR versus appropriately grown (AGA) fetuses delivered preterm (!37 weeks). STUDY DESIGN: Preterm FGR pregnancies (ultrasound-estimated fetal weight !10th% ile for gestational age and abnormal umbilical Doppler velocimetry) were compared with preterm AGA pregnancies. The umbilical artery was collected at delivery and prepared for examination by transmission electron microscopy. Because of potential differences in mechanical forces and hypoxic exposures between the inner and outer arterial wall, micrographs were taken at the outer, middle and inner 3rd at 30K magnification. Cross-sectional collagen fibril diameters were measured by the same examiner and converted from mm to nm using a standard magbar reference on each micrograph. The means and variances in fibril diameters were modeled using general linear models based on quasi-likelihood estimating functions. P!0.05 was considered significant. RESULTS: 1133 fibril diameters from 4 FGR pregnancies were compared with 1266 fibril diameters measured from 3 AGA pregnancies. Mean fibril diameters (95%CI) for FGR and AGA pregnancies were as follows: 33.7 (31.4-35.9) nm versus 37.4 (35.7-39.1) nm, P=0.04. The largest diameters were found in the outer 3rd of the arterial wall for both FGR and AGA pregnancies. Middle and inner 3rd diameters were similar among FGR pregnancies, while AGA pregnancies demonstrated a progressive decrease in fibril diameter toward the inner 3rd of the arterial wall. CONCLUSION: Collagen fibril diameters in the umbilical arteries of preterm FGR pregnancies are thinner than diameters of AGA pregnancies and vary depending on the arterial wall site which is sampled. This may be the result of ECM remodeling in FGR pregnancies and may contribute to the genesis of future cardiovascular disease.

Is Older Maternal Age a Risk Factor for Preterm Birth and Fetal Growth Restriction? A SystematicReview

To determine if there was an association between advancing maternal age and adverse pregnancy outcomes (preterm delivery and small-for-gestational-age births), a systematic review was conducted based on a comprehensive search of the literature from 1985 to 2002. Ten studies met the following inclusion criteria: (1) assessed risk factors for preterm birth by subtype (i.e., idiopathic preterm labor, preterm premature rupture of membranes) and small-for-gestational-age (SGA) birth (fetal growth restriction); (2) used acceptable definitions of these outcomes; (3) were published between January 1985 and December 2002; (4) were restricted to studies that have considered preterm birth due to idiopathic preterm labor or premature rupture of membranes or both; (5) were restricted to singleton live births; (6) were conducted in a developed country; and (7) were published in English. The majority of the studies reviewed found that older maternal age was associated with preterm birth. There is insufficient evidence to determine if older maternal age is an independent and direct risk factor for preterm birth and SGA birth, or a risk marker that exerts its influence on gestational age or birth weight or both through its association with age-dependent confounders. Future research is needed to quantify the independent and unconfounded impact of delayed childbearing on neonatal outcomes, as well as to identify the pathways involved.

Prediction of pregnancy complications by first‐trimester maternal serum PAPP‐A and free β‐hCG and with second‐trimester uterine artery Doppler

Previous studies have shown an association between low first trimester maternal serum free beta-hCG and PAPP-A and subsequent development of pregnancy complications. Similarly, uterine artery Doppler in the late second trimester has shown that high impedance to flow is associated with increased risk for preeclampsia and fetal growth restriction. The objective of this study is to determine whether there is an association between the maternal serum concentration of PAPP-A and free beta-hCG at 11-13(+6) weeks with the uterine artery pulsatility index (PI) at 22-24 weeks, and secondly, to compare the screening characteristics of the two methods in the prediction of adverse pregnancy outcome. Maternal serum PAPP-A and free beta-hCG at 11-13(+6) weeks and uterine artery PI at 22-24 weeks were measured in 4390 women with singleton pregnancies. Pregnancies with chromosomal defects or fetal anomalies were excluded. The biochemical and Doppler measurements were compared between those with normal outcome and those resulting in spontaneous preterm delivery, pre-eclampsia and fetal growth restriction (FGR). Detection rates using a combination of the biochemical and Doppler measurements were investigated. In the pregnancies resulting in pre-eclampsia (n = 64) and FGR (n = 172), the median PAPP-A was lower (0.844 and 0.813 MoM), the median uterine artery mean PI was higher (1.56 and 1.18) but the median free betahCG was not significantly different (0.923 and 0.933 MoM) than in the normal outcome group. In the preterm delivery group (n = 159), the median free beta-hCG (0.944 MoM) and uterine artery mean PI (1.06) were not significantly different from normal but the median PAPP-A (0.928 MoM) was significantly lower than normal. In screening for pre-eclampsia, the detection rate, for a 5% false-positive rate, was 14.1% for PAPP-A, 54.7% for uterine artery mean PI and 62.1% for a combination of PAPP-A and uterine artery mean PI. Maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes. The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia.

Hemoglobin concentration in pregnancy and perinatal mortality: A London-based cohort study

Failure of fetal growth during pregnancy, and preterm birth, are the major causes of stillbirth and early neonatal death. The objective of the study was to determine the association between maternal hemoglobin concentration during pregnancy and perinatal mortality. The design was prospective, using data on 222,614 first singleton pregnancies in the St Mary's Maternity Information System database in the Northwest Thames region of London. The association of perinatal mortality with maternal hemoglobin at first antenatal check was not statistically significant (P>.10), but a statistically significant (P<.001) U-shaped pattern was found with lowest recorded maternal hemoglobin concentration. Both early neonatal mortality and stillbirth rates were statistically significantly (P<.005) associated with lowest maternal hemoglobin concentration. The relationship of lowest hemoglobin with early neonatal mortality was largely mediated by the effect of preterm birth, and that between lowest hemoglobin and stillbirth by fetal growth restriction. The lowest perinatal mortality was associated with a lowest recorded maternal hemoglobin concentration of between 9-11 g/dL. There is an optimal range of lowest hemoglobin concentration in pregnancy, and on either side of this perinatal mortality is increased. The effect of lowest hemoglobin is largely mediated through associations with preterm birth and fetal growth restriction.

An emerging role for comprehensive proteome analysis in human pregnancy research

Elucidation of underlying cellular and molecular mechanisms is pivotal to the comprehension of biological systems. The successful progression of processes such as pregnancy and parturition depends on the complex interactions between numerous biological molecules especially within the uterine microenvironment. The tissue- and stage-specific expression of these bio-molecules is intricately linked to and modulated by several endogenous and exogenous factors. Malfunctions may manifest as pregnancy disorders such as preterm labour, pre-eclampsia and fetal growth restriction that are major contributors to maternal and perinatal morbidity and mortality. Despite the immense amount of information available, our understanding of several aspects of these physiological processes remains incomplete. This translates into significant difficulties in the timely diagnosis and effective treatment of pregnancy-related complications. However, the emergence of powerful mass spectrometry-based proteomic techniques capable of identifying and characterizing multiple proteins simultaneously has added a new dimension to the field of biomedical research. Application of these high throughput methodologies with more conventional techniques in pregnancy-related research has begun to provide a novel perspective on the biochemical blueprint of pregnancy and its related disorders. Further, by enabling the identification of proteins specific to a disease process, proteomics is likely to contribute, not only to the comprehension of the underlying pathophysiologies, but also to the clinical diagnosis of multifactorial pregnancy disorders. Although the application of this technology to pregnancy research is in its infancy, characterization of the cellular proteome, unearthing of functional networks and the identification of disease biomarkers can be expected to significantly improve maternal healthcare in the future.

Applications of proteomic methodologies to human pregnancy research: a growing gestation approaching delivery?

Maternal and perinatal morbidity and mortality rates are significantly higher in pregnancies complicated by preterm labor, pre-eclampsia and fetal growth restriction. Decades of research have not translated into a clear understanding of the underlying pathophysiologies or effective identification of women who are at high risk of developing these complications. Often the severity of these diseases does not correlate with the clinical symptoms, and current diagnostic methods are unable to accurately predict the conditions prior to clinical presentation. Though several potential markers have been proposed for each of these disorders, to date none have proven clinical utility. Emerging proteomic technology is only beginning to be employed in pregnancy research. A comprehensive analysis of gestational tissues can be expected to contribute to the elucidation of the complex molecular mechanisms of pregnancy and related complications. Comparison of the expression profiles of normal and pathogenic tissues and biofluids may also highlight novel candidate marker proteins that have so far remained undetected. More interestingly, rapidly evolving technologies using sophisticated bioinformatic tools are demonstrating their potential in disease diagnostics by using overall protein profiles to detect diseases. The clinical significance of these methodological advances is enormous. Early diagnosis together with improved understanding of underlying molecular mechanisms can enhance outcomes and increase effective management and therapeutic options.

Duty hours and pregnancy outcome among residents in obstetrics and gynecology

Objective To assess the present status of resident duty hours in obstetrics and gynecology, identify existing policies concerning work schedules during pregnancy, and evaluate pregnancy outcome in female house officers. Methods A questionnaire-based study was administered to residents taking the 2001 Council on Residency Education in Obstetrics and Gynecology examination. Results More than 90% of the residents reported that their institution had a maternity leave policy. The leave was usually 4–8 weeks long and was paid. Nearly 95% of residents reported that they had to take over the work of residents on maternity leave. Most women residents worked more than 80 hours weekly throughout pregnancy, and few took time off before delivery. Most pregnancies occurred during the fourth year of training and did not seem to be adversely affected by the long work hours. Conclusion This study, performed before the institution of the new Accreditation Council for Graduate Medical Education resident duty hour policies, demonstrated that, although women house officers continued to work more than 80 hours per week during pregnancy, most had a good pregnancy outcome. Nevertheless, there was a higher frequency of preterm labor, preeclampsia, and fetal growth restriction in female residents than in spouses or partners of male residents.

Duty Hours and Pregnancy Outcome Among Residents in Obstetrics and Gynecology

In Brief OBJECTIVE To assess the present status of resident duty hours in obstetrics and gynecology, identify existing policies concerning work schedules during pregnancy, and evaluate pregnancy outcome in female house officers. METHODS A questionnaire-based study was administered to residents taking the 2001 Council on Residency Education in Obstetrics and Gynecology examination. RESULTS More than 90% of the residents reported that their institution had a maternity leave policy. The leave was usually 4–8 weeks long and was paid. Nearly 95% of residents reported that they had to take over the work of residents on maternity leave. Most women residents worked more than 80 hours weekly throughout pregnancy, and few took time off before delivery. Most pregnancies occurred during the fourth year of training and did not seem to be adversely affected by the long work hours. CONCLUSION This study, performed before the institution of the new Accreditation Council for Graduate Medical Education resident duty hour policies, demonstrated that, although women house officers continued to work more than 80 hours per week during pregnancy, most had a good pregnancy outcome. Nevertheless, there was a higher frequency of preterm labor, preeclampsia, and fetal growth restriction in female residents than in spouses or partners of male residents. Most women residents in obstetrics and gynecology work more than 80 hours per week throughout pregnancy.

Preterm fetal growth restriction is associated with increased parathyroid hormone–related protein expression in the fetal membranes

Objective: Parathyroid hormone–related protein has roles in normal fetal growth, placental calcium transport, and vascular tone regulation; these factors are compromised in growth-restricted fetuses. Our objective was to determine whether intrauterine parathyroid hormone–related protein expression was increased in association with fetal growth restriction. Study Design: The expression of parathyroid hormone–related protein was examined in intrauterine tissues from women with idiopathic fetal growth restriction with preterm (n = 8-10) and term (n = 8-10) gestations and from gestation-matched control subjects. The abundance and immunoreactive content of parathyroid hormone–related protein messenger ribonucleic acid were determined by Northern blot and radioimmunoassay, respectively, in the placenta, amnion, and chorion-decidua. Results: The expression of parathyroid hormone–related protein messenger ribonucleic acid was increased in the amnion (placental and reflected) in association with preterm fetal growth restriction (P <.05). Both parathyroid hormone–related protein messenger ribonucleic acid and protein expression were increased in chorion-decidua in association with preterm fetal growth restriction (P <.05). In term gestations both parathyroid hormone–related protein messenger ribonucleic acid and protein expression were greater in amnion over placenta than in reflected amnion (P <.05); these in turn were greater than those in chorion-decidua (P <.05). No significant changes were detected in parathyroid hormone–related protein messenger ribonucleic acid or in protein expression in association with term fetal growth restriction. Conclusion: Either parathyroid hormone–related protein messenger ribonucleic acid or protein expression, or both, was increased in the fetal membranes in association with fetal growth restriction in preterm but not term gestations, suggesting that parathyroid hormone–related protein may be involved in the pathogenesis of preterm fetal growth restriction. (Am J Obstet Gynecol 2000;183:700-5.)

Placental pathology clues for inter disciplinary clarification of fetal disease

Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from infections (viral, bacterial, parasitic) or be of immune origin (maternal anti-fetal rejection). The 3 major lesions are villitis (when the inflammatory process affects the villous tree), chronic chorioamnionitis (which affects the chorioamniotic membranes), and chronic deciduitis (which involves the decidua basalis). Maternal cellular infiltration is a common feature of the lesions. Villitis of unknown etiology (VUE) is a destructive villous inflammatory lesion that is characterized by the infiltration of maternal T cells (CD8+ cytotoxic T cells) into chorionic villi. Migration of maternal T cells into the villi is driven by the production of T-cell chemokines in the affected villi. Activation of macrophages in the villi has been implicated in the destruction of the villous architecture. VUE has been reported in association with preterm and term fetal growth restriction, preeclampsia, fetal death, and preterm labor. Infants whose placentas have VUE are at risk for death and abnormal neurodevelopmental outcome at the age of 2 years. Chronic chorioamnionitis is the most common lesion in late spontaneous preterm birth and is characterized by the infiltration of maternal CD8+ T cells into the chorioamniotic membranes. These cytotoxic T cells can induce trophoblast apoptosis and damage the fetal membranes. The lesion frequently is accompanied by VUE. Chronic deciduitis consists of the presence of lymphocytes or plasma cells in the basal plate of the placenta. This lesion is more common in pregnancies that result from egg donation and has been reported in a subset of patients with premature labor. Chronic placental inflammatory lesions can be due to maternal anti-fetal rejection, a process associated with the development of a novel form of fetal systemic inflammatory response. The syndrome is characterized by an elevation of the fetal plasma T-cell chemokine. The evidence that maternal anti-fetal rejection underlies the pathogenesis of many chronic inflammatory lesions of the placenta is reviewed. This article includes figures and histologic examples of all chronic inflammatory lesions of the placenta.

Multifetal Reduction Increases the Risk of Preterm Delivery and Fetal Growth Restriction in Twins

Multifetal Reduction Increases the Risk of Preterm Delivery and Fetal Growth Restriction in Twins

Multifetal reduction increases the risk of preterm delivery and fetal growth restriction in twins: A case-control study

To compare pregnancy outcome in twin gestations resulting from multifetal reduction to "primary" twin pregnancies derived from either spontaneous conception or infertility therapy. Case-control study. University-affiliated tertiary center. Multifetal pregnancies (quadruplets or more) reduced to twins (group A) compared with twin gestations conceived either spontaneously (group B) or through infertility therapy (group C). Multifetal reduction for group A; perinatal care for groups A, B, and C. Comparison of perinatal complications between groups including antepartum bleeding, premature membrane rupture, and preterm labor. Neonatal outcomes compared including gestational age at delivery, birth weight, incidence of fetal growth restriction, and twin discordancy. A higher incidence of idiopathic preterm labor was noted in group A cases (14/18) compared with either of the control groups (B: 26/54, or C: 24/54). As a consequence, group A had the lowest gestational age at delivery (32.6 +/- 3.9 weeks) compared with groups B (33.6 +/- 4.4 weeks) and C (36.0 +/- 3.4 weeks). Corresponding birth weights of both first- and second-born twins were significantly lower in group A compared with group C, whereas the birth weight comparison between groups A and B showed a nonsignificant difference. The proportion of pregnancies in which one or both twins weighted less than the 10th percentile was greatest in group A pregnancies (A: 5/18 versus C: 5/54). Discordant birth weight among twin pairs was proportionately greater for group A cases at both the 20% and 30% discordance levels. Twin gestations resulting from multifetal reduction are at increased risk for preterm birth, fetal growth restriction, and discordancy when compared with fertility therapy-derived, nonreduced twins.

Low Birthweight — United States, 1975-1987

PregnancyoutcomesintheUnitedStatesandotherdevelopedcountries are considerably better than those in many developing countries. However, adverse pregnancy outcomes are generally more common in the United States than in other developed countries. Low-birth-weight infants, born after a preterm birth or secondary to intrauterine growth restriction, account for much of the increased morbidity,mortality,andcost.Widedisparitiesexistinbothpreterm birthandgrowthrestrictionamongdifferentpopulationgroups.Poor andblackwomen,forexample,havetwicethepretermbirthrateand higher rates of growth restriction than do most other women. Low birthweightingeneralisthoughttoplacetheinfantatgreaterriskof later adult chronic medical conditions, such as diabetes, hypertension, and heart disease. Of interest, maternal thinness is a strong predictor of both preterm birth and fetal growth restriction. However,intheUnitedStates,severalnutritionalinterventions,including high-protein diets, caloric supplementation, calcium and iron supplementation, and various other vitamin and mineral supplementations,havenotgenerallyreducedpretermbirthorgrowthrestriction. Bacterial intrauterine infections play an important role in the etiology of the earliest preterm births, but, at least to date, antibiotic treatment either before labor for risk factors such as bacterial vaginosis or during preterm labor have not consistently reduced the preterm birth rate. Most interventions have failed to reduce preterm birthorgrowthrestriction.Thesubstantialimprovementinnewborn survival in the United States over the past several decades is mostly due to better access to improved neonatal care for low-birth-weight infants. Am J Clin Nutr 2007;85(suppl):584S–90S.