https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=obgynfp

FIGO (international Federation of Gynecology and obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction

Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks’ gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

/pdf/circulating-mrnas-are-differentially-expressed-in-5bttcdjjn9.pdf

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth

Fetal growth restriction is associated with stillbirth and other adverse pregnancy outcomes, and the use of the correct weight standard is an essential proxy indicator of growth status and perinatal risk.This study aimed to assess the performance of two international birthweight standards for their ability to identify perinatal morbidity and mortality indicators associated with small for gestational age infants at term.This retrospective cohort study used data from a multicenter perinatal quality initiative, including a multiethnic dataset of 125,826 births from 2012 to 2017. Of the singleton term births, 92,622 had complete outcome data including stillbirth, neonatal death, 5-minute Apgar score <7, neonatal glucose instability and need for newborn transfer to a higher level of care or neonatal intensive care unit admission. The customized GROW and INTERGROWTH-21st birthweight standards were applied to determine small for gestational age (<10th percentile) according to their respective methods and formulae. The associations with adverse outcomes were expressed as relative risks with 95% confidence intervals and population attributable fractions.GROW and INTERGROWTH-21st classified 9578 (10.3%) and 4079 (4.4%) pregnancies as small for gestational age, respectively. For all of the outcomes assessed, GROW identified more small for gestational age infants with adverse outcomes than INTERGROWTH-21st, including more stillbirths, perinatal deaths, low Apgar scores, glucose instability, newborn seizure, and transfers to a higher level of care. Moreover, 13 of 27 stillbirths (48%) that were small for gestational age by either method were identified as small for gestational age by GROW but not by INTERGROWTH-21st. Similarly, additional cases of all other adverse outcome indicators were identified by GROW as small for gestational age, whereas INTERGROWTH-21st identified in only 1 category (glucose instability) 9 of 295 cases (3.1%), which were not identified as small for gestational age by GROW.Customized assessment using GROW resulted in increased identification of small for gestational age term infants that were at significantly increased risk of an array of adverse pregnancy outcomes. 

http://www.ajogmfm.org/article/S258993332100241X/pdf

Customized GROW vs INTERGROWTH-21st birthweight standards to identify small for gestational age associated perinatal outcomes at term

Diagnostic accuracy of fetal growth charts for placenta-related fetal growth restriction.

BACKGROUND
The assessment of birthweight for gestational age and the identification of small- and large-for-gestational age (SGA and LGA) infants remain contentious, despite the recent creation of the Intergrowth 21st Project and World Health Organisation (WHO) birthweight-for-gestational age standards.


OBJECTIVE
We carried out a study to identify birthweight-for-gestational age cut-offs, and corresponding population-based, Intergrowth 21st and WHO centiles associated with higher risks of adverse neonatal outcomes, and to evaluate their ability to predict serious neonatal morbidity and neonatal mortality (SNMM) at term gestation.


METHODS
The study population was based on non-anomalous, singleton live births between 37 and 41 weeks' gestation in the United States from 2003 to 2017. SNMM included 5-min Apgar score <4, neonatal seizures, need for assisted ventilation, and neonatal death. Birthweight-specific SNMM was modelled by gestational week using penalised B-splines. The birthweights at which SNMM odds were minimised (and higher by 10%, 50% and 100%) were estimated, and the corresponding population, Intergrowth 21st, and WHO centiles were identified. The clinical performance and population impact of these cut-offs for predicting SNMM were evaluated.


RESULTS
The study included 40,179,663 live births and 991,486 SNMM cases. Among female singletons at 39 weeks' gestation, SNMM odds was lowest at 3203 g birthweight, and 10% higher at 2835 g and 3685 g (population centiles 11th and 82nd, Intergrowth centiles 17th and 88th and WHO centiles 15th and 85th). Birthweight cut-offs were poor predictors of SNMM, for example, the cut-offs associated with 10% and 50% higher odds of SNMM among female singletons at 39 weeks' gestation resulted in a sensitivity, specificity, and population attributable fraction of 12.5%, 89.4%, and 2.1%, and 2.9%, 98.4% and 1.3%, respectively.


CONCLUSIONS
Reference- and standard-based birthweight-for-gestational age indices and centiles perform poorly for predicting adverse neonatal outcomes in individual infants, and their associated population impact is also small.

The clinical performance and population health impact of birthweight-for-gestational age indices at term gestation.

BACKGROUND: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population. METHODS AND FINDINGS: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, 10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart. CONCLUSIONS: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality.

/pdf/identification-of-the-optimal-growth-charts-for-use-in-a-egnckptjjx.pdf

Identification of the optimal growth charts for use in a preterm population: an Australian state-wide retrospective cohort study.

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Identification of the optimal growth charts for use in a preterm population: an Australian state-wide retrospective cohort study.