The Danish newborn standard and the International Fetal and Newborn Growth Consortium for the 21st Century newborn standard: a nationwide register-based cohort study.

BACKGROUND: It is a matter of debate whether 1 universal standard, such as the International Fetal and Newborn Growth Consortium for the 21st Century standard, can be applied to all populations. OBJECTIVE: The primary objective was to establish a Danish newborn standard based on the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard to compare the percentiles of these 2 standards. A secondary objective was to compare the prevalence and risk of fetal and neonatal deaths related to small for gestational age defined by the 2 standards when used in the Danish reference population. STUDY DESIGN: This was a register-based nationwide cohort study. The Danish reference population included 375,318 singletons born at 33 to 42 weeks of gestation in Denmark between January 1, 2008, and December 31, 2015. The Danish standard cohort included 37,811 newborns who fulfilled the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard. Birthweight percentiles were estimated using smoothed quantiles for each gestational week. The outcomes included birthweight percentiles, small for gestational age (defined as a birthweight of 3rd percentile), and adverse outcomes (defined as either fetal or neonatal death). RESULTS: At all gestational ages, the Danish standard median birthweights at term were higher than the International Fetal and Newborn Growth Consortium for the 21st Century standard median birthweights: 295g for females and 320 g for males. Therefore, the estimates of the prevalence rate of small for gestational age within the entire population were different: 3.9% (n=14,698) using the Danish standard vs 0.7% (n=2640) using the International Fetal and Newborn Growth Consortium for the 21st Century standard. Accordingly, the relative risk of fetal and neonatal deaths among small-for-gestational-age fetuses differed by SGA status defined by the different standards (4.4 [Danish standard] vs 9.6 [International Fetal and Newborn Growth Consortium for the 21st Century standard]). CONCLUSION: Our finding did not support the hypothesis that 1 universal standard birthweight curve can be applied to all populations.

T2* weighted fetal MRI and the correlation with placental dysfunction.

INTRODUCTION: Transverse relaxation time (T2*) is related to tissue oxygenation and morphology. We aimed to describe T2* weighted MRI in selected fetal organs in normal pregnancies, and to investigate the correlation between fetal organ T2* and placental T2*, birthweight (BW) deviation, and redistribution of fetal blood flow. METHODS: T2*-weighted MRI was performed in 126 singleton pregnancies between 23+6- and 41+3-weeks' gestation. The T2* value was obtained from the placenta and fetal organs (brain, lungs, heart, liver, kidneys, and spleen). In normal BW pregnancies (BW > 10th centile), the correlation between the T2* value and gestational age (GA) at MRI was estimated by linear regression. The correlation between fetal organ Z-score and BW group was demonstrated by boxplots and investigated by analysis of variance (ANOVA) for each organ. RESULTS: In normal BW pregnancies fetal organ T2* was negatively correlated with GA. We found a significant correlation between BW group and fetal organ T2* z-score in the fetal heart, kidney, lung and spleen. A positive linear correlation was demonstrated between fetal organ T2* and outcomes related to placental function such as BW deviation and placenta T2* in all investigated fetal organs except for the fetal liver. In the fetal heart, kidneys, and spleen the T2* value showed a significant correlation with fetal redistribution of blood flow (Middle cerebral artery Pulsatility Index) before delivery. DISCUSSION: Fetal T2* is correlated with BW, placental function, and redistribution of fetal blood flow, suggesting that fetal organ T2* reflects fetal oxygenation and morphological changes related to placental dysfunction.

T2*-weighted placental magnetic resonance imaging: a biomarker of placental dysfunction in small-for-gestational-age pregnancies.

BACKGROUND: The antenatal identification of placental dysfunction in small-for-gestational-age fetuses with normal fetal Doppler flows remains an obstetrical challenge. In a significant fraction of such pregnancies, placental dysfunction is revealed by clinical manifestations such as preeclampsia, preterm delivery, or severe small-for-gestational-age at birth or by abnormal findings in the postnatal placental histologic examination. Therefore, new methods to identify placental function directly in pregnancy at the time of small-for-gestational-age diagnosis is highly needed. T2*-weighted placental magnetic resonance imaging is sensitive to changes in placental morphology and oxygenation and is thereby related to placental function. Previous studies have demonstrated that pregnancies complicated by low birthweight and preeclampsia are characterized by low placental T2* values. However, the specific performance of placental T2* in the prediction of placenta-related outcomes in small-for-gestational-age pregnancies with normal fetal Doppler flows remains to be explored. OBJECTIVE: In small-for-gestational-age pregnancies with normal fetal Doppler flows, we aimed to evaluate T2*-weighted placental magnetic resonance imaging as an antenatal biomarker of placental dysfunction. In addition, we aimed to investigate the correlation between placental T2* and Doppler flow measurements of fetal and uterine arteries at the time of magnetic resonance imaging. STUDY DESIGN: In this prospective cohort study, the inclusion criterion was suspected small-for-gestational-age (ultrasound estimated fetal weight Z-score ≤-2.0 [2.3rd centile]) with normal fetal Doppler flows (middle cerebral artery pulsatility index Z-score > -2.0 and umbilical artery pulsatility index Z-score <2.0). The T2*-weighted placental magnetic resonance imaging scan was performed at inclusion in a 1.5 T system. The outcomes was placental dysfunction at birth defined by low birthweight (Z-score ≤-2.0), preeclampsia, preterm delivery (gestational age<37 weeks), or abnormal placental histologic examination such as placental vascular malperfusion according to the Amsterdam Consensus Statement. RESULTS: We included 92 pregnancies at 26+5 to 39+6 weeks gestation. The median time interval between the magnetic resonance imaging scan and birth was 4.6 weeks (interquartile range, 2.7-7.8 weeks). At birth, 55% (51/92) of pregnancies revealed at least 1 sign of placental dysfunction; 49% (40/81) had abnormal placental histologic examination, 29% (27/92) were born with low birthweight, 13% (12/92) were delivered preterm, and 7% (6/92) had preeclampsia. When adjusted for gestational age at magnetic resonance imaging, the placental T2* Z-score was a significant predictor of abnormal placental histologic examination (area under the curve, 0.73; P=.001), small-for-gestational-age at birth (area under the curve, 0.63; P=.030), preeclampsia (area under the curve, 0.88; P=.005), and preterm delivery (area under the curve, 0.81; P=.001). The placental T2* was reduced in pregnancies with a combination of clinical manifestations and abnormal placental histologic examination (T2* Z-score=-1.52±1.35 [mean±standard deviation]; P=.0001) and in clinically uneventful pregnancies with abnormal placental histologic examination (T2* Z-score=-0.79±0.97; P=.045). At the time of magnetic resonance imaging, the placental T2* Z-score showed a significant linear correlation with the uterine artery pulsatility index Z-scores (r=-0.24; P=.016) and the middle cerebral artery pulsatility index Z-scores (r=0.29; P=.017) but not with the umbilical artery pulsatility index Z-scores (r=0.18; P=.17) and the cerebroplacental ratio (r=0.03; P=.77). CONCLUSION: This study indicates that placental dysfunction is frequent in small-for-gestational-age fetuses with normal fetal Doppler flows. In this cohort, T2*-weighted placental magnetic resonance imaging is a sensitive biomarker of placental dysfunction regardless of the clinical manifestations. This finding supports a paradigm shift in the conception of placental dysfunction that may cover a wide spectrum of clinical and subclinical manifestations.

Perfusion fraction derived from IVIM analysis of diffusion-weighted MRI in the assessment of placental vascular malperfusion antenatally.

INTRODUCTION: Specific placental pathologies that may impact fetal development, such as vascular malperfusion, are diagnosed postpartum. We aimed to evaluate if placental perfusion fraction (f) derived from intravoxel incoherent motion (IVIM) analysis of diffusion-weighted magnetic resonance imaging (DWI) can be used to identify specific types of placental vascular malperfusion antenatally. METHOD: 93 women who underwent placental DWI with multiple b-values at 23.9-41.3 week's gestation and postpartum histological examination were identified in the local placental MRI research database. Based on the placental examination, 44 were defined as normal controls and 49 cases had placental vascular malperfusion. Vascular malperfusion was subdivided into fetal vascular malperfusion (n = 13), maternal vascular malperfusion (n = 30) or both (n = 6). For each placenta, regions of interest were drawn on three placental slices and their mean f was estimated using intravoxel incoherence motion analysis. RESULTS: In normal placentas mean f was 26.0 ± 4.6% (mean ± SD) and no linear correlation between f and gestational age was found, r = -0.05, p = 0.72. Placentas with fetal vascular malperfusion showed a significantly lower f (22.7 ± 4.4%) compared to normal controls, p = 0.03. In cases of maternal vascular malperfusion (25.2 ± 6.4%), no significant difference in f was revealed, p = 0.55. CONCLUSIONS: These results indicate that placental DWI-derived f may identify fetal vascular malperfusion in vivo. This study confirms a previous pilot study and provides initial evidence that fetal and maternal vascular malperfusion have different MRI signatures. Future studies are needed to further explore the clinical significance of this interesting finding.

Placental MRI: Longitudinal relaxation time (T1) in appropriate and small for gestational age pregnancies.

OBJECTIVE: The antenatal detection of small for gestational age (SGA) pregnancies is a challenge, which may be improved by placental MRI. The longitudinal relaxation time (T1) is a tissue constant related to tissue morphology and tissue oxygenation, thereby placental T1 may be related to placental function. The aim of this study is to investigate placental T1 in appropriate for gestational age (AGA) and SGA pregnancies. METHODS: A total of 132 singleton pregnancies were retrieved from our MRI research database. MRI and ultrasound estimated fetal weight (EFW) was performed at gestational week 20.6-41.7 in a 1.5 T system. SGA was defined as BW ≤ -15% of the expected for gestational age (≤10th centile). A subgroup of SGA pregnancies underwent postnatal placental histological examination (PHE) and abnormal PHE was defined as vascular malperfusion. The placental T1 values were converted into Z-scores adjusted for gestational age at MRI. The predictive performance of placental T1 and EFW was compared by receiver operating curves (ROC). RESULTS: In AGA pregnancies, placental T1 showed a negative linear correlation with gestational age (r = -0.36, p = 0.004) Placental T1 was significantly reduced in SGA pregnancies (mean Z-score = -0.34) when compared to AGA pregnancies, p = 0.03. Among SGA pregnancies placental T1 was not reduced in cases with abnormal PHE, p = 0.84. The predictive performance of EFW (AUC = 0.84, 95% CI, 0.77-0.91) was significantly stronger than placental T1 (AUC = 0.62, 95% CI, 0.52-0.72) (p = 0.002). DISCUSSION: A low placental T1 relaxation time is associated with SGA at birth. However, the predictive performance of placental T1 is not as strong as EFW.

T2* weighted placental MRI in relation to placental histology and birth weight.

INTRODUCTION: Placental dysfunction may be found among normal birth weight (BW) pregnancies, as indicated by abnormal histological findings in postnatal placental examination in some of these pregnancies. T2* weighted placental MRI provides non-invasive information on placental oxygenation and thereby placental function. The aim of this study was to investigate the correlation between placental T2*, BW and placental histology. METHODS: A total of 63 pregnant women underwent T2* weighted placental MRI at 15-40 week's gestation and a standardized placental histological examination (PHE). Abnormal PHE was defined by vascular malperfusion according to the Amsterdam workshop consensus. The correlation between PHE, BW z-score and T2* z-score was analyzed by logistic regression. RESULTS: Abnormal PHE was revealed in 28 pregnancies. Multiple logistic regression revealed a significant correlation between abnormal PHE and T2* z-score (OR = 0.34, p = 0.008), whereas BW z-score did not add significantly to the correlation of placental histology (OR = 0.52, p = 0.115). In BW z-score≥0, PHE was normal in 100% of pregnancies. In BW z-score ≤ -2, PHE was abnormal in 89% of pregnancies. In intermediate BW (z-score between -2 and 0), PPE was abnormal in 35% of pregnancies. In this intermediate group, placental T2* z-score was reduced (-1.52 ± 1.22 (mean SD)) when compared to normal PHE pregnancies (-0.28 ± 1.17), p = 0.006. DISCUSSION: This study demonstrates a correlation between abnormal placental histology and low placental T2* value regardless of fetal size. This indicates that T2* provides information of placental function in vivo even when fetal size is normal. This finding highlights that fetal size alone is not a valid marker of placental dysfunction.

Placental transverse relaxation time (T2) estimated by MRI: Normal values and the correlation with birthweight.

INTRODUCTION: Placental transverse relaxation time (T2) assessed by MRI may have the potential to improve the antenatal identification of small for gestational age. The aims of this study were to provide normal values of placental T2 in relation to gestational age at the time of MRI and to explore the correlation between placental T2 and birthweight. MATERIAL AND METHODS: A mixed cohort of 112 singleton pregnancies was retrieved from our placental MRI research database. MRI was performed at 23.6-41.3 weeks of gestation in a 1.5T system (TE (8): 50-440 ms, TR: 4000 ms). Normal pregnancies were defined by uncomplicated pregnancies with normal obstetric outcome and birthweight deviation within ±1 SD of the expected for gestational age. The correlation between placental T2 and birthweight was investigated using the following outcomes; small for gestational age (birthweight ≤-2 SD of the expected for gestational age) and birthweight deviation (birthweight Z-scores). RESULTS: In normal pregnancies (n = 27), placenta T2 showed a significant negative linear correlation with gestational age (r = -.91, P = .0001) being 184 ms ± 15.94 ms (mean ± SD) at 20 weeks of gestation and 89 ms ± 15.94 ms at 40 weeks of gestation. Placental T2 was significantly reduced among small-for-gestational-age pregnancies (mean Z-score -1.95, P < .001). Moreover, we found a significant positive correlation between placenta T2 deviation (Z-score) and birthweight deviation (Z-score) (R2  = .26, P = .0001). CONCLUSIONS: This study provides normal values of placental T2 to be used in future studies on placental MRI. Placental T2 is closely related to birthweight and may improve the antenatal identification of small-for-gestational-age pregnancies.

Screening for small-for-gestational-age fetuses.

INTRODUCTION: It is well established that correct antenatal identification of small-for-gestational-age (SGA) fetuses reduces their risk of adverse perinatal outcome with long-term consequences. Ultrasound estimates of fetal weight (EFWus ) are the ultimate tool for this identification. It can be conducted as a "universal screening", that is, all pregnant women at a specific gestational age. However, in Denmark it is conducted as "selective screening", that is, only on clinical indication. The aim of this study was to assess the performance of the Danish national SGA screening program and the consequences of false-positive and false-negative SGA cases. MATERIAL AND METHODS: In this retrospective cohort study, we included 2928 women with singleton pregnancies with due dates in 2015. We defined "risk of SGA" by an EFWus  ≤ -15% of expected for the gestational age and "SGA" as birthweight ≤-22% of expected for gestational age. RESULTS: At birth, the prevalence of SGA was 3.3%. The overall sensitivity of the Danish screening program was 62% at a false-positive rate of 5.6%. Within the entire cohort, 63% had an EFWus compared with 79% of the SGA cases. The sensitivity was 79% for those born before 37 weeks of gestation but only 40% for those born after 40 weeks of gestation. The sensitivity was also associated with birthweight deviation; 73% among extreme SGA cases (birthweight deviation ≤-33%) and 55% among mild SGA (birthweight deviation between -22% and -27%). False diagnosis of SGA was associated with an increased rate of induction of labor (ORadj  = 2.51, 95% CI 1.70-3.71) and cesarean section (ORadj  = 1.44, 95% CI 0.96-2.18). CONCLUSIONS: The performance of the Danish national screening program for SGA based on selective EFWus on clinical indication has improved considerably over the last 20 years. Limitations of the program are the large proportion of women referred to ultrasound scan and the low performance post-term.