This is a prospective study on pregnancies referred to a tertiary hospital with suspicion of SGA fetus. Patients were followed up in a special SGA clinic and they delivered in the same hospital.
Inclusion study criteria were: singleton pregnancy with no indication for nor signs of imminent delivery, fetal abdominal circumference (AC) at or below the 10th centile and/or estimated fetal weight (EFW) at or below the 10th centile and/or umbilical artery pulsatility index (UA-PI) at or above the 90th centile for gestation. Women with pre-eclampsia at presentation were excluded.
In the first visit (index visit) maternal and paternal demographics were recorded and maternal blood was drawn for analysis. The following fetal/maternal parameters were recorded: bi-parietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), estimated fetal weight (EFW), deepest pool of amniotic fluid, umbilical artery pulsatility index (Umb-PI), middle cerebral artery pulsatility index (MCA-PI), ductus venosus pulsatility index (DV-PI), mean uterine artery pulsatility index (Ut-PI), systolic and diastolic blood pressure.
Fetal measurements were obtained according to the ISUOG guidelines [5]. Maternal blood pressure was measured with automated device (Microlife, AG). Pregnant women were seated in a relaxed position with the left arm placed comfortably at the level of the heart and the second of two consecutive measurements was recorded.
Maternal serum was stored at -4°C and analyzed in retrospect. PLGF was measured with the Kryptor assay (Brahms Kryptor Compact PLUS) and PLGF results were converted to multiples of the median using the Fetal Medicine Foundation calculator of risk for pre-eclampsia (freely available form https://fetalmedicine.org). The results of PLGF were not made available to the clinicians.
Centiles were used for the analysis of the fetal parameters based on locally used charts.
Indications for iatrogenic delivery were pre-eclampsia, placental abruption and fetal deterioration based on Doppler studies and/or cardiotocograph. Before 32 weeks decision for delivery for fetal reasons was based on ductus venosus pulsatility index consistently increased above the 95th centile. Between 32 and 35 weeks absent or reversed end diastolic flow in the umblical artery or redistribution with CPR ≤ 5th centile accompanied by non-reactive trace in at least two separate examinations prompted delivery. After 36 weeks indications for delivery were increased umbilical artery PI ≥ 95th centile, reduced middle cerebral artery PI ≤ 5th centile, non-reactive trace or oligohydramnios.
The outcomes examined were preterm delivery < 37 weeks, iatrogenic preterm delivery < 37 weeks (because of fetal and/or maternal reasons)/intra-uterine death, pre-eclampsia (defined as sustained elevated blood pressure ≥ 140/90 mmHg and significant proteinuria ≥ 300mgr in 24h urine collection or other end organ damage), birthweight centile, delivery of an SGA ≤ 5th centile neonate and admission to the neonatal intensive care unit (NICU) [6].
The study was approved by the local ethics committee of the University of Athens Medical School and eligible women provided written informed consent.
Statistical analysis
Normal distributed variables are expressed as mean (standard deviation), while variables with skewed distribution are expressed as median (interquantile range). Qualitative variables are expressed as absolute and relative frequencies. For the comparison of proportions chi-square and Fisher’s exact tests were used. If the normality assumption was satisfied for the comparison of means between two groups, Student’s t-test was employed. Mann-Whitney test was used for the comparison of continuous variables between two groups when the distribution was not normal and Kruskall-Wallis test was used for the comparison of means of continuous variables among more than two groups. Spearman correlations coefficients (rho) were used to explore the association of two continuous variables. Multiple linear regression analysis was used with dependent the birth weight centile in a stepwise method (p for entry 0.05, p for removal 0.10). Adjusted regression coefficients (β) with standard errors (SE) were computed from the results of the linear regression analyses. Log transformations were made in linear regression analysis since birth weight centile was not normally distributed. Logistic regression analysis in a stepwise method (p for entry 0.05, p for removal 0.10) was used in order to find independent factors associated with the other dependent variables. Adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were computed from the results of the logistic regression analyses. ROC curves were created in order to estimate the prognostic ability of PLGF and calculate optimal cut-offs. All reported p values are two-tailed. Statistical significance was set at p < 0.05 and analyses were conducted using SPSS statistical software (version 22.0).