The added value of the sFlt-1/PlGF ratio in pregnant women with intrauterine growth restriction (IUGR) with or without preeclampsia on adverse pregnancy outcomes and neonatal morbidities: a retrospective study

The added value of the sFlt-1/PlGF ratio in pregnant women with intrauterine growth restriction (IUGR) with or without preeclampsia on adverse pregnancy outcomes and neonatal morbidities: a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The added value of the sFlt-1/PlGF ratio in pregnant women with intrauterine growth restriction (IUGR) with or without preeclampsia on adverse pregnancy outcomes and neonatal morbidities: a retrospective study Lieselot Arnouts, Karlijn Van Damme, Janne Terwingen, Dominique Mannaerts This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6612674/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Sep, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted 14 You are reading this latest preprint version Abstract BACKGROUND The sFlt-1/PlGF (soluble fms-like tyrosine kinase-1/placental growth factor) ratio in the serum of pregnant women is a predictive marker for preeclampsia (PE). PE is often associated with intrauterine growth restriction (IUGR). Overall, growth-restricted fetuses are at increased risk for neonatal morbidities and perinatal death. An increased sFlt-1/PlGF ratio may be valuable for discriminating between different causes of IUGR. The goal of this study was to investigate the added value of the sFlt-1/PlGF ratio in pregnant women with IUGR on adverse pregnancy outcomes, neonatal morbidities and mortality. METHODS This was a retrospective, monocenter, observational study conducted at the University Hospital of Antwerp. All singleton pregnancies with IUGR and known serum levels of sFlt-1/PlGF with a gestational age (GA) of 24 weeks until 37 weeks were included. The results were analyzed over a period of almost three years (January 2022 until October 2024). In total, 85 patients met the inclusion criteria, ten of whom had normal serum levels of sFlt-1/PlGF (values less than 85), whereas the other 75 patients had increased sFlt-1/PlGF ratios. The maternal characteristics, fetal and neonatal mortality rates, adverse pregnancy outcomes and neonatal morbidities of all the patients and their neonates were recorded and analyzed. RESULTS In IUGR fetuses with increased maternal serum sFlt-1/PlGF ratios, aberrant ultrasonic fetal doppler, fetal demise and obstetrical diseases such as PE are more often observed. In the group of neonates from mothers with a high sFlt-1/PlGF ratio, more neonatal morbidities, such as respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, early-onset sepsis, late-onset sepsis and retinopathy of prematurity, are observed. Nevertheless, it is important to correct those results for GA and birth weight since morbidities are more often observed in more premature neonates. CONCLUSION In patients with IUGR due to placental insufficiency, an increased sFlt-1/PlGF ratio is observed. IUGR sFlt-1/PlGF ratio maternal morbidities neonatal morbidities fetal mortality neonatal mortality Figures Figure 1 Introduction The sFlt-1/PlGF (soluble fms-like tyrosine kinase receptor-1/placental growth factor) ratio has been studied extensively as a predictive marker for preeclampsia (PE). The ratio represents the equilibrium among antiangiogenic factors (sFlt-1) and proangiogenic factors (PlGF). It can be measured in the serum of pregnant women. The ratio is directly related to the onset and severity of PE.( 1 ) Many studies on this topic have been published. However, the added value for neonatal outcomes has not yet been studied in detail. Intrauterine growth restriction (IUGR), a multicausal condition, is an important cause of fetal and neonatal morbidity and mortality. It affects 10–15% of all pregnancies worldwide.( 2 ) It has been defined as diminished growth velocity or the inability of the fetus to achieve its genetically determined growth potential.( 3 ) On the other hand, small for gestational age (SGA) refers to the size of the infant. It is a neonatal classification that describes newborns with a birth weight below the 10th percentile of a population-specific birth weight for a specific GA. Both IUGR and SGA are used synonymously for years in the literature despite the abovementioned distinction. In practice, it is important to differentiate between these two variables because IUGR reflects fetal distress, whereas SGA provides only a measure of size.( 4 ) Not all IUGR infants are SGA, and the other way around. The origin of IUGR can be fetal (e.g., multiple pregnancies, structural malformations, or infectious diseases such as cytomegalovirus and rubella), maternal (e.g., undernutrition, hypertension, PE, or substance use), placental or genetic (e.g., chromosomal abnormalities). Additionally, this can be due to a combination of any of these factors.( 3 ) Various factors for each origin are widely prescribed in the literature( 3 , 5 ). Mostly, IUGR is secondary to uteroplacental insufficiency.( 6 , 7 ) It describes reduced oxygen flow and nutrient transfer to the fetus.( 8 ) Uteroplacental insufficiency arises from conditions that interfere with placental vascular development.( 9 ) However, in up to 60% of cases, placental insufficiency is idiopathic.( 8 ) Angiogenesis is a placental function described as the development of new vascular structures.( 10 ) It is involved in the development of the villous vasculature and the formation of terminal villi in the human placenta. Vascular endothelial growth factor (VEGF) was one of the first angiogenic factors identified.( 11 ) It is widely believed to be the most important regulator of both normal and pathological angiogenesis.( 12 ) The activity of VEGF is inhibited by sFlt-1.( 6 ) The endogenous protein sFlt-1 captures and inactivates not only the proangiogenic protein VEGF but also the proangiogenic protein PlGF.( 13 ) Consequently, increased levels of sFlt-1 cause decreased levels of VEGF and PlGF.( 13 ) VEGF and PlGF receptors are found on the vascular wall in the placenta and in the maternal cardiovascular system. A hypoxic placenta produces high levels of sFlt-1, leading to systemic maternal endothelial dysfunction and resulting in hypertension. The literature describes increased maternal serum levels of sFlt-1 in patients with PE and IUGR.( 6 , 14 – 16 ) The sFlt-1/PlGF ratio has been widely used as a diagnostic tool for PE. A recent systematic review and meta-analysis revealed that an increased sFlt-1/PlGF ratio, defined as a value greater than or equal to 85, could be a potential predictor for IUGR and IUGR with PE, but more research is still necessary.( 17 ) A total of 238 IUGR cases and 101 IUGR with PE cases and 5111 controls were included in the abovementioned review and meta-analysis.( 17 ) The diagnosis of IUGR of uteroplacental origin is made after the most common genetic and infectious etiologies are excluded via amniocentesis. An elevated sFlt-1/PlGF ratio is associated with early-onset IUGR and even higher values if there is concurrent PE.( 18 ) Serial measurements of the ratio are of limited usefulness.( 18 ) Identifying IUGR is critical since infants have a fourfold greater risk of perinatal death and experience worse neurodevelopmental outcomes. The more severely a fetus is growth restricted, the greater the risk of fetal death.( 5 ) Growth-restricted fetuses redistribute their blood flow to vital organs such as the brain, myocardium and adrenal glands. This can be detected by altered flows in the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and uterine artery (UtA). An absent or reversed end-diastolic flow of the UA is a serious risk factor for adverse outcomes.( 5 ) Even after birth, risks are not over. Neonates born with growth restriction are at increased risk for complications, including hypoglycemia and hyperglycemia, sepsis, hypothermia, intraventricular hemorrhage (IVH), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), persistent pulmonary hypertension of the neonate (PPHN) and neonatal death.( 5 , 19 ) In the long-term, IUGR is associated with an increased risk of adverse infant outcomes and diseases in adulthood, such as hypertension, metabolic syndrome, insulin resistance, type 2 diabetes mellitus, coronary heart disease and stroke.( 5 , 7 , 19 ) Less is known about the sFlt-1/PlGF ratio and neonatal outcomes. There is growing interest in this topic, but few studies have been published.( 6 , 20 , 21 ) The first study included only 25 pregnant women.( 6 ) Pregnant women with IUGR or PE were included. They concluded that a high sFlt-1/PlGF ratio is associated with poor pregnancy and neonatal outcomes.( 6 ) The second study is a more recent and prospective observational multicenter cohort study that included 192 pregnant women with SGA.( 20 ) Kosińska-Kaczyńska K. et al. concluded that the sFlt-1/PlGF ratio seems to be an efficient predictive tool in adverse outcome risk assessment.( 20 ) The sFlt-1/PlGF ratio had a correlation of 0.6 with adverse outcomes. An elevated ratio results in high sensitivity (85.1%) but low specificity (35.9%).( 20 ) Shim SH. et al. investigated the predictive value of the sFlt-1/PlGF ratio for poor neonatal outcomes in SGA fetuses.( 21 ) They conducted a prospective study with SGA fetuses and a control group. They concluded that a higher ratio at 29–36 weeks and 6 days of GA was observed in SGA fetuses with poor outcomes than in the control group.( 21 ) This study even reported a cutoff of 28.15 at 29–36 weeks and 6 days of GA as a predictor of adverse neonatal outcomes in SGA neonates (sensitivity = 76.9%, specificity = 88%).( 21 ) More research is necessary to investigate the added value of the sFlt-1/PlGF ratio as an angiogenic biomarker of neonatal outcomes. The sFlt-1/PlGF ratio can be used in combined methods for the prediction and prevention of adverse pregnancy and neonatal outcomes. In the future, the sFlt-1/PlGF ratio may be valuable for counseling parents with a growth-restricted fetus. An elevated sFlt-1/PlGF ratio may play a role in discriminating between different origins of IUGR, whereas an elevated sFlt-1/PlGF ratio indicates placental origin. Moreover, the indications for amniocentesis could be determined more strictly. For example, if a patient with IUGR has an elevated sFlt-1/PlGF ratio, there is an indication for placental insufficiency, so amniocentesis would not be of any added value. Methods Aim of the study The purpose of this study was to investigate the added value of the sFlt-1/PlGF ratio in singleton pregnancies with IUGR with or without PE on adverse pregnancy outcomes, neonatal morbidities and mortality. Study design and setting This study is a retrospective, monocenter, observational study. The patients were enrolled at the University Hospital of Antwerp in the Gynecology and Neonatal Intensive Care Unit. Three investigators collected data in retrospect. Two investigators from the Department of Gynecology collected maternal data, and one investigator from the neonatal intensive care unit collected neonatal data. The data were not blinded. Study population All singleton pregnancies with IUGR and known serum sFlt-1/PlGF ratios were included. The IUGR is defined as published by Gordijn et al. (Table 1 ).( 22 ) Pregnancies with genetic or infectious causes of IUGR were excluded. Pregnancies at a GA of 24–37 weeks were included. The inclusions were separated into two groups, namely, patients with normal levels and those with increased levels. The cutoff for an increased sFlt-1/PlGF ratio was 85. The exclusion criteria were multiple pregnancies, women aged younger than 18 years and older than 40 years and fetuses with ultrasonic structural abnormalities. Multiple pregnancies are excluded because of the increased risk of PE, IUGR and preterm birth. The exclusion criteria were minimized to optimize the inclusion criteria. An interval of less than 21 days between the determination of the sFlt-1/PlGF ratio and giving birth was maintained for patients whose values were normal. This was done to avoid incorrect inclusions. For patients with an increased sFlt-1/PlGF ratio, an interval longer than 21 days between determination and giving birth was used. Table 1 Consensus-based definitions for early and late fetal growth restriction (FGR) in the absence of congenital anomalies.( 22 ) Early FGR: GA < 32 weeks, in absence of congenital anomalies Late FGR:GA ≥ 32 weeks, in absence of congenital anomalies AC/EFW < 3rd centile or UA-AEDF AC/EFW < 3rd centile Or Or at least two out of three of the following 1. AC/EFW < 10th centile combined with 1. AC/EFW 95th centile and/or 2. AC/EFW crossing centiles > 2 quartiles on growth centiles * 3. UA-PI > 95th centile 3. CPR 95th centile * Growth centiles are noncustomized centiles. AC = fetal abdominal circumference; AEDF = absent end-diastolic flow; CPR = cerebroplacental ratio; EFW = estimated fetal weight; GA = gestational age; PI = pulsatility index; UA = umbilical artery; UtA = uterine artery. Data registration and protection Data protection was pursued. Patients received a study number to protect their personal data and to assure anonymity. All the substantive data for the study were recorded in another file, so connection with the personal information of the patient was not possible. Data collection and analysis Data collection was performed by three investigators. The laboratory provided a file with all the documented sFlt-1/PlGF ratios from maternal serum during the inclusion period. Inclusion was performed from January 2022 until October 2024. The sFlt-1/PlGF ratio was determined 538 times during the inclusion period. Two investigators specializing in gynecology and obstetrics met the inclusion criteria. One investigator linked the study numbers from the neonate to those of their mother. Data were gathered from the infants during the first weeks and months of their lives, with a more specific focus on the time until discharge of the Neonatology Unit at the University Hospital of Antwerp. In the first month of life, the risk of having acute morbidities is highest. Substantive knowledge is needed, so we selected specialized investigators to prevent incorrect data collection. Results Subject characteristics In total, 85 patients were included; 75 patients with increased ratios and ten patients with normal ratios met the inclusion criteria. A visual representation is shown in Figure 1. Obstetrical characteristics The days of the GA are rounded to make statistical analysis possible. It was done in the following way: the days under four were rounded down, and likewise, everything started from four was rounded above. The exact data were registered and saved by the investigator to determine the precise interval between the determination of the sFlt-1/PlGF ratio and fetal death or delivery. In the group with an increased sFlt-1/PlGF ratio, the mean sFlt-1/PlGF ratio was 437. The median GA at determination of the increased ratio was 29 weeks. Ultrasonic growth at that moment has a mean percentile of 1.3 and a median percentile of zero. The results for 14.6% of the ultrasonic dopplers are normal. The present abnormal doppler signals include an increased pulsatile index (PI) in the UA, (intermittent) absent end diastolic flow (EDF) in the UA, reversed flow in the UA, brain sparing, increased PI in the DV and decreased PI in the MCA. Brain sparing is defined as a decreased pulsatility index in the MCA and increased flow in the UA. The mean interval between establishing an increased sFlt-1/PlGF ratio and fetal delivery or death was nine days. In 58.7% of the cases, the reason for delivery was strictly fetal, mostly due to deterioration in fetal condition, declared by abnormal cardiotocography or deterioration in ultrasonic fetal doppler. In six of those cases, intrauterine fetal death occurred. One termination of pregnancy was established due to extreme IUGR. In one case, a cesarean section was performed because of spontaneous contractions caused by premature rupture of membranes with a fetus in breech. In 33.3% of the cases, deterioration of maternal condition was the reason for delivery, explained by increasing and uncontrolled hypertension and increasing clinical symptoms. For 8% of mothers, a combination of decreases in maternal and fetal conditions was the reason for fetal delivery. In the group with a normal median sFlt-1/PlGF ratio, the mean sFlt-1/PlGF ratio was 37. The mean GA for determining the ratio is 32 weeks of GA. The mean ultrasonic estimated growth percentile is two. In 20% of the patients, normal ultrasonic fetal doppler signals were observed, whereas the other patients had abnormal ultrasonic doppler signals. The mean duration between the determination of the sFlt-1/PlGF ratio and fetal delivery was five days. A 40% decrease in maternal condition is the reason for delivery. In half of the cases, deterioration of the fetal condition is the reason for delivery. Only in 10% of the cases a combination of fetal and maternal conditions are the reason for delivery. The results are shown in Table 2. Table 2: Summary of the obstetrical characteristics of both groups. Raised sFlt-1/PlGF ratio Normal sFlt-1/PlGF ratio Mean sFlt-1/PlGF ratio 437 37 Mean GA 29 weeks 32 weeks Abnormal ultrasonic doppler 85.4% 80% Mean interval between determination of sFlt-1/PlGF ratio and delivery Nine days Five days Reason for delivery 58.7% fetal 33.3% maternal 8% fetal and maternal 50% fetal 40% maternal 10% fetal and maternal sFlt-1/PlGF = soluble fms-like tyrosine kinase receptor-1/placental growth factor ; GA = gestational age. Maternal characteristics General characteristics Table 3 shows a summary of the maternal characteristics of both groups. The median age of patients with increased and normal ratios is 30 years, so the ages are comparable. The median body mass index (BMI) was comparable between the two groups. In the group with an increased ratio, 64% of the patients were nullipara. For the multipara, a maximum of five already born children are observed. Among this group, 25.9% had a history of stillbirth, 22.2% had IUGR, and 33.3% had PE. In the group with a normal ratio, 40% were nullipara. Only a 10% history of stillbirth was observed, and no other previous obstetrical diseases were described. Obstetrical disease In the group with an increased sFlt-1/PlGF ratio, PE was diagnosed in 68% of the patients, HELLP syndrome was diagnosed in 10.6% of the patients, and pregnancy-induced hypertension was detected in 13.3% of the patients. In 32% an elevated sFlt-1/PlGF ratio was observed without PE. For this interesting group, a comprehensive subanalysis is performed, as shown in Table 4. The mean sFlt-1/PlGF ratio of this group was 364, with a range of 100 until 1036. The mean GA at the moment of determination of the raised ratio was 27 weeks. The mean interval between the determination of the increased sFlt-1/PlGF ratio and giving birth was 13 days, which was greater than that of the whole study group with an elevated sFlt-1/PlGF ratio, where the mean interval was nine days. Even in seven patients, the range was greater than three weeks. One of them has the lowest increase ratio, namely, 100, and the largest interval, namely, 60 days. Almost all patients have fetal indications for giving birth. Two patients had preexisting hypertension, and antihypertensive drugs were given during pregnancy. One patient in this group terminated pregnancy because of extreme growth restrictions. In 16.7% of the group, intrauterine fetal death occurred during pregnancy because of extreme IUGR. These cases are discussed below. In this subgroup, two neonates died postnatally. These cases will be discussed in the “neonatal characteristics” section. In the group with a normal sFlt-1/PlGF ratio, 30% developed PE with the need to start antihypertensive drugs. A total of 10% had pregnancy-induced hypertension. Mode of delivery Most of the patients received a cesarean delivery, namely, 88% of the patients with a raised ratio and 90% of the patients with a normal ratio. If we excluded patients with IUFD who gave birth vaginally, 97.1% of the patients had a cesarean delivery among patients with a high sFlt-1/PlGF ratio. Medication Among patients whose ratios were increased, 76% received magnesium sulfate intravenously. Thirty percent of the patients in the group with a normal sFlt-1/PlGF ratio received magnesium sulfate intravenously. Among the group with an increased ratio, 62.6% received antihypertensive drugs. All the patients with PE received antihypertensive drugs. Three of the ten patients with preexisting hypertension did not develop PE but were indicated for antihypertensive drugs for their preexisting hypertension. The other six patients with preexisting hypertension developed PE and received antihypertensive drugs for both indications. Abuse Many data concerning substance abuse are missing. Therefore, the results can be false low. Only in 6.6% of the files was smoking registered, of which four patients stopped smoking at the beginning of their pregnancy. Alcohol abuse is not registered in any of the patients’ files. One patient used cannabis during pregnancy. None of the patients with a normal sFlt-1/PlGF ratio reported substance abuse. Fetal death In 9.3% of the patients with an increased ratio, the fetus died intrauterine because of extreme growth restriction, and even growth stop. We briefly discuss each patient. The first patient had an increased sFlt-1/PlGF ratio of 780 at 24 weeks of gestation. She gave birth almost three weeks later (at a GA of 26 weeks and 6 days) to a stillborn fetus with a birth weight of 307 grams. The second patient was diagnosed with IUGR at 23 weeks of GA and gave birth two weeks later, with a birth weight of 350 grams. The sFlt-1/PlGF ratio was 1036. The patient with the lowest value of the sFlt-1/PlGF ratio (100) and the largest interval (60 days) presented an increased ratio at 27 weeks of GA. She gave birth eight weeks later, at 35 weeks and 4 days of GA, after the IUFD of a fetus with a birth weight of 1330 grams was diagnosed. The next patient with a raised ratio of 236 had an IUFD at 25 weeks GA with birth a few days later of a fetus with a birth weight of 545 grams. The following patient was diagnosed early with IUGR, namely, at 23 weeks of GA with a ratio of 348. She gave birth three weeks later, with a birth weight of 406 grams. The latter patient received a very early diagnosis of IUGR, namely, at 23 weeks of GA. The sFlt-1/PlGF ratio was 588. Two weeks later, the fetus died intra uterine, and one day later, she gave birth to a fetus with a birthweight of 341 grams. In one case, the pregnancy was terminated because of extreme growth restriction and a fatal neonatal prognosis. Five children died postnatally. These cases will be discussed in the next chapter, “Neonatal characteristics”. None of the fetuses from patients with a normal sFlt-1/PlGF ratio died intra- or postnatally. Table 3: Maternal characteristics. Maternal characteristics Raised sFlt-1/PlGF ratio (75) Normal sFlt-1/PlGF ratio (10) Age (median – years) ( range ) 30 ( 21-39 ) 30 ( 24-38 ) BMI (median) ( range ) 28 ( 19-41 ) 31 ( 24-42 ) Parity Nulliparous ( amount) Multiparous: mean parity 64% 1 40% 1 Obstetrical history Stillbirth IUGR Hypertension (without PE) PE Preterm birth Cesarean delivery 27 multipara patients 25.9% (7) 22.2% (6) 25.9% (7) 33.3% (9) 37% (10) 40.7% (11) 6 multipara patients 16.6% (1) 0 0 0 0 71.4% (5) Preexisting hypertension 13.3% 20% Obstetrical disease PE HELLP syndrome Pregnancy induced hypertension 68% 10.6% 13.3% 30% 0 10% Mode of delivery Cesarean delivery 88% 90% Medication Magnesiumsulphate Anti-hypertensive drugs 76% 62.6% 30% 30% Abuse* Smoking Alcohol Drugs 8.0% 0 1.3% 0 0 0 IUFD Postnatal death 9.3% 6.6% 0 0 sFlt-1/PlGF = soluble fms-like tyrosine kinase receptor-1/placental growth factor; BMI = body mass index; IUGR = intrauterine growth restriction; PE = preeclampsia; HELLP= hemolysis, elevated liver enzyme levels, low platelet levels; IUFD = intrauterine fetal death. *: There are many missing data in patient files regarding substance abuse. Table 4: Subgroup of patients with increased sFlt-1/PlGF ratios without preeclampsia. Case number sFlt-1/PlGF ratio GA (weeks) at raised ratio Interval (days) Reason delivery F/M GA (weeks) at delivery Postnatal death Point of attention R.01 266 32 8 F 31 No Preexisting hypertension R.03 583 24 7 F 25 Yes R.05 165 24 22 F N.A. N.A. Termination of pregnancy due to extreme IUGR R.13 868 26 1 F 26 Yes R.20 780 23 24 F N.A. N.A. IUFD R.21 395 27 4 F 27 No R.22 297 29 6 F 30 No R.23 204 28 3 F 28 No R.26 322 30 11 F 31 No R.27 224 27 26 F 30 No R.30 144 28 30 F 32 No R.33 348 29 1 F 28 No R.34 1036 23 13 F N.A. N.A. IUFD R.41 100 27 60 M N.A. N.A. IUFD, section cause of abruptio placentae R.45 236 25 3 F N.A. N.A. IUFD R.52 525 32 0 F+M 33 No R.53 100 24 9 F 26 No R.61 129 29 2 F 30 No R.66 542 33 1 F 30 No R.67 136 30 2 F 30 No R.68 640 25 21 F 28 No R.69 121 34 1 F 34 No R.71 236 25 29 F 29 No R.72 348 23 18 F 26 No sFlt-1/PlGF = soluble fms-like tyrosine kinase receptor-1/placental growth factor; GA = gestational age; F = fetal; M = maternal; N.A. = not applicable; IUGR = intrauterine growth restriction; IUFD = intrauterine fetal death. Neonatal characteristics Neonatal morbidities associated with increased and normal sFlt-1/PlGF are summarized in Table 5. In total, 78 neonatal files were investigated. Sixty-eight neonates were from mothers with increased sFlt-1/PlGF ratios, and ten neonates were from mothers with normal sFlt-1/PlGF ratios. Neonatal death In the group with an increased sFlt-1/PlGF ratio, five patients died postnatally, but none of the patients of the group with normal sFlt-1/PlGF ratio. The first case of postnatal death was a patient with a sFlt-1/PlGF ratio of 583 at 24 weeks of GA. This was her third pregnancy with an obstetrical history of one term birth of a dysmature child by cesarean section and one miscarriage. The fetus showed IUGR with abnormal ultrasonic doppler, anhydramnion and expanded intestinal loops without any fetal movements on ultrasound. At 25 weeks of GA, a cesarean section was performed after the administration of corticosteroids and magnesium sulfate. The neonate is born with a birth weight of 400 grams. Postnatally, multiple pathologies are retained (RDS and PPHN), and major intracranial bleeding with a midline shift is observed. Owing to a poor prognosis, curative treatment was discontinued. The second patient had an obstetrical history of two miscarriages. At 26 weeks of GA, a sFlt-1/PlGF ratio of 868 was established with an already known IUGR. Amniocentesis showed normal results. Fetal growth restriction continued, and abnormal fetal doppler occurred (reversed flow of UA), resulting in hospital admission with corticosteroids. The patient developed hypertension and needed medication, so a diagnosis of PE was made. The next day, no fetal movements were observed by the patient or by ultrasound, and cardiotocography was abnormal; therefore, an urgent cesarean section was performed. Uterus bicornis was assessed during the procedure. Postnatally, the neonate had RDS, PPHN, IVH grade one, cardiac failure, prerenal kidney insufficiency and metabolic acidosis. Additionally, the neonate developed septic shock due to serratia marcescens with cardiorespiratory failure, resulting in neonatal death. The next case involved a pregnancy established by oocyte donation. It was the patients’ first pregnancy. IUGR was observed at 22 weeks of GA with abnormal ultrasonic doppler (reversed EDF AU and brainsparing). The sFlt-1/PlGF ratio of 176 was determined at 25 weeks of GA. Essential hypertension was established with antihypertensive drugs at the beginning of pregnancy. A cesarean section was performed at 26 weeks due to deterioration of the fetal condition. The neonate developed RDS with pneumothorax, drainage and intubation, IVH grade 2, late-onset sepsis, myocardhypertrophy, NEC with laparotomic partial small bowel resection, acute kidney insufficiency and secondary adrenal cortex insufficiency. There was an evolution to severe PVL (grade 3) with a poor neurological prognosis. Curative treatment was discontinued, and the neonate died. The fourth patient with neonatal death was a multipara with an obstetrical history of two miscarriages and one preterm vaginal birth at 35 weeks of GA after preterm rupture of membranes. At 23 weeks and 6 days GA, a diagnosis of PE was made. Antihypertensive drugs were started. Ultrasound revealed IUGR with abnormal ultrasonic doppler (intermittent absent flow UA and brainsparing). The sFlt-1/PlGF ratio was 536 on the day of admission to the hospital for corticosteroid administration at 23 weeks and 6 days. Deterioration of the fetal condition led to cesarean section after complete corticosteroid administration. The neonate developed RDS and sepsis with progressive circulatory failure, resulting in neonatal death. The last patient was diagnosed with IUGR at 23 weeks and 6 days of GA with an increased sFlt-1/PlGF ratio of 1014. Ultrasonic doppler investigations revealed that the brain was abnormal. The mother is known to have therapy-resistant essential hypertension. During pregnancy, HELLP was diagnosed. The patient’s blood pressure increased where intravenous antihypertensive drugs were started. Because of preterminal cardiotocography, an urgent cesarean was performed. She gave birth to a daughter at a GA of 24 weeks, with a birth weight of 400 grams. The neonate needed respiratory care; therefore, intubation was performed. Suboptimal heart function was observed when inotropic medication was started. Early- and late-onset sepsis were suspected so being treated with antibiotics. The neonate developed NEC with intestinal perforation and cardiocirculatory/respiratory problems, which caused neonatal death one week postpartum. General characteristics In both groups, no resuscitation at birth was necessary. Resuscitation is classified as thoracic compressions at birth. Nevertheless, respiratory support with intubation was necessary in 26.5% of the cases with an increased ratio and 20% of the cases with a normal ratio. The mean GA at birth was 30 weeks in the group with an increased ratio, ranging from 24 weeks to 37 weeks of GA. The group with a normal ratio had a mean GA at birth of 31 weeks, with a range from 27 weeks to 36 weeks of GA. The birth weight percentiles in the group with increased ratios varied from percentile zero to 40, with a mean of 13, and those in the group with normal ratios ranged from the 3rd--49th percentile, with a mean of 33. In the group with an increased ratio, 47.1% of the neonates were born SGA. In the group with a normal ratio, 40% of the neonates were born SGA. There was an unequal distribution of sex in both groups, with 42.6% of the males in the group with an increased ratio and 70% in the group with a normal ratio. An Apgar score of less than five at five minutes after birth was chosen as a variable because this value is a predictor of asphyxia. This was the case for 5.8% of the patients in the raised ratio group and none of the patients in the normal ratio group. The mean lactate level of the umbilical cord was comparable in both groups (4.0 in the group with an increased ratio and 3.6 in the group with a normal ratio). The pH values of the umbilical artery and at admission to the neonatal unit were also comparable. In the group of neonates from mothers with a high sFlt-1/PlGF ratio, markedly more morbidities were observed, but neonates in this group were also born at a lower GA and had a lower birth weight. Half of the patients (51.5%) had respiratory distress syndrome (RDS) and needed surfactant treatment. Bronchopulmonary dysplasia (BPD) was observed in 20.5% of the patients. Grade one BPD was observed in 35.7%, grade two BPD in 42.9%, and grade three BPD in 21.4% of the patients. (23) Grade one or two intraventricular hemorrhage (IVH) is observed in 11.8% and grade three IVH in 1.5% of patients.(24) Only 4.4% of the patients had periventricular leukomalacia (PVL), 2.9% of the patients had grade 1 PVL, and 1.5% of the patients had grade 3 PVL. (25) Sepsis is divided into early-onset (EOS) and late-onset sepsis (LOS). In 4.4% of the cases, EOS was diagnosed, and in 22.1% of the cases, LOS was diagnosed. Necrotizing enterocolitis (NEC) is observed in 5.9% of patients. Hypoglycemia in the first seven days of life, defined as a plasma glucose level lower than 45 mg/dl (milligrams/deciliter), is observed in 25% of neonates. Hyperglycemia in the first seven days of life, defined as a plasma glucose level higher than 150 mg/dl, is observed in almost half of the patients (48.5%). Retinopathy of prematurity (ROP) is established in 13.2% of patients. Hypotension requiring inotropic medication or vasopressors is present in 13.2% of neonates. Persistent pulmonary hypertension of the neonate (PPHN) was observed in only 2.9% of the patients. Most of the neonates (92.6%) had hyperbilirubinemia with the need for phototherapy. A quarter of the neonates (26.5%) needed to be intubated for respiratory support. In the group of neonates from mothers with a normal sFlt-1/PlGF ratio, the same patient had RDS, BPD grade three, PVL, LOS, hypotension with the need for inotropic drugs, hypo- and hyperglycemia and hyperbilirubinemia. The same patient also needed to be intubated. This neonate is born most prematurely, namely, at a GA of 27 weeks and two days. Moreover, this neonate is born SGA. One other neonate had RDS or BPD and was intubated. Hyperbilirubinemia was detected in 70% of the neonates, and hypoglycemia was detected in 60%. Table 5: Perinatal outcomes. Neonatal outcomes Raised sFlt-1/PlGF ratio (68) Normal sFlt-1/PlGF ratio (10) Postnatal fetal demise 7.4% 0 Resuscitation 0 0 Neonate GA (weeks – mean) ( range ) Birth weight percentile (mean and median) ( range ) SGA Gender (M/F) Apgar score <5 at 5 minutes 30 ( 24 – 37 ) p13 – p11 ( p0 – p40 ) 47.1% M = 42.6%/F = 57.4% 5.8% 31 (27 – 36 ) p33 – p34 ( p3 – p49 ) 40% M = 70%/F = 30% 0 Morbidities RDS BPD IVH PVL EOS LOS NEC Hypoglycemia Hyperglycemia ROP Hypotension PPHN Hyperbilirubinemia 51.5% 20.5% 13.2% 4.4% 4.4% 22.1% 5.9% 25% 48.5% 13.2% 13.2% 4.4% 92.6% 20% 20% 0 10% 0 10% 10% 60% 20% 0 10% 0 70% Respiratory support Intubation 26.5% 20% sFlt-1/PlGF = soluble fms-like tyrosine kinase receptor-1/placental growth factor; GA = gestational age; SGA = small for gestational age; M/F = male/female; RDS = respiratory distress syndrome; BPD = bronchopulmonary dysplasia; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; EOS = early-onset sepsis; LOS = late-onset sepsis; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity; PPHN = persistent pulmonary hypertension of the neonate. Subanalysis based on gestational age Since neonatal outcomes are influenced by GA, a subanalysis was performed on neonates born to mothers with increased sFlt-1/PlGF ratios. These data are summarized in Table 6. In this subanalysis, exact GA dates are used. Three subcategories of preterm birth are made based on GA, namely: extremely low gestational age neonates (ELGANs) = less than 28 weeks very preterm = 28 to less than 32 weeks moderate to late preterm = 32 to 37 weeks No separate subanalysis was performed on neonates born to mothers with a normal sFlt-1/PlGF ratio since the inclusion number was too limited. In this group, only one patient was born to an ELGAN, three patients were born very preterm, and the other six patients were born moderately to late preterm. Table 6: Neonatal outcomes adapted based on gestational age at the time of delivery from neonates with mothers with increased sFlt-1/PlGF ratios. Neonatal outcomes ELGAN Very preterm Moderate to late preterm Postnatal fetal demise 22.2% 0 0 Resuscitation 0 0 0 Neonate GA (weeks – mean) Birth weight percentile (mean and median) SGA Gender (M/F) Apgar score <5 at 5 minutes 26 p8 – p8 66.6% M = 33.3%/F = 66.6% 11% 30 p18 – p15 35.3% M = 47.1%/F = 52.9% 5.9% 34 p10 – p9 50% M = 43.8%/F = 56.2% 0 Morbidities RDS BPD IVH PVL EOS LOS NEC Hypoglycemia Hyperglycemia ROP Hypotension PPHN Hyperbilirubinemia 83.3% 61.1% 27.7% 5.6% 22.2% 72.2% 11.1% 22.2% 94.4% 38.9% 38.9% 16.7% 94.4% 58.8% 11.8% 5.9% 2.9% 0 8.8% 5.9% 20.6% 47.1% 5.9% 2.9% 0 94.1% 0 0 0 0 0 0 0 37.5% 6.3% 0 0 0 87.5% Respiratory support Intubation 55.5% 17.6% 6.3% ELGAN: extremely low gestational age neonate; GA = gestational age; SGA = small for gestational age; M/F = male/female; RDS = respiratory distress syndrome; BPD = bronchopulmonary dysplasia; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; EOS = early-onset sepsis; LOS = late-onset sepsis; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity; PPHN = persistent pulmonary hypertension of the neonate. The lowest mean and median growth percentiles, as well as the largest amount of SGA, are observed in the ELGAN group. Higher lactate levels in the umbilical cord were observed in the ELGAN group. The majority of ELGANs (83.3%) and very preterm neonates (58.5%) had RDS, in contrast to none of the neonates in the moderate- to late-preterm group. BPD is seen much more often in the ELGAN group. The grade of BPD (mild, moderate or severe) was determined in both the ELGAN group and the very preterm group. Additionally, IVH and PVL were observed more frequently in the ELGAN group (44.4% and 22.2%, respectively). Sepsis occurred more often in the ELGAN group, especially late-onset sepsis. EOS is only observed in the ELGAN group. The LOS was much greater, namely, in 72.2% of patients. Hypotension with the need for inotropics or vasopressors was observed more often in the ELGAN group. Intubation is performed more often in more premature neonates. Postnatal fetal death was observed only in the ELGAN group (22.2%). Discussion IUGR is an important indicator of the health status of a fetus. At this point, a diagnosis is made by ultrasound. Cardiotocography can provide additional information that reflects the well-being of the fetus at an exact moment in time. It cannot predict outcomes. An extra parameter to make a good estimation of fetal health status and even to predict neonatal outcome is highly valuable. The sFlt-1/PlGF ratio may provide this information. It can provide additional information to pregnant people with IUGR, even in the absence of PE. Survival is the greatest point of interest in healthcare. In our research, we observed only intrauterine death and postnatal death in pregnant women with increased sFlt-1/PlGF ratios. Even in one case, a termination of pregnancy was performed due to extreme IUGR and a fatal prognosis. In four cases, the IUGR was diagnosed very early, namely, at 23 weeks of GA. Those patients gave birth to stillborn fetuses two to four weeks after the diagnosis of IUGR. Only one patient had an interval of eight weeks between the diagnosis of IUGR and fetal death. This is the only patient who gave birth moderately to late preterm, namely, at 35 weeks and 4 days of GA. The other patients gave birth before 27 weeks of GA. The GA itself is also an important parameter for the risk of IUFD. Postnatal deaths were also observed only in neonates born before 28 weeks of GA. In the group with a normal ratio, no intrauterine or postnatal death was observed. In that way, the sFlt-1/PlGF ratio can be of added value for estimating survival. In the group with an increased ratio, more obstetrical diseases are observed; for example, 68% of the patients are diagnosed with PE. This percentage is particularly higher than that reported in previous studies, whereas only 38.5% of the women with increased sFlt-1/PlGF ratios were diagnosed with PE.( 6 ) This may be due to a change in the diagnostic criteria for PE. Proteinuria is no longer mandatory, but hypertension with signs of organ dysfunction, such as IUGR, can also be used to diagnose PE.( 26 ) HELLP syndrome was diagnosed only in the group with an increased sFlt-1/PlGF ratio. In contrast, in the group with a normal ratio, 30% of the patients were diagnosed with PE without increased sFlt-1/PlGF. These findings indicate that increased sFlt-1/PlGF ratio is not mandatory for the diagnosis of PE. These three patients received antihypertensive drugs. Two of these three patients had preexisting hypertension and received aspirin as medication. Magnesium sulfate was given more often to patients with an increased sFlt-1/PlGF ratio because of maternal indication (PE) and for fetal indication (neuroprotection when giving birth before 32 weeks of GA). Cesarean delivery was performed most of the time in both groups. The indication for giving birth was mostly due to a decline in fetal condition, but maternal indications were also present, mostly uncontrolled hypertension or an increase in PE-related complaints. There was a discrepancy in the time of delivery between the two groups. In the group with an increased ratio, 23.5% gave birth moderately to late preterm, half of the patients very preterm and 26.5% ELGANs. In the group with a normal sFlt-1/PlGF ratio, 60% gave birth moderately to late preterm, 30% very preterm and only one patient (10%) who gave birth to an ELGAN, namely, at 27 weeks of gestation. In the study of Chang et al., some women had a normal sFlt-1/PlGF ratio and IUGR but maintained pregnancy until late preterm, and their neonates had fewer morbidities.( 6 ) We may consider the sFlt-1/PlGF ratio a biomarker for deteriorating placental function. However, more investigations are necessary to confirm this hypothesis. We observed many more perinatal morbidities in the group with a higher sFlt-1/PlGF ratio than in the group with a normal sFlt-1/PlGF ratio. RDS occurs in half of the neonates from mothers with a raised ratio, whereas it occurs in only 20% of the neonates with a normal ratio. Other morbidities, such as IVH (13.2%, 0%), EOS (4.4%, 0%), LOS (22.1%, 10%), ROP (13.2%, 0%), hypotension (13.2%, 10%) and PPHN (4.4%, 0%), are observed more often in the group with an increased ratio than in the group with a normal ratio. The presence of BPD is comparable. This can also be attributed to the younger GA of patients with increased sFlt-1/PlGF ratios, namely, a mean GA at the time of delivery of 30 weeks versus 31 weeks of GA in the group with normal ratios. PVL was significantly more common in the group with a normal ratio (10%) than in the group with an increased ratio (4.4%) but was observed only in one patient from the group with a normal ratio versus three patients from the group with an increased ratio. This is due to the limited number of patients included in the group with a normal ratio. Similar results were observed for NEC, namely, 10% of the patients had a normal ratio (one patient) versus 5.9% of the patients with an increased ratio (four patients). A possible next step is to sample serial sFlt-1/PlGF ratios in pregnant women with IUGR and correlate them with maternal and fetal morbidities. In this way, we investigated whether there was a linear correlation between the sFlt-1/PlGF ratio and mortality and neonatal morbidity. One of the patients with postnatal fetal demise has an increased sFlt-1/PlGF ratio of 176, which is not as high as that of other patients (maximum value of 1907). Patients with IUFD have a wide range of sFlt-1/PlGF ratios, ranging from 100 to 1036. The patient who underwent termination of pregnancy due to extreme IUGR had a sFlt-1/PlGF ratio of 165. Importantly, this blood sample was taken 22 days before termination. A higher value at the time of termination is very likely. Nevertheless, these findings indicate that there is no linear correlation between the sFlt-1/PlGF ratio and fetal death. Second, our research does not provide a clear general cutoff that can predict worse morbidity or mortality. If serial measurements are taken, maybe this could be determined. In addition, there was no clear correlation between a higher sFlt-1/PlGF ratio and a shorter interval to fetal delivery or death. The sFlt-1/PlGF ratio is not an indicator of the interval between establishing a high sFlt-1/PlGF ratio and the day of fetal delivery or death. The indication for delivery is independent of the sFlt-1/PlGF ratio. There were no additional maternal indications described for fetal delivery with increasing sFlt-1/PlGF ratios. In conclusion, our research does not reveal a linear correlation between the sFlt-1/PlGF ratio and fetal or neonatal mortality, neonatal morbidity, the interval to fetal delivery or death. It is important to correct for GA and birth weight. In the group with a normal sFlt-1/PlGF ratio, all neonates were born after a GA of 27 weeks, whereas in the group with a raised sFlt-1/PlGF ratio, neonates were born at 24 weeks of GA. With our inclusion numbers, it is not possible to correct for the GA in these two groups. A subanalysis for GA was performed in the group with an elevated sFlt-1/PlGF ratio, as shown in Table 6 . These findings indicate increased morbidity and mortality with lower GA. This finding supports already known knowledge and other research.( 27 , 28 ) Neonatal death occurred only in the ELGAN group. In the ELGAN group of patients with increased sFlt-1/PlGF ratios, a subanalysis was performed to investigate whether the sFlt-1/PlGF ratio could predict neonatal outcomes such as SGA or neonatal death. Table 7 shows the results with increasing sFlt-1/PlGF ratios. For example, a patient with a raised sFlt-1/PlGF ratio of 176 at 25 weeks of GA gave birth one week later. The neonate was SGA and even died. In this case, the interval between the determination of the sFlt-1/PlGF ratio and birth was only one week. In addition, the patient with a very high sFlt-1/PlGF ratio (1270) in this group gave birth at 25 weeks and four days of GA with a birthweight of 550 grams, which made the neonate SGA. The neonate did have RDS and moderate BPD but was not intubated or passed away postnatally. Given this information, we can conclude that a strong linear correlation between the sFlt-1/PlGF ratio and neonatal morbidities cannot be made in this research. Table 7 Subgroup of extremely low gestational age neonates (ELGANs): increasing sFlt-1/PlGF ratio and the presence of SGA and postnatal fetal death. sFlt-1/PlGF ratio GA at birth (weeks) GA at birth (days) SGA Postnatal fetal demise 154 26 5 167 27 3 SGA 176 26 0 SGA Yes 345 25 5 367 26 4 SGA 395 27 6 SGA 420 25 5 SGA 457 25 3 460 24 6 SGA 536 24 3 SGA Yes 583 25 2 SGA Yes 651 25 4 868 26 0 SGA Yes 1014 24 0 SGA Yes 1102 27 4 SGA 1173 25 1 SGA 1253 27 5 1270 25 4 SGA sFlt-1/PlGF = soluble fms-like tyrosine kinase receptor-1/placental growth factor; GA = gestational age; SGA = small for gestational age. The fact that few patients have a normal sFlt-1/PlGF ratio and IUGR does provide information. This finding indicates that IUGR is often associated with an increased sFlt-1/PlGF ratio and that indications for the determination of this ratio are well established. We focused on the sFlt-1/PlGF ratio and IUGR in our study since it is a serious cause of neonatal morbidity and even mortality. Nevertheless, sFlt-1 and PlGF are angiogenic-related factors, so they can be meaningful in the diagnosis and follow-up of other pregnancy-related diseases, such as gestational diabetes. Further research is necessary since it was not the scope of this research. The sFlt-1/PlGF ratio can be of much greater interest than is currently known. The major limitation of this research is the limited inclusion number, namely, the group with a normal sFlt-1/PlGF ratio. However, no further statistical analysis was performed to determine whether the increased incidence of neonatal morbidities in the increased sFlt-1/PlGF ratio group was independent of prematurity itself. The second limitation is the design of the study, namely, a retrospective, monocentric, observational study. This limits inclusion numbers, especially for the group with a normal sFlt-1/PlGF ratio. The next step is to perform a prospective observational multicenter cohort study. The third limitation is the follow-up. In our study, only the results from the NICU were analyzed. A neonatal follow-up with development assessment of the children, also after dismission from the hospital, would be highly valuable. However, our study highlights the high interest in the sFlt-1/PlGF ratio in pregnant women with IUGR. We conclude that an increased sFlt-1/PlGF ratio can indicate worse neonatal outcomes and mortality. More research is necessary to further explore the added value of the sFlt-1/PlGF ratio on adverse pregnancy outcomes and neonatal mortality and morbidity in pregnant women with IUGR. Conclusion Our research highlights the great added value of the sFlt-1/PlGF ratio in predicting pregnancy and neonatal outcomes. Only patients with increased sFlt-1/PlGF ratios experienced intrauterine fetal death and postnatal death. During pregnancy, more obstetrical diseases and a greater need for medication were observed. Additionally, more neonatal morbidities were observed in patients whose mothers had higher sFlt-1/PlGF ratios. Nevertheless, owing to the limited number of inclusions in the group with a normal sFlt-1/PlGF ratio, statistically validated conclusions cannot be drawn, and no correction for GA or birth weight was possible. More advanced research with an expansion of the database is necessary. Our research indicates that the sFlt-1/PlGF ratio is an interesting angiogenic biomarker and can be of great value in predicting pregnancy and fetal outcomes in patients with IUGR. Abbreviations sFlt-1/PlGF soluble fms-like tyrosine kinase receptor-1/placental growth factor IUGR intrauterine growth restriction FGR fetal growth restriction PE preeclampsia HELLP Hemolysis, elevated liver enzyme levels, low platelet levels IUFD intrauterine fetal death VEGF Vascular endothelial growth factor BMI body mass index GA gestational age PI pulsatile index UA umbilical artery EDF end diastolic flow DV ductus venosus UtA uterine artery MCA middle cerebral artery F fetal M maternal mg/dl milligrams/deciliter N.A. not applicable SGA small for gestational age RDS respiratory distress syndrome BPD bronchopulmonary dysplasia IVH intraventricular hemorrhage PVL periventricular leukomalacia EOS early-onset sepsis LOS late-onset sepsis NEC necrotizing enterocolitis ROP retinopathy of prematurity PPHN persistent pulmonary hypertension of the neonate Declarations Ethical aspects Application for approval for this study was submitted by the Ethical Commission of the University Hospital of Antwerp. Request was submitted in July 2023 and approval was obtained in August 2023 (Attachment 1) . Since it is a retrospective study, providing an informed consent is not necessary according to the Ethical Commission of the University Hospital of Antwerp according to national regulations. More information is written down in the quality manual of the Ethical Commission of the University Hospital of Antwerp on (part two, chapter one). Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Not applicable. Author contributions Study conception: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme Writing the protocol: Dr. Lieselot Arnouts led by Prof. Dr. Dominique Mannarts Acquisition of data: Dr. Lieselot Arnouts, Janne Terwingen and Dr. Karlijn van Damme Analysis and interpretation of data: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme Critical vision: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme Acknowledgements Not applicable. References Verlohren S, Brennecke SP, Galindo A, Karumanchi SA, Mirkovic LB, Schlembach D, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens. 2022;27:42–50. Armengaud JB, Yzydorczyk C, Siddeek B, Peyter AC, Simeoni U. Intrauterine growth restriction: Clinical consequences on health and disease at adulthood. Reprod Toxicol. 2021;99:168–76. Sharma D, Shastri S, Sharma P. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6612674","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":458309202,"identity":"f74fc650-edae-4366-b582-8af6db46dec3","order_by":0,"name":"Lieselot Arnouts","email":"data:image/png;base64,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","orcid":"","institution":"Antwerp University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lieselot","middleName":"","lastName":"Arnouts","suffix":""},{"id":458309203,"identity":"d9933256-8bc2-47c7-a9a5-bc7d8bcbbb31","order_by":1,"name":"Karlijn Van Damme","email":"","orcid":"","institution":"Antwerp University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Karlijn","middleName":"Van","lastName":"Damme","suffix":""},{"id":458309204,"identity":"4ee35da0-333e-4e09-b221-84d23903e51c","order_by":2,"name":"Janne Terwingen","email":"","orcid":"","institution":"Antwerp University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Janne","middleName":"","lastName":"Terwingen","suffix":""},{"id":458309205,"identity":"f9d0b11c-c8d2-4c66-8ef8-2ee6f9296e5a","order_by":3,"name":"Dominique Mannaerts","email":"","orcid":"","institution":"Antwerp University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dominique","middleName":"","lastName":"Mannaerts","suffix":""}],"badges":[],"createdAt":"2025-05-07 14:08:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6612674/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6612674/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12884-025-08057-2","type":"published","date":"2025-09-30T15:58:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83041200,"identity":"e9f73f36-030f-4b92-ab80-a2cb44f11695","added_by":"auto","created_at":"2025-05-19 10:44:13","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":295623,"visible":true,"origin":"","legend":"\u003cp\u003eAscending sFlt-1/PlGF ratios and their values. The orange line indicates the border between the normal and increased sFlt-1/PlGF ratios (value of 85).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003esFlt-1/PlGF =\u003c/em\u003e\u003cem\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/em\u003e\u003cem\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6612674/v1/8aec33053efc47a344d87188.jpeg"},{"id":92884637,"identity":"7ee20d47-5b4b-4f22-8f71-a7251a62d57f","added_by":"auto","created_at":"2025-10-06 16:13:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1690408,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6612674/v1/8be69891-f654-43ed-bab4-e4ea4abf545d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The added value of the sFlt-1/PlGF ratio in pregnant women with intrauterine growth restriction (IUGR) with or without preeclampsia on adverse pregnancy outcomes and neonatal morbidities: a retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe sFlt-1/PlGF (soluble fms-like tyrosine kinase receptor-1/placental growth factor) ratio has been studied extensively as a predictive marker for preeclampsia (PE). The ratio represents the equilibrium among antiangiogenic factors (sFlt-1) and proangiogenic factors (PlGF). It can be measured in the serum of pregnant women. The ratio is directly related to the onset and severity of PE.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Many studies on this topic have been published. However, the added value for neonatal outcomes has not yet been studied in detail.\u003c/p\u003e \u003cp\u003eIntrauterine growth restriction (IUGR), a multicausal condition, is an important cause of fetal and neonatal morbidity and mortality. It affects 10–15% of all pregnancies worldwide.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) It has been defined as diminished growth velocity or the inability of the fetus to achieve its genetically determined growth potential.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) On the other hand, small for gestational age (SGA) refers to the size of the infant. It is a neonatal classification that describes newborns with a birth weight below the 10th percentile of a population-specific birth weight for a specific GA. Both IUGR and SGA are used synonymously for years in the literature despite the abovementioned distinction. In practice, it is important to differentiate between these two variables because IUGR reflects fetal distress, whereas SGA provides only a measure of size.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Not all IUGR infants are SGA, and the other way around.\u003c/p\u003e \u003cp\u003eThe origin of IUGR can be fetal (e.g., multiple pregnancies, structural malformations, or infectious diseases such as cytomegalovirus and rubella), maternal (e.g., undernutrition, hypertension, PE, or substance use), placental or genetic (e.g., chromosomal abnormalities). Additionally, this can be due to a combination of any of these factors.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Various factors for each origin are widely prescribed in the literature(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Mostly, IUGR is secondary to uteroplacental insufficiency.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) It describes reduced oxygen flow and nutrient transfer to the fetus.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Uteroplacental insufficiency arises from conditions that interfere with placental vascular development.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) However, in up to 60% of cases, placental insufficiency is idiopathic.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Angiogenesis is a placental function described as the development of new vascular structures.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) It is involved in the development of the villous vasculature and the formation of terminal villi in the human placenta. Vascular endothelial growth factor (VEGF) was one of the first angiogenic factors identified.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) It is widely believed to be the most important regulator of both normal and pathological angiogenesis.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) The activity of VEGF is inhibited by sFlt-1.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) The endogenous protein sFlt-1 captures and inactivates not only the proangiogenic protein VEGF but also the proangiogenic protein PlGF.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Consequently, increased levels of sFlt-1 cause decreased levels of VEGF and PlGF.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) VEGF and PlGF receptors are found on the vascular wall in the placenta and in the maternal cardiovascular system. A hypoxic placenta produces high levels of sFlt-1, leading to systemic maternal endothelial dysfunction and resulting in hypertension. The literature describes increased maternal serum levels of sFlt-1 in patients with PE and IUGR.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) The sFlt-1/PlGF ratio has been widely used as a diagnostic tool for PE. A recent systematic review and meta-analysis revealed that an increased sFlt-1/PlGF ratio, defined as a value greater than or equal to 85, could be a potential predictor for IUGR and IUGR with PE, but more research is still necessary.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) A total of 238 IUGR cases and 101 IUGR with PE cases and 5111 controls were included in the abovementioned review and meta-analysis.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) The diagnosis of IUGR of uteroplacental origin is made after the most common genetic and infectious etiologies are excluded via amniocentesis. An elevated sFlt-1/PlGF ratio is associated with early-onset IUGR and even higher values if there is concurrent PE.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Serial measurements of the ratio are of limited usefulness.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIdentifying IUGR is critical since infants have a fourfold greater risk of perinatal death and experience worse neurodevelopmental outcomes. The more severely a fetus is growth restricted, the greater the risk of fetal death.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Growth-restricted fetuses redistribute their blood flow to vital organs such as the brain, myocardium and adrenal glands. This can be detected by altered flows in the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and uterine artery (UtA). An absent or reversed end-diastolic flow of the UA is a serious risk factor for adverse outcomes.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Even after birth, risks are not over. Neonates born with growth restriction are at increased risk for complications, including hypoglycemia and hyperglycemia, sepsis, hypothermia, intraventricular hemorrhage (IVH), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), persistent pulmonary hypertension of the neonate (PPHN) and neonatal death.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) In the long-term, IUGR is associated with an increased risk of adverse infant outcomes and diseases in adulthood, such as hypertension, metabolic syndrome, insulin resistance, type 2 diabetes mellitus, coronary heart disease and stroke.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eLess is known about the sFlt-1/PlGF ratio and neonatal outcomes. There is growing interest in this topic, but few studies have been published.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) The first study included only 25 pregnant women.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Pregnant women with IUGR or PE were included. They concluded that a high sFlt-1/PlGF ratio is associated with poor pregnancy and neonatal outcomes.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) The second study is a more recent and prospective observational multicenter cohort study that included 192 pregnant women with SGA.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Kosińska-Kaczyńska K. et al. concluded that the sFlt-1/PlGF ratio seems to be an efficient predictive tool in adverse outcome risk assessment.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) The sFlt-1/PlGF ratio had a correlation of 0.6 with adverse outcomes. An elevated ratio results in high sensitivity (85.1%) but low specificity (35.9%).(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eShim SH. et al. investigated the predictive value of the sFlt-1/PlGF ratio for poor neonatal outcomes in SGA fetuses.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) They conducted a prospective study with SGA fetuses and a control group. They concluded that a higher ratio at 29–36 weeks and 6 days of GA was observed in SGA fetuses with poor outcomes than in the control group.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) This study even reported a cutoff of 28.15 at 29–36 weeks and 6 days of GA as a predictor of adverse neonatal outcomes in SGA neonates (sensitivity = 76.9%, specificity = 88%).(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eMore research is necessary to investigate the added value of the sFlt-1/PlGF ratio as an angiogenic biomarker of neonatal outcomes. The sFlt-1/PlGF ratio can be used in combined methods for the prediction and prevention of adverse pregnancy and neonatal outcomes. In the future, the sFlt-1/PlGF ratio may be valuable for counseling parents with a growth-restricted fetus. An elevated sFlt-1/PlGF ratio may play a role in discriminating between different origins of IUGR, whereas an elevated sFlt-1/PlGF ratio indicates placental origin. Moreover, the indications for amniocentesis could be determined more strictly. For example, if a patient with IUGR has an elevated sFlt-1/PlGF ratio, there is an indication for placental insufficiency, so amniocentesis would not be of any added value.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eAim of the study\u003c/p\u003e\u003cp\u003eThe purpose of this study was to investigate the added value of the sFlt-1/PlGF ratio in singleton pregnancies with IUGR with or without PE on adverse pregnancy outcomes, neonatal morbidities and mortality.\u003c/p\u003e\u003cp\u003eStudy design and setting\u003c/p\u003e\u003cp\u003eThis study is a retrospective, monocenter, observational study. The patients were enrolled at the University Hospital of Antwerp in the Gynecology and Neonatal Intensive Care Unit. Three investigators collected data in retrospect. Two investigators from the Department of Gynecology collected maternal data, and one investigator from the neonatal intensive care unit collected neonatal data. The data were not blinded.\u003c/p\u003e\u003cp\u003eStudy population\u003c/p\u003e\u003cp\u003eAll singleton pregnancies with IUGR and known serum sFlt-1/PlGF ratios were included. The IUGR is defined as published by Gordijn et al. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Pregnancies with genetic or infectious causes of IUGR were excluded. Pregnancies at a GA of 24–37 weeks were included. The inclusions were separated into two groups, namely, patients with normal levels and those with increased levels. The cutoff for an increased sFlt-1/PlGF ratio was 85. The exclusion criteria were multiple pregnancies, women aged younger than 18 years and older than 40 years and fetuses with ultrasonic structural abnormalities. Multiple pregnancies are excluded because of the increased risk of PE, IUGR and preterm birth. The exclusion criteria were minimized to optimize the inclusion criteria. An interval of less than 21 days between the determination of the sFlt-1/PlGF ratio and giving birth was maintained for patients whose values were normal. This was done to avoid incorrect inclusions. For patients with an increased sFlt-1/PlGF ratio, an interval longer than 21 days between determination and giving birth was used.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eConsensus-based definitions for early and late fetal growth restriction (FGR) in the absence of congenital anomalies.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly FGR: GA \u0026lt; 32 weeks, in absence of congenital anomalies\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLate FGR:GA ≥ 32 weeks, in absence of congenital anomalies\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAC/EFW \u0026lt; 3rd \u0026nbsp;centile\u0026nbsp;\u003cem\u003eor\u003c/em\u003e\u0026nbsp;UA-AEDF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAC/EFW \u0026lt; 3rd \u0026nbsp;centile\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOr\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOr at least two out of three of the following\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. AC/EFW \u0026lt; 10th \u0026nbsp;centile\u0026nbsp;\u003cem\u003ecombined with\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1. AC/EFW \u0026lt; 10th \u0026nbsp;centile\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. UtA-PI \u0026gt; 95th \u0026nbsp;centile\u0026nbsp;\u003cem\u003eand/or\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2. AC/EFW crossing centiles \u0026gt; 2 quartiles on growth centiles\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. UA-PI \u0026gt; 95th \u0026nbsp;centile\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3. CPR \u0026lt; 5th \u0026nbsp;centile\u0026nbsp;\u003cem\u003eor\u003c/em\u003e\u0026nbsp;UA-PI \u0026gt; 95th \u0026nbsp;centile\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e \u003cem\u003e* Growth centiles are noncustomized centiles.\u003c/em\u003e \u003c/p\u003e\u003cp\u003e \u003cem\u003eAC = fetal abdominal circumference; AEDF = absent end-diastolic flow; CPR = cerebroplacental ratio; EFW = estimated fetal weight; GA = gestational age; PI = pulsatility index; UA = umbilical artery; UtA = uterine artery.\u003c/em\u003e \u003c/p\u003e\u003cp\u003eData registration and protection\u003c/p\u003e\u003cp\u003eData protection was pursued. Patients received a study number to protect their personal data and to assure anonymity. All the substantive data for the study were recorded in another file, so connection with the personal information of the patient was not possible.\u003c/p\u003e\u003cp\u003eData collection and analysis\u003c/p\u003e\u003cp\u003eData collection was performed by three investigators. The laboratory provided a file with all the documented sFlt-1/PlGF ratios from maternal serum during the inclusion period. Inclusion was performed from January 2022 until October 2024. The sFlt-1/PlGF ratio was determined 538 times during the inclusion period. Two investigators specializing in gynecology and obstetrics met the inclusion criteria. One investigator linked the study numbers from the neonate to those of their mother. Data were gathered from the infants during the first weeks and months of their lives, with a more specific focus on the time until discharge of the Neonatology Unit at the University Hospital of Antwerp. In the first month of life, the risk of having acute morbidities is highest. Substantive knowledge is needed, so we selected specialized investigators to prevent incorrect data collection.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eSubject characteristics\u003c/h2\u003e\n\u003cp\u003eIn total, 85 patients were included; 75 patients with increased ratios and ten patients with normal ratios met the inclusion criteria. A visual representation is shown in Figure 1.\u003c/p\u003e\n\u003ch2 id=\"_Toc162873028\"\u003eObstetrical characteristics\u003c/h2\u003e\n\u003cp\u003eThe days of the GA are rounded to make statistical analysis possible. It was done in the following way: the days under four were rounded down, and likewise, everything started from four was rounded above. The exact data were registered and saved by the investigator to determine the precise interval between the determination of the sFlt-1/PlGF ratio and fetal death or delivery.\u003c/p\u003e\n\u003cp\u003eIn the group with an increased sFlt-1/PlGF ratio, the mean sFlt-1/PlGF ratio was 437. The median GA at determination of the increased ratio was 29 weeks. Ultrasonic growth at that moment has a mean percentile of 1.3 and a median percentile of zero. The results for 14.6% of the ultrasonic dopplers are normal. The present abnormal doppler signals include an increased pulsatile\u003cem\u003e\u0026nbsp;\u003c/em\u003eindex (PI) in the UA, (intermittent) absent end diastolic flow (EDF) in the UA, reversed flow in the UA, brain sparing, increased PI in the DV and decreased PI in the MCA. Brain sparing is defined as a decreased pulsatility index in the MCA and increased flow in the UA. The mean interval between establishing an increased sFlt-1/PlGF ratio and fetal delivery or death was nine days. In 58.7% of the cases, the reason for delivery was strictly fetal, mostly due to deterioration in fetal condition, declared by abnormal cardiotocography or deterioration in ultrasonic fetal doppler. In six of those cases, intrauterine fetal death occurred. One termination of pregnancy was established due to extreme IUGR. In one case, a cesarean section was performed because of spontaneous contractions caused by premature rupture of membranes with a fetus in breech. In 33.3% of the cases, deterioration of maternal condition was the reason for delivery, explained by increasing and uncontrolled hypertension and increasing clinical symptoms. For 8% of mothers, a combination of decreases in maternal and fetal conditions was the reason for fetal delivery.\u003c/p\u003e\n\u003cp\u003eIn the group with a normal median sFlt-1/PlGF ratio, the mean sFlt-1/PlGF ratio was 37. The mean GA for determining the ratio is 32 weeks of GA. The mean ultrasonic estimated growth percentile is two. In 20% of the patients, normal ultrasonic fetal doppler signals were observed, whereas the other patients had abnormal ultrasonic doppler signals. The mean duration between the determination of the sFlt-1/PlGF ratio and fetal delivery was five days. A 40% decrease in maternal condition is the reason for delivery. In half of the cases, deterioration of the fetal condition is the reason for delivery. Only in 10% of the cases a combination of fetal and maternal conditions are the reason for delivery. The results are shown in Table 2.\u003c/p\u003e\n\u003cp\u003eTable 2: Summary of the obstetrical characteristics of both groups.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRaised sFlt-1/PlGF ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal sFlt-1/PlGF ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean sFlt-1/PlGF ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003e437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean GA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003e29 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003e32 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal ultrasonic doppler\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003e85.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean interval between determination of sFlt-1/PlGF ratio and delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003eNine days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003eFive days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.2185%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReason for delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8013%;\"\u003e\n \u003cp\u003e58.7% fetal\u003c/p\u003e\n \u003cp\u003e33.3% maternal\u003c/p\u003e\n \u003cp\u003e8% fetal and maternal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.9801%;\"\u003e\n \u003cp\u003e50% fetal\u003c/p\u003e\n \u003cp\u003e40% maternal\u003c/p\u003e\n \u003cp\u003e10% fetal and maternal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003e\u003cspan id=\"_Toc193893317\"\u003esFlt-1/PlGF =\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor\u003c/em\u003e; \u003cem\u003eGA = gestational age.\u003c/em\u003e\u003c/p\u003e\n\u003ch2\u003eMaternal characteristics\u003c/h2\u003e\n\u003ch3 id=\"_Toc193893318\"\u003eGeneral characteristics\u003c/h3\u003e\n\u003cp\u003eTable 3 shows a summary of the maternal characteristics of both groups. The median age of patients with increased and normal ratios is 30 years, so the ages are comparable. The median body mass index (BMI) was comparable between the two groups. In the group with an increased ratio, 64% of the patients were nullipara. For the multipara, a maximum of five already born children are observed. Among this group, 25.9% had a history of stillbirth, 22.2% had IUGR, and 33.3% had PE. In the group with a normal ratio, 40% were nullipara. Only a 10% history of stillbirth was observed, and no other previous obstetrical diseases were described.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893319\"\u003eObstetrical disease\u003c/h3\u003e\n\u003cp\u003eIn the group with an increased sFlt-1/PlGF ratio, PE was diagnosed in 68% of the patients, HELLP syndrome was diagnosed in 10.6% of the patients, and pregnancy-induced hypertension was detected in 13.3% of the patients. In 32% an elevated sFlt-1/PlGF ratio was observed without PE. For this interesting group, a comprehensive subanalysis is performed, as shown in Table 4. The mean sFlt-1/PlGF ratio of this group was 364, with a range of 100 until 1036. The mean GA at the moment of determination of the raised ratio was 27 weeks. The mean interval between the determination of the increased sFlt-1/PlGF ratio and giving birth was 13 days, which was greater than that of the whole study group with an elevated sFlt-1/PlGF ratio, where the mean interval was nine days. Even in seven patients, the range was greater than three weeks. One of them has the lowest increase ratio, namely, 100, and the largest interval, namely, 60 days. Almost all patients have fetal indications for giving birth. Two patients had preexisting hypertension, and antihypertensive drugs were given during pregnancy. One patient in this group terminated pregnancy because of extreme growth restrictions. In 16.7% of the group, intrauterine fetal death occurred during pregnancy because of extreme IUGR. These cases are discussed below. In this subgroup, two neonates died postnatally. These cases will be discussed in the \u0026ldquo;neonatal characteristics\u0026rdquo; section.\u003c/p\u003e\n\u003cp\u003eIn the group with a normal sFlt-1/PlGF ratio, 30% developed PE with the need to start antihypertensive drugs. A total of 10% had pregnancy-induced hypertension.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893320\"\u003eMode of delivery\u003c/h3\u003e\n\u003cp\u003eMost of the patients received a cesarean delivery, namely, 88% of the patients with a raised ratio and 90% of the patients with a normal ratio. If we excluded patients with IUFD who gave birth vaginally, 97.1% of the patients had a cesarean delivery among patients with a high sFlt-1/PlGF ratio.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893321\"\u003eMedication\u003c/h3\u003e\n\u003cp\u003eAmong patients whose ratios were increased, 76% received magnesium sulfate intravenously. Thirty percent of the patients in the group with a normal sFlt-1/PlGF ratio received magnesium sulfate intravenously. Among the group with an increased ratio, 62.6% received antihypertensive drugs. All the patients with PE received antihypertensive drugs. Three of the ten patients with preexisting hypertension did not develop PE but were indicated for antihypertensive drugs for their preexisting hypertension. The other six patients with preexisting hypertension developed PE and received antihypertensive drugs for both indications.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893322\"\u003eAbuse\u003c/h3\u003e\n\u003cp\u003eMany data concerning substance abuse are missing. Therefore, the results can be false low. Only in 6.6% of the files was smoking registered, of which four patients stopped smoking at the beginning of their pregnancy. Alcohol abuse is not registered in any of the patients\u0026rsquo; files. One patient used cannabis during pregnancy. None of the patients with a normal sFlt-1/PlGF ratio reported substance abuse.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893323\"\u003eFetal death\u003c/h3\u003e\n\u003cp\u003eIn 9.3% of the patients with an increased ratio, the fetus died intrauterine because of extreme growth restriction, and even growth stop. We briefly discuss each patient. The first patient had an increased sFlt-1/PlGF ratio of 780 at 24 weeks of gestation. She gave birth almost three weeks later (at a GA of 26 weeks and 6 days) to a stillborn fetus with a birth weight of 307 grams. The second patient was diagnosed with IUGR at 23 weeks of GA and gave birth two weeks later, with a birth weight of 350 grams. The sFlt-1/PlGF ratio was 1036. The patient with the lowest value of the sFlt-1/PlGF ratio (100) and the largest interval (60 days) presented an increased ratio at 27 weeks of GA. She gave birth eight weeks later, at 35 weeks and 4 days of GA, after the IUFD of a fetus with a birth weight of 1330 grams was diagnosed. The next patient with a raised ratio of 236 had an IUFD at 25 weeks GA with birth a few days later of a fetus with a birth weight of 545 grams. The following patient was diagnosed early with IUGR, namely, at 23 weeks of GA with a ratio of 348. She gave birth three weeks later, with a birth weight of 406 grams. The latter patient received a very early diagnosis of IUGR, namely, at 23 weeks of GA. The sFlt-1/PlGF ratio was 588. Two weeks later, the fetus died intra uterine, and one day later, she gave birth to a fetus with a birthweight of 341 grams. In one case, the pregnancy was terminated because of extreme growth restriction and a fatal neonatal prognosis. Five children died postnatally. These cases will be discussed in the next chapter, \u0026ldquo;Neonatal characteristics\u0026rdquo;. None of the fetuses from patients with a normal sFlt-1/PlGF ratio died intra- or postnatally.\u003c/p\u003e\n\u003cp\u003eTable 3: Maternal characteristics.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"623\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRaised\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esFlt-1/PlGF ratio (75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esFlt-1/PlGF ratio (10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (median \u0026ndash; years) (\u003cem\u003erange\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e30 (\u003cem\u003e21-39\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e30 (\u003cem\u003e24-38\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e (median) (\u003cem\u003erange\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e28 (\u003cem\u003e19-41\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e31 (\u003cem\u003e24-42\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNulliparous (\u003cem\u003eamount)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eMultiparous: mean parity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64%\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObstetrical history\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eStillbirth\u003c/p\u003e\n \u003cp\u003eIUGR\u003c/p\u003e\n \u003cp\u003eHypertension (without PE)\u003c/p\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003cp\u003ePreterm birth\u003c/p\u003e\n \u003cp\u003eCesarean delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u003cu\u003e27 multipara patients\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e25.9% (7)\u003c/p\u003e\n \u003cp\u003e22.2% (6)\u003c/p\u003e\n \u003cp\u003e25.9% (7)\u003c/p\u003e\n \u003cp\u003e33.3% (9)\u003c/p\u003e\n \u003cp\u003e37% (10)\u003c/p\u003e\n \u003cp\u003e40.7% (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u003cu\u003e6 multipara patients\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e16.6% (1)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e71.4% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreexisting hypertension\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e13.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObstetrical disease\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003cp\u003eHELLP syndrome\u003c/p\u003e\n \u003cp\u003ePregnancy induced hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e68%\u003c/p\u003e\n \u003cp\u003e10.6%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMode of delivery\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCesarean delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedication\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMagnesiumsulphate\u003c/p\u003e\n \u003cp\u003eAnti-hypertensive drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e76%\u003c/p\u003e\n \u003cp\u003e62.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbuse*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003cp\u003eAlcohol\u003c/p\u003e\n \u003cp\u003eDrugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8.0%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8812%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal death\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.7817%;\"\u003e\n \u003cp\u003e9.3%\u003c/p\u003e\n \u003cp\u003e6.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.3371%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003esFlt-1/PlGF =\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor; BMI = body mass index; IUGR = intrauterine growth restriction; PE = preeclampsia; HELLP= hemolysis, elevated liver enzyme levels, low platelet levels; IUFD = intrauterine fetal death.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e*: There are many missing data in patient files regarding substance abuse.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTable 4: Subgroup of patients with increased sFlt-1/PlGF ratios without preeclampsia.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCase number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e\u003cstrong\u003esFlt-1/PlGF ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGA (weeks) at raised ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterval (days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReason delivery F/M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGA (weeks) at delivery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal death\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePoint of attention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003ePreexisting hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.9844%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003eTermination of pregnancy due to extreme IUGR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e868\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.9844%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003eIUFD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e395\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e297\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e1036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003eIUFD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.9844%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003eIUFD, section cause of abruptio placentae\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003eIUFD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e525\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF+M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e640\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.2324%;\"\u003e\n \u003cp\u003eR.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.9204%;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.51638%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.82839%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.9844%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.0764%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.6131%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003esFlt-1/PlGF =\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor; GA = gestational age; F = fetal; M = maternal; N.A. = not applicable; IUGR = intrauterine growth restriction; IUFD = intrauterine fetal death.\u003c/em\u003e\u003c/p\u003e\n\u003ch2 id=\"_Toc162873029\"\u003eNeonatal characteristics\u003c/h2\u003e\n\u003cp\u003eNeonatal morbidities associated with increased and normal sFlt-1/PlGF are summarized in Table 5. In total, 78 neonatal files were investigated. Sixty-eight neonates were from mothers with increased sFlt-1/PlGF ratios, and ten neonates were from mothers with normal sFlt-1/PlGF ratios.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893325\"\u003eNeonatal death\u003c/h3\u003e\n\u003cp\u003eIn the group with an increased sFlt-1/PlGF ratio, five patients died postnatally, but none of the patients of the group with normal sFlt-1/PlGF ratio. The first case of postnatal death was a patient with a sFlt-1/PlGF ratio of 583 at 24 weeks of GA. This was her third pregnancy with an obstetrical history of one term birth of a dysmature child by cesarean section and one miscarriage. The fetus showed IUGR with abnormal ultrasonic doppler, anhydramnion and expanded intestinal loops without any fetal movements on ultrasound. At 25 weeks of GA, a cesarean section was performed after the administration of corticosteroids and magnesium sulfate. The neonate is born with a birth weight of 400 grams. Postnatally, multiple pathologies are retained (RDS and PPHN), and major intracranial bleeding with a midline shift is observed. Owing to a poor prognosis, curative treatment was discontinued.\u003c/p\u003e\n\u003cp\u003eThe second patient had an obstetrical history of two miscarriages. At 26 weeks of GA, a sFlt-1/PlGF ratio of 868 was established with an already known IUGR. Amniocentesis showed normal results. Fetal growth restriction continued, and abnormal fetal doppler occurred (reversed flow of UA), resulting in hospital admission with corticosteroids. The patient developed hypertension and needed medication, so a diagnosis of PE was made. The next day, no fetal movements were observed by the patient or by ultrasound, and cardiotocography was abnormal; therefore, an urgent cesarean section was performed. Uterus bicornis was assessed during the procedure. Postnatally, the neonate had RDS, PPHN, IVH grade one, cardiac failure, prerenal kidney insufficiency and metabolic acidosis. Additionally, the neonate developed septic shock due to \u003cem\u003eserratia marcescens\u003c/em\u003e with cardiorespiratory failure, resulting in neonatal death.\u003c/p\u003e\n\u003cp\u003eThe next case involved a pregnancy established by oocyte donation. It was the patients\u0026rsquo; first pregnancy. IUGR was observed at 22 weeks of GA with abnormal ultrasonic doppler (reversed EDF AU and brainsparing). The sFlt-1/PlGF ratio of 176 was determined at 25 weeks of GA. Essential hypertension was established with antihypertensive drugs at the beginning of pregnancy. A cesarean section was performed at 26 weeks due to deterioration of the fetal condition. The neonate developed RDS with pneumothorax, drainage and intubation, IVH grade 2, late-onset sepsis, myocardhypertrophy, NEC with laparotomic partial small bowel resection, acute kidney insufficiency and secondary adrenal cortex insufficiency. There was an evolution to severe PVL (grade 3) with a poor neurological prognosis. Curative treatment was discontinued, and the neonate died.\u003c/p\u003e\n\u003cp\u003eThe fourth patient with neonatal death was a multipara with an obstetrical history of two miscarriages and one preterm vaginal birth at 35 weeks of GA after preterm rupture of membranes. At 23 weeks and 6 days GA, a diagnosis of PE was made. Antihypertensive drugs were started. Ultrasound revealed IUGR with abnormal ultrasonic doppler (intermittent absent flow UA and brainsparing). The sFlt-1/PlGF ratio was 536 on the day of admission to the hospital for corticosteroid administration at 23 weeks and 6 days. Deterioration of the fetal condition led to cesarean section after complete corticosteroid administration. The neonate developed RDS and sepsis with progressive circulatory failure, resulting in neonatal death.\u003c/p\u003e\n\u003cp\u003eThe last patient was diagnosed with IUGR at 23 weeks and 6 days of GA with an increased sFlt-1/PlGF ratio of 1014. Ultrasonic doppler investigations revealed that the brain was abnormal. The mother is known to have therapy-resistant essential hypertension. During pregnancy, HELLP was diagnosed. The patient\u0026rsquo;s blood pressure increased where intravenous antihypertensive drugs were started. Because of preterminal cardiotocography, an urgent cesarean was performed. She gave birth to a daughter at a GA of 24 weeks, with a birth weight of 400 grams. The neonate needed respiratory care; therefore, intubation was performed. Suboptimal heart function was observed when inotropic medication was started. Early- and late-onset sepsis were suspected so being treated with antibiotics. The neonate developed NEC with intestinal perforation and cardiocirculatory/respiratory problems, which caused neonatal death one week postpartum.\u003c/p\u003e\n\u003ch3 id=\"_Toc193893326\"\u003eGeneral characteristics\u003c/h3\u003e\n\u003cp\u003eIn both groups, no resuscitation at birth was necessary. Resuscitation is classified as thoracic compressions at birth. Nevertheless, respiratory support with intubation was necessary in 26.5% of the cases with an increased ratio and 20% of the cases with a normal ratio.\u003c/p\u003e\n\u003cp\u003eThe mean GA at birth was 30 weeks in the group with an increased ratio, ranging from 24 weeks to 37 weeks of GA. The group with a normal ratio had a mean GA at birth of 31 weeks, with a range from 27 weeks to 36 weeks of GA. The birth weight percentiles in the group with increased ratios varied from percentile zero to 40, with a mean of 13, and those in the group with normal ratios ranged from the 3rd--49th percentile, with a mean of 33. In the group with an increased ratio, 47.1% of the neonates were born SGA. In the group with a normal ratio, 40% of the neonates were born SGA. There was an unequal distribution of sex in both groups, with 42.6% of the males in the group with an increased ratio and 70% in the group with a normal ratio.\u003c/p\u003e\n\u003cp\u003eAn Apgar score of less than five at five minutes after birth was chosen as a variable because this value is a predictor of asphyxia. This was the case for 5.8% of the patients in the raised ratio group and none of the patients in the normal ratio group. The mean lactate level of the umbilical cord was comparable in both groups (4.0 in the group with an increased ratio and 3.6 in the group with a normal ratio). The pH values of the umbilical artery and at admission to the neonatal unit were also comparable.\u003c/p\u003e\n\u003cp\u003eIn the group of neonates from mothers with a high sFlt-1/PlGF ratio, markedly more morbidities were observed, but neonates in this group were also born at a lower GA and had a lower birth weight. Half of the patients (51.5%) had respiratory distress syndrome (RDS) and needed surfactant treatment. Bronchopulmonary dysplasia (BPD) was observed in 20.5% of the patients. Grade one BPD was observed in 35.7%, grade two BPD in 42.9%, and grade three BPD in 21.4% of the patients. (23) Grade one or two intraventricular hemorrhage (IVH) is observed in 11.8% and grade three IVH in 1.5% of patients.(24) Only 4.4% of the patients had periventricular leukomalacia (PVL), 2.9% of the patients had grade 1 PVL, and 1.5% of the patients had grade 3 PVL. (25) Sepsis is divided into early-onset (EOS) and late-onset sepsis (LOS). In 4.4% of the cases, EOS was diagnosed, and in 22.1% of the cases, LOS was diagnosed. Necrotizing enterocolitis (NEC) is observed in 5.9% of patients. Hypoglycemia in the first seven days of life, defined as a plasma glucose level lower than 45 mg/dl (milligrams/deciliter), is observed in 25% of neonates. Hyperglycemia in the first seven days of life, defined as a plasma glucose level higher than 150 mg/dl, is observed in almost half of the patients (48.5%). Retinopathy of prematurity (ROP) is established in 13.2% of patients. Hypotension requiring inotropic medication or vasopressors is present in 13.2% of neonates. Persistent pulmonary hypertension of the neonate (PPHN) was observed in only 2.9% of the patients. Most of the neonates (92.6%) had hyperbilirubinemia with the need for phototherapy. A quarter of the neonates (26.5%) needed to be intubated for respiratory support.\u003c/p\u003e\n\u003cp\u003eIn the group of neonates from mothers with a normal sFlt-1/PlGF ratio, the same patient had RDS, BPD grade three, PVL, LOS, hypotension with the need for inotropic drugs, hypo- and hyperglycemia and hyperbilirubinemia. The same patient also needed to be intubated. This neonate is born most prematurely, namely, at a GA of 27 weeks and two days. Moreover, this neonate is born SGA. One other neonate had RDS or BPD and was intubated. Hyperbilirubinemia was detected in 70% of the neonates, and hypoglycemia was detected in 60%.\u003c/p\u003e\n\u003cp\u003eTable 5: Perinatal outcomes.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"640\" style=\"margin-right: calc(1%); width: 99%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNeonatal outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRaised\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esFlt-1/PlGF ratio (68)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003esFlt-1/PlGF ratio (10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal fetal demise\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e7.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResuscitation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeonate\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eGA (weeks \u0026ndash; mean) (\u003cem\u003erange\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003eBirth weight percentile (mean and median) (\u003cem\u003erange\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003eSGA\u003c/p\u003e\n \u003cp\u003eGender (M/F)\u003c/p\u003e\n \u003cp\u003eApgar score \u0026lt;5 at 5 minutes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30 (\u003cem\u003e24 \u0026ndash; 37\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep13 \u0026ndash; p11 (\u003cem\u003ep0 \u0026ndash; p40\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e47.1%\u003c/p\u003e\n \u003cp\u003eM = 42.6%/F = 57.4%\u003c/p\u003e\n \u003cp\u003e5.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31 (27\u003cem\u003e\u0026nbsp;\u0026ndash; 36\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep33 \u0026ndash; p34 (\u003cem\u003ep3 \u0026ndash; p49\u003c/em\u003e)\u003c/p\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003cp\u003eM = 70%/F = 30%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eRDS\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003cp\u003eIVH\u003c/p\u003e\n \u003cp\u003ePVL\u003c/p\u003e\n \u003cp\u003eEOS\u003c/p\u003e\n \u003cp\u003eLOS\u003c/p\u003e\n \u003cp\u003eNEC\u003c/p\u003e\n \u003cp\u003eHypoglycemia\u003c/p\u003e\n \u003cp\u003eHyperglycemia\u003c/p\u003e\n \u003cp\u003eROP\u003c/p\u003e\n \u003cp\u003eHypotension\u003c/p\u003e\n \u003cp\u003ePPHN\u003c/p\u003e\n \u003cp\u003eHyperbilirubinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51.5%\u003c/p\u003e\n \u003cp\u003e20.5%\u003c/p\u003e\n \u003cp\u003e13.2%\u003c/p\u003e\n \u003cp\u003e4.4%\u003c/p\u003e\n \u003cp\u003e4.4%\u003c/p\u003e\n \u003cp\u003e22.1%\u003c/p\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003cp\u003e48.5%\u003c/p\u003e\n \u003cp\u003e13.2%\u003c/p\u003e\n \u003cp\u003e13.2%\u003c/p\u003e\n \u003cp\u003e4.4%\u003c/p\u003e\n \u003cp\u003e92.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.5694%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory support\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eIntubation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.2933%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.1373%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003esFlt-1/PlGF =\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor; GA = gestational age; SGA = small for gestational age; M/F = male/female; RDS = respiratory distress syndrome; BPD = bronchopulmonary dysplasia; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; EOS = early-onset sepsis; LOS = late-onset sepsis; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity; PPHN = persistent pulmonary hypertension of the neonate.\u003c/em\u003e\u003c/p\u003e\n\u003ch3 id=\"_Toc193893327\"\u003eSubanalysis based on gestational age\u003c/h3\u003e\n\u003cp\u003eSince neonatal outcomes are influenced by GA, a subanalysis was performed on neonates born to mothers with increased sFlt-1/PlGF ratios. These data are summarized in Table 6. In this subanalysis, exact GA dates are used. Three subcategories of preterm birth are made based on GA, namely:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eextremely low gestational age neonates (ELGANs) = less than 28 weeks\u003c/li\u003e\n \u003cli\u003every preterm = 28 to less than 32 weeks\u003c/li\u003e\n \u003cli\u003emoderate to late preterm = 32 to 37 weeks\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNo separate subanalysis was performed on neonates born to mothers with a normal sFlt-1/PlGF ratio since the inclusion number was too limited. In this group, only one patient was born to an ELGAN, three patients were born very preterm, and the other six patients were born moderately to late preterm.\u003c/p\u003e\n\u003cp\u003eTable 6: Neonatal outcomes adapted based on gestational age at the time of delivery from neonates with mothers with increased sFlt-1/PlGF ratios.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\" class=\"fr-table-selection-hover\" style=\"margin-right: calc(-1%); width: 101%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNeonatal outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eELGAN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eVery preterm\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate to late preterm\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal fetal demise\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResuscitation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeonate\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eGA (weeks \u0026ndash; mean)\u003c/p\u003e\n \u003cp\u003eBirth weight percentile (mean and median)\u003c/p\u003e\n \u003cp\u003eSGA\u003c/p\u003e\n \u003cp\u003eGender (M/F)\u003c/p\u003e\n \u003cp\u003eApgar score \u0026lt;5 at 5 minutes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep8 \u0026ndash; p8\u003c/p\u003e\n \u003cp\u003e66.6%\u003c/p\u003e\n \u003cp\u003eM = 33.3%/F = 66.6%\u003c/p\u003e\n \u003cp\u003e11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep18 \u0026ndash; p15\u003c/p\u003e\n \u003cp\u003e35.3%\u003c/p\u003e\n \u003cp\u003eM = 47.1%/F = 52.9%\u003c/p\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep10 \u0026ndash; p9\u003c/p\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003cp\u003eM = 43.8%/F = 56.2%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eRDS\u003c/p\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003cp\u003eIVH\u003c/p\u003e\n \u003cp\u003ePVL\u003c/p\u003e\n \u003cp\u003eEOS\u003c/p\u003e\n \u003cp\u003eLOS\u003c/p\u003e\n \u003cp\u003eNEC\u003c/p\u003e\n \u003cp\u003eHypoglycemia\u003c/p\u003e\n \u003cp\u003eHyperglycemia\u003c/p\u003e\n \u003cp\u003eROP\u003c/p\u003e\n \u003cp\u003eHypotension\u003c/p\u003e\n \u003cp\u003ePPHN\u003c/p\u003e\n \u003cp\u003eHyperbilirubinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e83.3%\u003c/p\u003e\n \u003cp\u003e61.1%\u003c/p\u003e\n \u003cp\u003e27.7%\u003c/p\u003e\n \u003cp\u003e5.6%\u003c/p\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003cp\u003e72.2%\u003c/p\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003cp\u003e94.4%\u003c/p\u003e\n \u003cp\u003e38.9%\u003c/p\u003e\n \u003cp\u003e38.9%\u003c/p\u003e\n \u003cp\u003e16.7%\u003c/p\u003e\n \u003cp\u003e94.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.8%\u003c/p\u003e\n \u003cp\u003e11.8%\u003c/p\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003cp\u003e2.9%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e8.8%\u003c/p\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003cp\u003e20.6%\u003c/p\u003e\n \u003cp\u003e47.1%\u003c/p\u003e\n \u003cp\u003e5.9%\u003c/p\u003e\n \u003cp\u003e2.9%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e94.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e37.5%\u003c/p\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e87.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.6626%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory support\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eIntubation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e55.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eELGAN: extremely low gestational age neonate; GA = gestational age; SGA = small for gestational age; M/F = male/female; RDS = respiratory distress syndrome; BPD = bronchopulmonary dysplasia; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; EOS = early-onset sepsis; LOS = late-onset sepsis; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity; PPHN = persistent pulmonary hypertension of the neonate.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe lowest mean and median growth percentiles, as well as the largest amount of SGA, are observed in the ELGAN group. Higher lactate levels in the umbilical cord were observed in the ELGAN group. The majority of ELGANs (83.3%) and very preterm neonates (58.5%) had RDS, in contrast to none of the neonates in the moderate- to late-preterm group. BPD is seen much more often in the ELGAN group. The grade of BPD (mild, moderate or severe) was determined in both the ELGAN group and the very preterm group. Additionally, IVH and PVL were observed more frequently in the ELGAN group (44.4% and 22.2%, respectively). Sepsis occurred more often in the ELGAN group, especially late-onset sepsis. EOS is only observed in the ELGAN group. The LOS was much greater, namely, in 72.2% of patients. Hypotension with the need for inotropics or vasopressors was observed more often in the ELGAN group. Intubation is performed more often in more premature neonates. Postnatal fetal death was observed only in the ELGAN group (22.2%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIUGR is an important indicator of the health status of a fetus. At this point, a diagnosis is made by ultrasound. Cardiotocography can provide additional information that reflects the well-being of the fetus at an exact moment in time. It cannot predict outcomes. An extra parameter to make a good estimation of fetal health status and even to predict neonatal outcome is highly valuable. The sFlt-1/PlGF ratio may provide this information. It can provide additional information to pregnant people with IUGR, even in the absence of PE.\u003c/p\u003e \u003cp\u003eSurvival is the greatest point of interest in healthcare. In our research, we observed only intrauterine death and postnatal death in pregnant women with increased sFlt-1/PlGF ratios. Even in one case, a termination of pregnancy was performed due to extreme IUGR and a fatal prognosis. In four cases, the IUGR was diagnosed very early, namely, at 23 weeks of GA. Those patients gave birth to stillborn fetuses two to four weeks after the diagnosis of IUGR. Only one patient had an interval of eight weeks between the diagnosis of IUGR and fetal death. This is the only patient who gave birth moderately to late preterm, namely, at 35 weeks and 4 days of GA. The other patients gave birth before 27 weeks of GA. The GA itself is also an important parameter for the risk of IUFD. Postnatal deaths were also observed only in neonates born before 28 weeks of GA. In the group with a normal ratio, no intrauterine or postnatal death was observed. In that way, the sFlt-1/PlGF ratio can be of added value for estimating survival.\u003c/p\u003e \u003cp\u003eIn the group with an increased ratio, more obstetrical diseases are observed; for example, 68% of the patients are diagnosed with PE. This percentage is particularly higher than that reported in previous studies, whereas only 38.5% of the women with increased sFlt-1/PlGF ratios were diagnosed with PE.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) This may be due to a change in the diagnostic criteria for PE. Proteinuria is no longer mandatory, but hypertension with signs of organ dysfunction, such as IUGR, can also be used to diagnose PE.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) HELLP syndrome was diagnosed only in the group with an increased sFlt-1/PlGF ratio. In contrast, in the group with a normal ratio, 30% of the patients were diagnosed with PE without increased sFlt-1/PlGF. These findings indicate that increased sFlt-1/PlGF ratio is not mandatory for the diagnosis of PE. These three patients received antihypertensive drugs. Two of these three patients had preexisting hypertension and received aspirin as medication. Magnesium sulfate was given more often to patients with an increased sFlt-1/PlGF ratio because of maternal indication (PE) and for fetal indication (neuroprotection when giving birth before 32 weeks of GA). Cesarean delivery was performed most of the time in both groups. The indication for giving birth was mostly due to a decline in fetal condition, but maternal indications were also present, mostly uncontrolled hypertension or an increase in PE-related complaints.\u003c/p\u003e \u003cp\u003eThere was a discrepancy in the time of delivery between the two groups. In the group with an increased ratio, 23.5% gave birth moderately to late preterm, half of the patients very preterm and 26.5% ELGANs. In the group with a normal sFlt-1/PlGF ratio, 60% gave birth moderately to late preterm, 30% very preterm and only one patient (10%) who gave birth to an ELGAN, namely, at 27 weeks of gestation. In the study of Chang et al., some women had a normal sFlt-1/PlGF ratio and IUGR but maintained pregnancy until late preterm, and their neonates had fewer morbidities.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) We may consider the sFlt-1/PlGF ratio a biomarker for deteriorating placental function. However, more investigations are necessary to confirm this hypothesis.\u003c/p\u003e \u003cp\u003eWe observed many more perinatal morbidities in the group with a higher sFlt-1/PlGF ratio than in the group with a normal sFlt-1/PlGF ratio. RDS occurs in half of the neonates from mothers with a raised ratio, whereas it occurs in only 20% of the neonates with a normal ratio. Other morbidities, such as IVH (13.2%, 0%), EOS (4.4%, 0%), LOS (22.1%, 10%), ROP (13.2%, 0%), hypotension (13.2%, 10%) and PPHN (4.4%, 0%), are observed more often in the group with an increased ratio than in the group with a normal ratio. The presence of BPD is comparable. This can also be attributed to the younger GA of patients with increased sFlt-1/PlGF ratios, namely, a mean GA at the time of delivery of 30 weeks versus 31 weeks of GA in the group with normal ratios. PVL was significantly more common in the group with a normal ratio (10%) than in the group with an increased ratio (4.4%) but was observed only in one patient from the group with a normal ratio versus three patients from the group with an increased ratio. This is due to the limited number of patients included in the group with a normal ratio. Similar results were observed for NEC, namely, 10% of the patients had a normal ratio (one patient) versus 5.9% of the patients with an increased ratio (four patients).\u003c/p\u003e \u003cp\u003eA possible next step is to sample serial sFlt-1/PlGF ratios in pregnant women with IUGR and correlate them with maternal and fetal morbidities. In this way, we investigated whether there was a linear correlation between the sFlt-1/PlGF ratio and mortality and neonatal morbidity. One of the patients with postnatal fetal demise has an increased sFlt-1/PlGF ratio of 176, which is not as high as that of other patients (maximum value of 1907). Patients with IUFD have a wide range of sFlt-1/PlGF ratios, ranging from 100 to 1036. The patient who underwent termination of pregnancy due to extreme IUGR had a sFlt-1/PlGF ratio of 165. Importantly, this blood sample was taken 22 days before termination. A higher value at the time of termination is very likely. Nevertheless, these findings indicate that there is no linear correlation between the sFlt-1/PlGF ratio and fetal death. Second, our research does not provide a clear general cutoff that can predict worse morbidity or mortality. If serial measurements are taken, maybe this could be determined. In addition, there was no clear correlation between a higher sFlt-1/PlGF ratio and a shorter interval to fetal delivery or death. The sFlt-1/PlGF ratio is not an indicator of the interval between establishing a high sFlt-1/PlGF ratio and the day of fetal delivery or death. The indication for delivery is independent of the sFlt-1/PlGF ratio. There were no additional maternal indications described for fetal delivery with increasing sFlt-1/PlGF ratios. In conclusion, our research does not reveal a linear correlation between the sFlt-1/PlGF ratio and fetal or neonatal mortality, neonatal morbidity, the interval to fetal delivery or death.\u003c/p\u003e \u003cp\u003eIt is important to correct for GA and birth weight. In the group with a normal sFlt-1/PlGF ratio, all neonates were born after a GA of 27 weeks, whereas in the group with a raised sFlt-1/PlGF ratio, neonates were born at 24 weeks of GA. With our inclusion numbers, it is not possible to correct for the GA in these two groups. A subanalysis for GA was performed in the group with an elevated sFlt-1/PlGF ratio, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. These findings indicate increased morbidity and mortality with lower GA. This finding supports already known knowledge and other research.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) Neonatal death occurred only in the ELGAN group.\u003c/p\u003e \u003cp\u003eIn the ELGAN group of patients with increased sFlt-1/PlGF ratios, a subanalysis was performed to investigate whether the sFlt-1/PlGF ratio could predict neonatal outcomes such as SGA or neonatal death. Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e shows the results with increasing sFlt-1/PlGF ratios. For example, a patient with a raised sFlt-1/PlGF ratio of 176 at 25 weeks of GA gave birth one week later. The neonate was SGA and even died. In this case, the interval between the determination of the sFlt-1/PlGF ratio and birth was only one week. In addition, the patient with a very high sFlt-1/PlGF ratio (1270) in this group gave birth at 25 weeks and four days of GA with a birthweight of 550 grams, which made the neonate SGA. The neonate did have RDS and moderate BPD but was not intubated or passed away postnatally. Given this information, we can conclude that a strong linear correlation between the sFlt-1/PlGF ratio and neonatal morbidities cannot be made in this research.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup of extremely low gestational age neonates (ELGANs): increasing sFlt-1/PlGF ratio and the presence of SGA and postnatal fetal death.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003esFlt-1/PlGF ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGA at birth (weeks)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA at birth\u003c/p\u003e \u003cp\u003e(days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePostnatal fetal demise\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e367\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e651\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e868\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003esFlt-1/PlGF\u0026thinsp;=\u0026thinsp;soluble fms-like tyrosine kinase receptor-1/placental growth factor; GA\u0026thinsp;=\u0026thinsp;gestational age; SGA\u0026thinsp;=\u0026thinsp;small for gestational age.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe fact that few patients have a normal sFlt-1/PlGF ratio and IUGR does provide information. This finding indicates that IUGR is often associated with an increased sFlt-1/PlGF ratio and that indications for the determination of this ratio are well established.\u003c/p\u003e \u003cp\u003eWe focused on the sFlt-1/PlGF ratio and IUGR in our study since it is a serious cause of neonatal morbidity and even mortality. Nevertheless, sFlt-1 and PlGF are angiogenic-related factors, so they can be meaningful in the diagnosis and follow-up of other pregnancy-related diseases, such as gestational diabetes. Further research is necessary since it was not the scope of this research. The sFlt-1/PlGF ratio can be of much greater interest than is currently known.\u003c/p\u003e \u003cp\u003eThe major limitation of this research is the limited inclusion number, namely, the group with a normal sFlt-1/PlGF ratio. However, no further statistical analysis was performed to determine whether the increased incidence of neonatal morbidities in the increased sFlt-1/PlGF ratio group was independent of prematurity itself. The second limitation is the design of the study, namely, a retrospective, monocentric, observational study. This limits inclusion numbers, especially for the group with a normal sFlt-1/PlGF ratio. The next step is to perform a prospective observational multicenter cohort study. The third limitation is the follow-up. In our study, only the results from the NICU were analyzed. A neonatal follow-up with development assessment of the children, also after dismission from the hospital, would be highly valuable.\u003c/p\u003e \u003cp\u003eHowever, our study highlights the high interest in the sFlt-1/PlGF ratio in pregnant women with IUGR. We conclude that an increased sFlt-1/PlGF ratio can indicate worse neonatal outcomes and mortality. More research is necessary to further explore the added value of the sFlt-1/PlGF ratio on adverse pregnancy outcomes and neonatal mortality and morbidity in pregnant women with IUGR.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur research highlights the great added value of the sFlt-1/PlGF ratio in predicting pregnancy and neonatal outcomes. Only patients with increased sFlt-1/PlGF ratios experienced intrauterine fetal death and postnatal death. During pregnancy, more obstetrical diseases and a greater need for medication were observed. Additionally, more neonatal morbidities were observed in patients whose mothers had higher sFlt-1/PlGF ratios. Nevertheless, owing to the limited number of inclusions in the group with a normal sFlt-1/PlGF ratio, statistically validated conclusions cannot be drawn, and no correction for GA or birth weight was possible. More advanced research with an expansion of the database is necessary. Our research indicates that the sFlt-1/PlGF ratio is an interesting angiogenic biomarker and can be of great value in predicting pregnancy and fetal outcomes in patients with IUGR.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003esFlt-1/PlGF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esoluble fms-like tyrosine kinase receptor-1/placental growth factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIUGR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintrauterine growth restriction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFGR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efetal growth restriction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epreeclampsia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHELLP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHemolysis, elevated liver enzyme levels, low platelet levels\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIUFD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintrauterine fetal death\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVEGF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVascular endothelial growth factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egestational age\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulsatile index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eumbilical artery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eend diastolic flow\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eductus venosus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUtA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003euterine artery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emiddle cerebral artery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efetal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ematernal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emg/dl\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emilligrams/deciliter\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eN.A.\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enot applicable\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esmall for gestational age\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erespiratory distress syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchopulmonary dysplasia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintraventricular hemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePVL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperiventricular leukomalacia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eearly-onset sepsis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elate-onset sepsis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enecrotizing enterocolitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eretinopathy of prematurity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPHN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epersistent pulmonary hypertension of the neonate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical aspects\u003c/h2\u003e\n\u003cp\u003eApplication for approval for this study was submitted by the Ethical Commission of the University Hospital of Antwerp. Request was submitted in July 2023 and approval was obtained in August 2023 \u003cem\u003e(Attachment 1)\u003c/em\u003e. Since it is a retrospective study, providing an informed consent is not necessary according to the Ethical Commission of the University Hospital of Antwerp according to national regulations. More information is written down in the quality manual of the Ethical Commission of the University Hospital of Antwerp on (part two, chapter one).\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2 id=\"_Toc193893331\"\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eStudy conception: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme\u003c/p\u003e\n\u003cp\u003eWriting the protocol: Dr. Lieselot Arnouts led by Prof. Dr. Dominique Mannarts\u003c/p\u003e\n\u003cp\u003eAcquisition of data: Dr. Lieselot Arnouts, Janne Terwingen and Dr. Karlijn van Damme\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme\u003c/p\u003e\n\u003cp\u003eCritical vision: Prof. Dr. Dominque Mannaerts, Dr. Lieselot Arnouts and Dr. Karlijn Van Damme\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVerlohren S, Brennecke SP, Galindo A, Karumanchi SA, Mirkovic LB, Schlembach D, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens. 2022;27:42\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmengaud JB, Yzydorczyk C, Siddeek B, Peyter AC, Simeoni U. Intrauterine growth restriction: Clinical consequences on health and disease at adulthood. Reprod Toxicol. 2021;99:168\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma D, Shastri S, Sharma P. Intrauterine Growth Restriction: Antenatal and Postnatal Aspects. Clin Med Insights Pediatr. 2016;10:67\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSacchi C, Marino C, Nosarti C, Vieno A, Visentin S, Simonelli A. Association of Intrauterine Growth Restriction and Small for Gestational Age Status With Childhood Cognitive Outcomes: A Systematic Review and Meta-analysis. JAMA Pediatr. 2020;174(8):772\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican College of O. Gynecologists' Committee on Practice B-O, the Society f-F. ACOG Practice Bulletin 204: Fetal Growth Restriction. Obstet Gynecol. 2019;133(2):e97\u0026ndash;109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang YS, Chen CN, Jeng SF, Su YN, Chen CY, Chou HC, et al. The sFlt-1/PlGF ratio as a predictor for poor pregnancy and neonatal outcomes. Pediatr Neonatol. 2017;58(6):529\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLees CC, Stampalija T, Baschat A, da Silva Costa F, Ferrazzi E, Figueras F, et al. ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol. 2020;56(2):298\u0026ndash;312.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalhotra A, Allison BJ, Castillo-Melendez M, Jenkin G, Polglase GR, Miller SL. Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact. Front Endocrinol (Lausanne). 2019;10:55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaschat AA. Fetal responses to placental insufficiency: an update. BJOG. 2004;111(10):1031\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJarvenpaa J, Vuoristo JT, Savolainen ER, Ukkola O, Vaskivuo T, Ryynanen M. Altered expression of angiogenesis-related placental genes in preeclampsia associated with intrauterine growth restriction. Gynecol Endocrinol. 2007;23(6):351\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg YS, Krilleke D, Shima DT. VEGF function in vascular pathogenesis. Exp Cell Res. 2006;312(5):527\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarut F, Barut A, Gun BD, Kandemir NO, Harma MI, Harma M, et al. Intrauterine growth restriction and placental angiogenesis. Diagn Pathol. 2010;5:24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res. 2008;75(1):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaiworapongsa T, Espinoza J, Gotsch F, Kim YM, Kim GJ, Goncalves LF, et al. The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation. J Matern Fetal Neonatal Med. 2008;21(1):25\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRomero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21(1):9\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSavvidou MD, Yu CK, Harland LC, Hingorani AD, Nicolaides KH. Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction. Am J Obstet Gynecol. 2006;195(6):1668\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen W, Wei Q, Liang Q, Song S, Li J. Diagnostic capacity of sFlt-1/PlGF ratio in fetal growth restriction: A systematic review and meta-analysis. Placenta. 2022;127:37\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerraiz I, Quezada MS, Rodriguez-Calvo J, Gomez-Montes E, Villalain C, Galindo A. Longitudinal change of sFlt-1/PlGF ratio in singleton pregnancy with early-onset fetal growth restriction. Ultrasound Obstet Gynecol. 2018;52(5):631\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKesavan K, Devaskar SU. Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes. Pediatr Clin North Am. 2019;66(2):403\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKosinska-Kaczynska K, Chaberek K, Szymecka-Samaha N, Brawura-Biskupski-Samaha R, Czapska A, Zebrowska K, et al. Is the sFlt-1/PlGF ratio efficient in predicting adverse neonatal outcomes in small-for-gestational-age newborns? A prospective observational multicenter cohort study. Front Med (Lausanne). 2024;11:1414381.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShim SH, Jeon HJ, Ryu HJ, Kim SH, Min SG, Kang MK, et al. Prenatal serum sFlt-1/PlGF ratio predicts the adverse neonatal outcomes among small-for-gestational-age fetuses in normotensive pregnant women: A prospective cohort study. Med (Baltim). 2021;100(8):e24681.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, Baschat AA, Baker PN, et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016;48(3):333\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurihara C, Zhang L, Mikhael M. Newer bronchopulmonary dysplasia definitions and prediction of health economics impacts in very preterm infants. Pediatr Pulmonol. 2021;56(2):409\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStarr R, De Jesus O, Shah SD, Borger J. Periventricular and Intraventricular Hemorrhage. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Orlando De Jesus declares no relevant financial relationships with ineligible companies. Disclosure: Sanket Shah declares no relevant financial relationships with ineligible companies. Disclosure: Judith Borger declares no relevant financial relationships with ineligible companies.2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImamura T, Ariga H, Kaneko M, Watanabe M, Shibukawa Y, Fukuda Y, et al. Neurodevelopmental outcomes of children with periventricular leukomalacia. Pediatr Neonatol. 2013;54(6):367\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanner MS, Davey MA, Mol BW, Rolnik DL. The evolution of the diagnostic criteria of preeclampsia-eclampsia. Am J Obstet Gynecol. 2022;226(2S):S835\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120(6):1337\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLianou L, Petropoulou C, Lipsou N, Bouza H. Difference in Mortality and Morbidity Between Extremely and Very Low Birth Weight Neonates. Neonatal Netw. 2022;41(5):257\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"IUGR, sFlt-1/PlGF ratio, maternal morbidities, neonatal morbidities, fetal mortality, neonatal mortality","lastPublishedDoi":"10.21203/rs.3.rs-6612674/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6612674/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBACKGROUND\u003c/h2\u003e \u003cp\u003eThe sFlt-1/PlGF (soluble fms-like tyrosine kinase-1/placental growth factor) ratio in the serum of pregnant women is a predictive marker for preeclampsia (PE). PE is often associated with intrauterine growth restriction (IUGR). Overall, growth-restricted fetuses are at increased risk for neonatal morbidities and perinatal death. An increased sFlt-1/PlGF ratio may be valuable for discriminating between different causes of IUGR. The goal of this study was to investigate the added value of the sFlt-1/PlGF ratio in pregnant women with IUGR on adverse pregnancy outcomes, neonatal morbidities and mortality.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003eThis was a retrospective, monocenter, observational study conducted at the University Hospital of Antwerp. All singleton pregnancies with IUGR and known serum levels of sFlt-1/PlGF with a gestational age (GA) of 24 weeks until 37 weeks were included. The results were analyzed over a period of almost three years (January 2022 until October 2024). In total, 85 patients met the inclusion criteria, ten of whom had normal serum levels of sFlt-1/PlGF (values less than 85), whereas the other 75 patients had increased sFlt-1/PlGF ratios. The maternal characteristics, fetal and neonatal mortality rates, adverse pregnancy outcomes and neonatal morbidities of all the patients and their neonates were recorded and analyzed.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eIn IUGR fetuses with increased maternal serum sFlt-1/PlGF ratios, aberrant ultrasonic fetal doppler, fetal demise and obstetrical diseases such as PE are more often observed. In the group of neonates from mothers with a high sFlt-1/PlGF ratio, more neonatal morbidities, such as respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, early-onset sepsis, late-onset sepsis and retinopathy of prematurity, are observed. Nevertheless, it is important to correct those results for GA and birth weight since morbidities are more often observed in more premature neonates.\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eIn patients with IUGR due to placental insufficiency, an increased sFlt-1/PlGF ratio is observed.\u003c/p\u003e","manuscriptTitle":"The added value of the sFlt-1/PlGF ratio in pregnant women with intrauterine growth restriction (IUGR) with or without preeclampsia on adverse pregnancy outcomes and neonatal morbidities: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-19 10:44:08","doi":"10.21203/rs.3.rs-6612674/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-12T05:42:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-06T15:30:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-27T08:21:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-18T18:41:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275479301841699178540188033541898155264","date":"2025-05-18T07:14:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118122834702761375104996217867638862870","date":"2025-05-17T15:23:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"120871860329740815781465596856200934278","date":"2025-05-17T15:21:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276603464489091851596662297235738077178","date":"2025-05-16T16:13:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326483069979801170715895759468975060452","date":"2025-05-16T10:58:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-15T15:12:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-15T14:54:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-14T13:57:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-13T18:20:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2025-05-13T18:19:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fab792b7-9e5c-456c-8dac-412b5dc0998e","owner":[],"postedDate":"May 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:12:10+00:00","versionOfRecord":{"articleIdentity":"rs-6612674","link":"https://doi.org/10.1186/s12884-025-08057-2","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2025-09-30 15:58:01","publishedOnDateReadable":"September 30th, 2025"},"versionCreatedAt":"2025-05-19 10:44:08","video":"","vorDoi":"10.1186/s12884-025-08057-2","vorDoiUrl":"https://doi.org/10.1186/s12884-025-08057-2","workflowStages":[]},"version":"v1","identity":"rs-6612674","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6612674","identity":"rs-6612674","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}