The relationship between placental characteristics and birthweight discordance in different types of selective intrauterine growth restriction in monochorionic diamniotic twins: A single-center 7 year cohort study.

OBJECTIVE: To clarify the relationships between placental characteristics and birthweight discordance in three types of selective intrauterine growth restriction (sIUGR) in monochorionic diamniotic twins. METHODS: A retrospective cohort study was conducted between april 2013 and april 2020. Associations between placental characteristics and birthweight discordance were evaluated through multiple linear regression analyses with two models for each sIUGR type. Model A was adjusted for gestational age, Model B additionally adjusted for the impact of placental characteristics interacted. RESULTS: In cases of type I sIUGR, birthweight discordance ratio was positively associated with placental territory discordance ratio [(ß = 0.181,95%CI(0.072,0.290), p < 0.05), (ß = 0.239,95%CI(0.125, 0.353), p < 0.05)] under both Model A and Model B. In-type II sIUGR [(ß = -0.012,95%CI(-0.020, -0.004), p < 0.05) (ß = -0.010,95%CI (-0.018, -0.002), p < 0.05)] and type III sIUGR [(ß = -0.011,95%CI (-0.021, -0.001), p < 0.05), (ß = -0.012,95%CI(-0.022, -0.003), p < 0.05)], birthweight discordance ratio was negatively associated with the total diameter of all the anastomoses as calculated with both Model A and Model B. CONCLUSION: Birthweight discordance is primarily related to placental territory discordance in type I sIUGR, whereas vascular anastomoses play important roles for growth-restricted fetal compensation in type II and III sIUGR.

Twin twin transfusion syndrome with and without selective fetal growth restriction: Predictors of donor demise.

OBJECTIVE: Evaluate survival in twin twin transfusion syndrome (TTTS) with and without selective fetal growth restriction (sFGR) after fetoscopic laser surgery (FLS). METHODS: Retrospective study of monochorionic diamniotic twins undergoing FLS. The cohort was classified as TTTS and TTTS with sFGR. Baseline, intra-operative and postoperative variables were analyzed. Mann-Whitney U, Pearson chi-square, Fisher's exact, t-test and receiver operating characteristic (ROC) curve analysis were performed. RESULTS: Four hundred and ninety-two pregnancies were included, 304 (61.78%) TTTS and 188 (38.22%) TTTS with sFGR. No difference in donor outcomes. TTTS group had higher donor estimated fetal weight (EFW%) percentile (19.7 ± 18.8 vs. 2.2 ± 2.1, p < 0.001). Significant predictors for demise at 30 days were 37% intertwin weight discordance (IWD) with donor EFW% < first (area under ROC curve [AUC] = 0.85, p = 0.001) or IWD >25% and intertwin umbilical artery pulsatility index discordance (DUAPI) ≥0.4 (AUC = 0.71, p = 0.001). CONCLUSION: Combination of IWD of 37% and donor EFW%

Prediction of adverse pregnancy outcome in monochorionic diamniotic twin pregnancy complicated by selective fetal growth restriction.

OBJECTIVE: To identify key factors associated with adverse perinatal outcome in monochorionic diamniotic twin pregnancy complicated by selective fetal growth restriction (sFGR). METHODS: This was a retrospective cohort study of all monochorionic diamniotic twin pregnancies diagnosed with sFGR at ≥ 16 weeks' gestation, in a single tertiary referral center between March 2000 and May 2015. The presence of coexisting twin-twin transfusion syndrome (TTTS) was noted. Fetal biometry and Doppler indices, including those of the umbilical artery (UA) and ductus venosus (DV), were recorded at the time of diagnosis. The type of sFGR was diagnosed according to the pattern of end-diastolic flow in the UA of the smaller twin. DV pulsatility indices for veins (DV-PIV) were converted to Z-scores and estimated fetal weight values to centiles, to correct for gestational age (GA). Cox proportional hazards model was used to examine for independent predictors of adverse perinatal outcome, which was defined according to survival and included both intrauterine fetal demise and neonatal death of the FGR twin. RESULTS: We analyzed 104 pregnancies, of which 66 (63.5%) were diagnosed with Type-I and 38 (36.5%) with Type-II sFGR at initial presentation. In pregnancies complicated by Type-II sFGR, the diagnosis of sFGR was made earlier than in those complicated by Type-I sFGR (mediam GA, 19.6 vs 21.5 weeks; P = 0.012), and Type-II sFGR was associated with increased risk of adverse perinatal outcome (intrauterine demise of the smaller twin, 34.2% vs 10.6%; P = 0.004). Twin pregnancies complicated by sFGR resulting in perinatal demise had a significantly earlier diagnosis (P = 0.002) and lower birth-weight centile of the smaller twin (P < 0.01), those with Type-I sFGR had earlier GA at delivery (P = 0.007) and those with Type-II sFGR had higher DV-PIV Z-score of the smaller twin (P = 0.003), when compared with pregnancies resulting in live birth. Coexisting TTTS had no significant impact on the perinatal outcome of pregnancies diagnosed with either Type-I or Type-II sFGR (P > 0.05 for both). Earlier GA at diagnosis (hazard ratio (HR), 0.70 (95% CI, 0.56-0.88); P = 0.002), Type-II sFGR (HR, 3.53 (95% CI, 1.37-9.07); P = 0.008) and higher DV-PIV Z-score (HR, 1.36 (95% CI, 1.12-1.65); P = 0.001) were significantly associated with increased risk of adverse perinatal outcome of the smaller twin. CONCLUSIONS: Pregnancies complicated by Type-II sFGR are diagnosed significantly earlier and are associated with increased risk of adverse perinatal outcome compared with those with Type-I sFGR. Coexisting TTTS has no significant impact on the perinatal outcome of pregnancies diagnosed with either Type-I or Type-II sFGR. Earlier GA at diagnosis, Type-II sFGR and higher DV-PIV Z-score are associated significantly with increased risk of adverse perinatal outcome of the smaller twin. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

IMAGe and Related Undergrowth Syndromes: The Complex Spectrum of Gain-of-Function CDKN1C Mutations.

CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.

Consensus definition of fetal growth restriction: a Delphi procedure.

OBJECTIVE: To determine, by expert consensus, a definition for early and late fetal growth restriction (FGR) through a Delphi procedure. METHOD: A Delphi survey was conducted among an international panel of experts on FGR. Panel members were provided with 18 literature-based parameters for defining FGR and were asked to rate the importance of these parameters for the diagnosis of both early and late FGR on a 5-point Likert scale. Parameters were described as solitary parameters (parameters that are sufficient to diagnose FGR, even if all other parameters are normal) and contributory parameters (parameters that require other abnormal parameter(s) to be present for the diagnosis of FGR). Consensus was sought to determine the cut-off values for accepted parameters. RESULTS: A total of 106 experts were approached, of whom 56 agreed to participate and entered the first round, and 45 (80%) completed all four rounds. For early FGR (< 32 weeks), three solitary parameters (abdominal circumference (AC) < 3(rd) centile, estimated fetal weight (EFW) < 3(rd) centile and absent end-diastolic flow in the umbilical artery (UA)) and four contributory parameters (AC or EFW < 10(th) centile combined with a pulsatility index (PI) > 95(th) centile in either the UA or uterine artery) were agreed upon. For late FGR (≥ 32 weeks), two solitary parameters (AC or EFW < 3(rd) centile) and four contributory parameters (EFW or AC < 10(th) centile, AC or EFW crossing centiles by > two quartiles on growth charts and cerebroplacental ratio < 5(th) centile or UA-PI > 95(th) centile) were defined. CONCLUSION: Consensus-based definitions for early and late FGR, as well as cut-off values for parameters involved, were agreed upon by a panel of experts. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol.

Small fetuses are defined as those with an ultrasound estimated weight below a threshold, most commonly the 10th centile. The first clinically relevant step is the distinction of 'true' fetal growth restriction (FGR), associated with signs of abnormal fetoplacental function and poorer perinatal outcome, from constitutional small-for-gestational age, with a near-normal perinatal outcome. Nowadays such a distinction should not be based solely on umbilical artery Doppler, since this index detects only early-onset severe forms. FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile, and, possibly in the near future, maternal angiogenic factors. Once the diagnosis is established, differentiating into early- and late-onset FGR is useful mainly for research purposes, because it distinguishes two clear phenotypes with differences in severity, association with preeclampsia, and the natural history of fetal deterioration. As a second clinically relevant step, management of FGR and the decision to deliver aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration and establishes follow-up intervals and optimal delivery timings, which may facilitate decisions and reduce practice variability in this complex clinical condition.

[Systemic production of cytokines and growth factors in various forms of syndrome of delayed fetal growth].

The syndrome of delayed fetal growth (SDFG) is one of the most wide-spread pathological conditions while course of pregnancy; it is characterized by disorder of the feto-placental system function. Its incidence is from 3 to 8%. The studying of peculiarities of the system and local immune disorders, coinciding with SDFG, would permit to establish the immune mechanisms of its formation. Revealing of immunoregulation disorders on systemic and local levels would promote the creation of a concept, depicting participation of the immune system in formation of asymmetrical and symmetrical forms of SDFG, to elaborate new approaches for prognosis and diagnosis.

Nutritional requirements and feeding recommendations for small for gestational age infants.

We define the small for gestational age (SGA) infant as an infant born ≥ 35 weeks' gestation and <10th percentile on the Fenton Growth Chart. Policy statements from many organizations recommend mother's own milk for SGA infants because it meets most of their nutritional requirements and provides short- and long-term benefits. Several distinct patterns of intrauterine growth restriction are identified among the heterogeneous grouping of SGA infants; each varies with regard to neonatal morbidities, requirements for neonatal management, postnatal growth velocities, neurodevelopmental progress, and adult health outcomes. There is much we do not know about nutritional management of the SGA infant. We need to identify and define: infants who have "true" growth restriction and are at high risk for adverse metabolic outcomes in later life; optimal growth velocity and "catch-up" growth rates that are conducive with life-long health and well being; global approaches to management of hypoglycemia; and an optimal model for postdischarge care. Large, rigorously conducted trials are required to determine whether aggressive feeding of SGA infants results in improved nutritional rehabilitation, growth, and neurodevelopmental outcomes. Before birth, maternal supplementation with specific nutrients reduces the rate and severity of growth restriction and may prevent nutrient deficiency states if infants are born SGA. After birth, the generally accepted goal is to provide enough nutrients to achieve postnatal growth similar to that of a normal fetus. In addition, we recommend SGA infants be allowed to "room in" with their mothers to promote breastfeeding, mother-infant attachment, and skin-to-skin contact to assist with thermoregulation.

Expectant management in type II selective intrauterine growth restriction and abnormal cord insertion in monochorionic twins.

OBJECTIVE: To assess perinatal outcome in type II monochorionic (MC) diamniotic twin pregnancies (DA) affected by selective intrauterine growth restriction (sIUGR) and abnormal cord insertion managed expectantly. METHODS: A prospective longitudinal study from June 2008 and July 2011 on 24 MCDA sIUGR twins. sIUGR was defined as estimated fetal weight below the 10th percentile in one twin and was classified into three groups based on umbilical artery (UA) Doppler diastolic flow (I: presence; II: constantly absent/reverse (AEDF/ARED); III: intermittently absent or reverse). Marginal cord insertion was defined as insertion within 2 cm of the placental disc edge, and velamentous insertion as a cord insertion into the fetal membranes. Expectant management was chosen in these twins, and absent or reverse A wave in the ductus venosus (DV) was a criterion for delivery. Neonatal outcome was available for all twins delivered. Pathological examination and vascular cast of placentas were performed in all cases. RESULTS: Fourteen twin pregnancies were type II sIUGR, and ten presented an abnormal umbilical cord insertion. Median gestational age (GA) at diagnosis of sIUGR was 18 weeks' gestation (range 16-20 weeks), and all sIUGR co-twins showed AEDF of UA at a median gestational age of 20 weeks (range 18-22 weeks). Median gestational age at delivery was 30 weeks (range 28-34 weeks) with a median birth weight of 1285 g (range 307-1725 g). pH at birth and base excess (BE) were normal in all IUGR co-twin (pH>7.10, median BE 5.5); Apgar score at 5 min was >7. Perinatal outcome was favorable in all cases. Placental pathological examination confirmed the marginal insertion of the umbilical cord and the absence of anastomosis between the two portions of umbilical insertion. CONCLUSIONS: This study highlights that expectant management for sIUGR type II twins with or without an abnormal cord insertion should be a valid option to time delivery for these fetuses as shown by the favorable neonatal outcome.

Fetal growth restriction: current knowledge to the general Obs/Gyn.

BACKGROUND: Fetal growth restriction (FGR) is a condition that affects 5-10 % of gestations, and it is the second primary cause of perinatal mortality. In this review the most recent knowledge about FGR is presented focusing on its concept, etiology, classification, diagnosis, management, and prognosis. METHODS: Searches were conducted in Pubmed, Embase and Lilacs database using the term fetal growth restriction. RESULTS: FGR is classified as type I (symmetric), manifested early, in which there is a proportional reduction of all fetal parts, generally associated with chromosome abnormalities; type II (asymmetric), with late onset, in which there is a more accentuated reduction of the abdomen, generally related to placental insufficiency; and type III (mixed), with early manifestation, resulting from infections or exposure to toxic agents. Diagnosis may be clinical, although ultrasound associated with arterial and venous Doppler is essential for diagnosis and follow-up. Currently there is no treatment capable of controlling FGR, and the moment of interruption of pregnancy is of vital importance in order to protect maternal and fetal interests. CONCLUSION: Early diagnosis of FGR is very important, because it permits the etiological identification and adequate monitoring of fetal vitality, minimizing the risks related to prematurity and intrauterine hypoxia.

Are twins growth restricted?

It is now well established that IUGR is associated with an increased risk of a range of adult onset diseases, including cardiovascular disease, obesity, and type 2 diabetes. Infants from twin pregnancies are generally born smaller than singletons; therefore, it has been suggested that twins represent a naturally occurring model of IUGR. Although twin gestations contribute significantly to the population burden of preterm birth and small size at birth, whether twins have the same long-term health consequences as IUGR singletons remains unclear. The purpose of this review is to consider what is currently known about the clinical implications of twinning, the differences that exist between the growth and developmental profiles of singleton and twin fetuses, and to use this as a basis for exploring the question of whether fetuses conceived as twins are analogous to IUGR singletons of similar birthweight and gestation. This question is increasingly important in both the clinical and research settings, because the incidence of twinning is increasing and the long-term implications of reduced size at birth are mostly investigated in species which bear multiple offspring.

[Unadjusted and customized fetal growth curves: a comparative study in a sub-Saharan population]. / Courbes de croissance fœtale non ajustées et personnalisées: une étude comparative dans une population du Sud du Sahara.

The purpose of this study was to compare the unadjusted EPOPé M0 curve with the customized Gardosi curve in the diagnosis of small-for-gestational-age (SGA) fetuses in a sub-Saharan population. We compared the Gardosi et al. and EPOPé M0 classifications. Classification differences were analyzed according to patient characteristics and obstetric conditions. Data collected from FileMaker software were analyzed using SPSS 20.0 and R Studio software. The statistical tests were carried out according to applicability conditions. Alpha risk was set at 0.05. The Gardosi curve showed that the rate of SGA newborns was higher (31.4% versus 28.9%) and did not differ between overweight and normal-weight women. The rate of severe SGA in preterm infants was also higher (23.6 versus 19.7%). Diseases were more frequent in newborns classified as severe SGA by the customized growth curve. The customized curve is recommended for the sub-Saharan Africa population.

Approaching the diagnosis of growth-restricted neonates: a cohort study.

BACKGROUND: The consequences of in utero growth restriction have been attracting scholarly attention for the past two decades. Nevertheless, the diagnosis of growth-restricted neonates is as yet an unresolved issue. Aim of this study is the evaluation of the performance of simple, common indicators of nutritional status, which are used in the identification of growth-restricted neonates. METHODS: In a cohort of 418 consecutively born term and near term neonates, four widely used anthropometric indices of body proportionality and subcutaneous fat accretion were applied, singly and in combination, as diagnostic markers for the detection of growth-restricted babies. The concordance of the indices was assessed in terms of positive and negative percent agreement and of Cohen's kappa. RESULTS: The agreement between the anthropometric indices was overall poor with a highest positive percent agreement of 62.5% and a lowest of 27.9% and the kappa ranging between 0.19 and 0.58. Moreover, 6% to 32% of babies having abnormal values in just one index were apparently well-grown and the median birth weight centile of babies having abnormal values of either of two indices was found to be as high as the 46th centile for gestational age (95%CI 35.5 to 60.4 and 29.8 to 63.9, respectively). On the contrary, the combination of anthropometric indices appeared to have better distinguishing properties among apparently and not apparently well-grown babies. The median birth weight centile of babies having abnormal values in two (or more) indices was the 11th centile for gestational age (95%CI 6.3 to 16.3). CONCLUSIONS: Clinical assessment and anthropometric indices in combination can define a reference standard with better performance compared to the same indices used in isolation. This approach offers an easy-to-use tool for bedside diagnosis of in utero growth restriction.

Intrauterine growth retardation (IUGR) as determinant and environment as modulator of infant mortality and morbidity: the Tanjungsari Cohort Study in Indonesia.

BACKGROUND AND OBJECTIVES: Intrauterine growth retardation (IUGR) is related to mortality and morbidity. However, defining IUGR by suitable field methods remains a challenge. A maternal-child Risk-Approach- Strategy (during 1988-1989) and follow-on Tanjungsari Cohort Study (TCS) (1989-1990), aimed to generate a practical classification of IUGR and explore its usage in predicting growth, mortality and morbidity of infants in the cohort. STUDY DESIGN: Some 3892 singleton live-birth infants were followed. IUGR was defined by birth weight (BW) and length (BL) classified as: acute, chronic, non-IUGR or 'probably preterm'. Growth, mortality, and survival curve were calculated to prove that the classification identified the most vulnerable infants. Fever >3 days and diarrhoea were assessed based on IUGR classification, sex, exclusive breastfeeding, and environmental factors. RESULTS: IUGR infant weight and length did not catch-up with the non-IUGR in the first year. Infant mortality rate was 44.7 per 1000 where some 61% died within 90 days. Using age specific mortality by BW, 23.6% of all deaths occurred when it was <2500 g compared to 66.2% from IUGR and preterm groups. Fever and diarrhoea rates increased over 12 months. Diarrhoea was associated with poor source-of-drinking-water and latrine. CONCLUSION: The IUGR classification predicted one-year growth curves and survival, besides age and sex. IUGR based on BW and BL identified a larger group of at-risk infants than did low BW. High morbidity rates were partly explained by poor environmental conditions. IUGR inclusive of BL has value in optimizing nutritional status in the first 1000 days of life.

Doppler vascular changes in intrauterine growth restriction.

Intrauterine growth restriction (IUGR) secondary to placental insufficiency is a major cause of perinatal morbidity and mortality in the United States. Historically, Doppler changes occurring in IUGR fetuses play an important role in the diagnosis and management of these fetuses, and now, based on these changes, we have proposed a staging system for IUGR fetuses that demonstrates prognostic value. This manuscript also summarizes a practical classification for IUGR fetuses. We believe that future studies should differentiate among the different types of IUGR fetuses.

Fetal growth restriction in twins.

Twin pregnancies are more likely to be affected by fetal growth restriction (FGR), preterm birth and perinatal loss. The management of fetal growth restriction in multiple pregnancy, particularly where only one fetus is affected is complicated by the need to consider the interests of both twins. Selective growth restriction in monochorionic (MC) twins is a pathophysiological process distinct from FGR in dichorionic (DC) pregnancies and management demands an understanding of the monochorionic placental structure and interdependent fetal circulations. The introduction of fetal therapy has introduced a range of potential interventions for the antenatal management of sFGR including selective fetal reduction and laser photocoagulation of the placental communicating vessels. This review summarizes up to date evidence on diagnosis, classification and management of sFGR and considers research directions likely to be of benefit in the future.

[Preeclampsia: New Classifications]. / Präeklampsie: neue Definitionen.

Preeclampsia: New Classifications Abstract. Preeclampsia is a multisystem disease leading to systemic impairment of the maternal endothelial function. A dysbalance of pro- and antiangiogenic factors appears to be significantly involved. The vascular disease leads to the manifestation of symptoms such as arterial hypertension and involvement of end organs such as kidney, liver and brain. The classical diagnostic criterion for arterial hypertension, 'proteinuria' has been downgraded and is no longer obligatory for diagnosis, if other criteria, as maternal organ dysfunction or intrauterine growth retardation, are present. In addition, white-coat hypertension has been included in the classification of hypertension in pregnancy. To classify preeclampsia as 'mild' is being discouraged in the clinical setting to account for the possibility of rapid worsening with significant danger for mother and foetus.

Variation in the definition of intrauterine growth restriction in routine antenatal care: a physician survey among gynecologists in Northwest Germany.

OBJECTIVE: To assess how intrauterine growth restriction (IUGR) is defined by gynecologists in routine practice. MATERIALS AND METHODS: We surveyed primary care gynecologists in Bremen and Lower Saxony, Northwest Germany, between January and July 2014. Descriptive statistics were used to analyze the data; consensus was considered as 90% agreement among the respondents. Multiple logistic regression models were performed for the associations between respondents' background characteristics and choice of the small for gestational age (SGA) cutoff values. RESULTS: Overall, 185 primary care gynecologists participated in the survey. Consensus was only observed in two items: (1) an accurate determination of gestational age (91%) and (2) repeated measurement of the abdominal circumference (91%). Umbilical artery Doppler (76%) and repeated ultrasonography (76%) were the most frequently used methods to confirm suspected IUGR diagnoses, but different responses prevailed. Notably, only 46% of the respondents opted for the 10th percentile of estimated fetal weight as a cutoff for SGA classification, which is the internationally recommended value. CONCLUSIONS: The results of this survey indicate considerable practice variation regarding detection and management of IUGR pregnancies. There is a need for better agreement in terminology and definition of core aspects of IUGR in antenatal care.

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study.

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.