Severe Intrauterine Growth Restriction Research Articles

The Role of the Placenta in Intrauterine Growth Restriction (IUGR)

Intrauterine growth restriction (IUGR) represents a reduction from the physiological growth rate. Fetal growth depends from the maternal supply of nutrients through the placenta into the umbilical circulation. Consequently, fetal growth restriction is associated with a reduced nutritional placental supply and this can result from a decrease in utero-placental blood flows as well as a reduced placental transport capacity. In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal-fetal gradients of glucose are increased in severe IUGR fetuses, i. e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated. Mouse and human models suggest that epigenetic regulation of fetal growth may also play a significant role, through placental imprinted genes. This review summarizes the current knowledge about placental role in intrauterine growth restriction.

Broad Clinical Spectrum in Silver-Russell Syndrome and Consequences for Genetic Testing in Growth Retardation

Silver-Russell syndrome is a heterogenous disorder characterized by severe intrauterine growth restriction, lack of catch-up after birth, and specific dysmorphisms. In approximately 10% of patients, maternal uniparental disomy of chromosome 7 is detectable, but hypomethylation of the imprinting in 11p15 is the major epigenetic disturbance in Silver-Russell syndrome. The use of strict clinical criteria, indeed, results in relatively high detection rates for the 11p15 epimutation, but we feel that the application of a strict clinical scoring system is not useful in clinical workaday life because of the broad clinical spectrum in 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers. We report on our experience of molecular testing in 188 patients referred for routine diagnostics of Silver-Russell syndrome and in a group of 20 patients with isolated intrauterine growth restriction/postnatal growth retardation. The molecular genetic results in both groups of data showed that 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers did not always show the unambiguous Silver-Russell syndrome phenotype. In addition to patients with the classical Silver-Russell syndrome phenotype fulfilling the Silver-Russell syndrome-specific scores, genetic testing for the 11p15 epimutation and/or maternal uniparental disomy of chromosome 7 should also be considered in case of "Silver-Russell syndrome-like" phenotypes, for example, mild intrauterine growth restriction and postnatal growth retardation associated with a prominent forehead and triangular face or asymmetry as the only clinical signs. In particular, the lack of intrauterine growth restriction in patients with a Silver-Russell syndrome-like phenotype should not automatically result in exclusion from molecular testing.

Profound Intrauterine Growth Restriction (IUGR) Due to Donohue Syndrome: the Story of One Family

We describe the obstetric care delivered to a woman over the course of three pregnancies during which time she and her partner were diagnosed as carriers of a rare autosomal recessive disorder: Donohue syndrome. She went on to deliver two affected children and one child who was unaffected. The first baby was growth restricted in utero and had many classical clinical and biochemical features of the syndrome. This infant died at the age of five months. The mother declined prenatal testing in her subsequent pregnancies. Fortunately, she was to deliver a healthy baby in her second pregnancy. However, her third pregnancy was again complicated by severe intrauterine growth restriction. She was delivered of the second affected baby who again demonstrated many of the features and abnormalities associated with Donohue syndrome. This baby died at thirteen months of age. The process leading to the diagnosis, the ultrasound growth charts related to affected and unaffected fetuses and the implications for subsequent management are described.

L-Arginine treatment for severe vascular fetal intrauterine growth restriction: A randomized double-bind controlled trial

Infants born with severe IUGR are exposed to higher neonatal mortality and morbidity rates, as compared with appropriate-for-gestational-age. They are exposed to a higher risk of developing chronic disease such as hypertension, coronary artery disease, obesity, and type 2 diabetes in adulthood. L-Arginine is a precursor of nitric oxide (NO) and may play a role in placental vascular mediation or local vasodilatation. The current study was designed to determine whether oral supplementation of gravid patients suffering from severe intrauterine growth restriction (IUGR) with L-arginine, would enhance birth weight and/or decrease neonatal morbidity. Forty-four patients with a singleton pregnancy who had been referred for IUGR detected by ultrasonic examination were included. Vascular IUGR was defined by fetal abdominal circumference less than or equal to the 3rd percentile, associated with abnormal uterine Doppler. After double-blind randomization, patients received either 14 g/day of L-arginine, or a placebo. The characteristics of the two groups of patients (IUGR with L-arginine vs IUGR with placebo) were similar upon randomization. There was no significant difference between the two groups concerning birth weight (1042+/-476 vs. 1068+/-452 g). At delivery, maternal and neonatal characteristics were similar in the two groups. There was no difference in the Clinical Risk Index for Babies (CRIB) score, the duration of ventilatory assistance, nor the delay between birth and full enteral feeding between the two groups. In this study which is, at the best of our knowledge, the first double-bind, multicenter, randomized trial in this condition, L-arginine is not an effective treatment for severe vascular growth restriction.

Neurodevelopmental Outcome of Appropriate and Small for Gestational Age Very Low Birth Weight Infants

Prematurity and intrauterine growth restriction are associated with neurodevelopment delay. A prospective cohort study included all 96 very low birth weight infants discharged from our neonatal unit from November 2003 to June 2005. The authors compared 41 appropriate and 55 small for gestational age very low birth weight infants' neurodevelopment at 24 months corrected age. Bayley Scales were similar between both groups at 8, 12, 18, and 24 months corrected age even after adjustment for gestational age and improved from 8 to 24 months corrected age. Small for gestational age infants with and without severe intrauterine growth restriction had similar neurodevelopment outcome. Neurodevelopment delay is frequent in very low birth weight infants with no differences between appropriate and small for gestational age. The authors suggest that Bayley Scales evaluation should be performed in every very low birth weight infant at least at 24 months corrected age to detect those requiring therapeutic stimuli.

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

Mammalian placentation is a highly regulated process and is dependent on the proper development of specific trophoblast cell lineages. The two major types of trophoblast, villous and extravillous, show mitotic arrest during differentiation. In mice, the transcription factor, glial cell missing-1 (Gcm1), blocks mitosis and is required for syncytiotrophoblast formation and morphogenesis of the labyrinth, the murine equivalent of the villous placenta. The human homolog GCM1 has an analogous expression pattern, but its function is presently unknown. We studied GCM1 function in the human-derived BeWo choriocarcinoma cell line and in first trimester human placental villous and extravillous explants. The GCM1 expression was either inhibited by siRNA and antisense oligonucleotides methods or upregulated by forskolin treatment. Inhibition of GCM1 resulted in an increased rate of proliferation, but prevented de novo syncytiotrophoblast formation in syncytially denuded floating villous explants. GCM1 inhibition prevented extravillous differentiation along the invasive pathway in extravillous explants on matrigel. By contrast, forskolin-induced expression of GCM1 reduced the rate of proliferation and increased the rate of syncytialization in the floating villous explant model. Our studies show that GCM1 has a distinct role in the maintenance, development and turnover of the human trophoblast. Alterations in GCM1 expression or regulation may explain several aspects of two divergent severe placental insufficiency syndromes, namely preeclampsia and intrauterine growth restriction, which cause extreme preterm birth.

Severe Intrauterine Growth Restriction Is Associated With Higher Spontaneous Carbohydrate Intake in Young Women

Intrauterine growth restriction (IUGR) is associated with metabolic disorders in adulthood. In rats, an early adverse environment alters food preferences in adult life. We investigated whether IUGR is associated with spontaneous macronutrient preferences in humans. Two thousand sixty-three participants from a Brazilian birth cohort were evaluated at 24 y of age using a food frequency questionnaire, physical examination, anthropometric measurements, and biochemical assays (glucose, insulin, cholesterol, and triglycerides). IUGR was defined by the birth weight ratio (BWR = birth weight/mean weight for gestational age). Individuals were classified as non growth restricted (BWR > or =0.85), moderately growth restricted (0.85 > BWR > or = 0.75), and severely growth restricted (BWR <0.75). Severe IUGR women consumed a greater carbohydrate to protein ratio, even after controlling for social variables. There was a continuous association between growth restriction and later carbohydrate to protein ratio consumption in women. Women from both IUGR groups had a larger waist to hip ratio (WHR). The prevalence of metabolic syndrome was comparable between the groups. IUGR women preferred carbohydrates to protein in their regular diet, suggesting that spontaneous food choices may precede the appearance and contribute to the risk for metabolic diseases in this group.

Chronic intervillositis of unknown etiology (CIUE): Relation between placental lesions and perinatal outcome

Objectives To evaluate perinatal outcome of pregnancies complicated by chronic intervillositis of unknown etiology (CIUE) and to study the relation between extent of such placental histological lesions and clinical expression. Study design Descriptive and retrospective study including all cases of CIUE diagnosed between 2000 and 2006 in the university hospital of Toulouse (France). Perinatal outcome was evaluated according to the extent of placental lesions assessed by semi-quantitative graduation. Results Twenty pregnancies complicated by CIUE were included (14 patients). Three pregnancies were prematurely interrupted spontaneously during the first trimester. Perinatal outcome of the remaining 17 pregnancies beyond 22 WG was: 4 intrauterine fetal deaths, 3 terminations of pregnancy for early and severe intrauterine growth restriction (IUGR), and 10 live births (58.8%). All fetal deaths, 82.3% of pregnancies beyond 22 WG and 70% of live births were growth restricted. Severe intervillositis with massive fibrinoid deposition was associated with a severe perinatal prognosis whereas focal forms had a best evolution. The rate of recurrence was 100% in the reported cases. Conclusion CIUE have a poor perinatal outcome and a high rate of recurrence. There is a relation between clinical expression and histological lesions.

The significance of visualising coronary blood flow in early onset severe growth restricted fetuses with reverse flow in the ductus venosus

Objective. To evaluate the incidence and significance of coronary blood flow visualisation in early onset severe intrauterine growth restriction (IUGR) fetuses and to assess its relationship with the presence of reverse flow in ductus venosus (DV).Methods. The examination of coronary artery was performed at a gestational age <26 weeks in 19 IUGR fetuses from mothers without medical complications and characterised by the presence of reverse flow in DV. Visualisation or non-visualisation of coronary circulation were compared with fetal and neonatal outcome.Results. Coronary flow was seen in 7/19 (36.8%) of the IUGR fetuses and these fetuses showed a higher incidence of fetal death (71.4%vs. 16.6%, p = 0.044), delivery or fetal death at an earlier gestational age (23.71 vs. 26.57 weeks, p = 0.011) and a lower birthweight (310 vs. 586 g, p = 0.011). Kaplan–Meier survival analysis demonstrated that visualisation or non-visualisation of coronary flow in such fetuses provides an independent contribution in the prediction of the time interval between Doppler study and delivery or fetal death (chi square = 15.36, p < 0.001).Conclusions. Visualisation of coronary flow in IUGR fetuses with reverse flow in the DV identifies a subgroup of fetuses with a poorer fetal and neonatal outcome.

304: Aortic isthmus doppler transitional phase in IUGR fetuses

Aortic isthmus (AoI) reversed flow (RF) is one of the late cardiovascular changes occurring in severe intrauterine growth-restricted (IUGR) fetuses. The guiding hypothesis for this work is that in severe IUGR fetuses, the time from aortic isthmus reversed flow appearance to intrauterine fetal demise (IUFD), or non-reassuring fetal testing is variable. As such, there must be a transitional phase between normal end-diastolic forward flow (FF) and reversed end-diastolic flow (A/REDF).

426: Underestimation of fetal weight in preterm extremely growth restricted fetuses

Intrauterine growth restriction (IUGR) due to severe placental disease places additional risks for prenatal survival and handicap upon the preterm fetus. For any specific gestational age, the degree of growth restriction negatively impacts on the likelihood of survival. The purpose of this study was therefore to determine the accuracy of ultrasound estimations of fetal weight (EFW) in severe preterm IUGR when such information is used in antenatal-neonatal counseling sessions.

Reply

We thank Drs Salomon and Bernard for their interest in our paper. In fetuses with a short femur, the outcome was primarily dependent on the coexistence of other abnormalities. So, while the risk of an underlying skeletal dysplasia, genetic syndrome or chromosomal abnormality was high in fetuses with non-isolated short femur, no such outcomes were found in fetuses in which the short femur was isolated (defined as bilateral and symmetrical shortening of the femur in the absence of associated fetal abnormalities). We would therefore like to qualify their statement that ‘One should not fear such a high incidence of abnormalities when finding an isolated short femur in a first-trimester screened woman.’ In such cases with isolated short femur we showed that in about half the cases this will remain unexplained (defined as cases in which intrauterine growth restriction (IUGR) did not develop, or no postnatal diagnosis of skeletal dysplasia or genetic abnormality was made), in about 10% of the cases subsequent re-measurement will find the femur length to be within the normal range, while in the remainder (about 40%) severe IUGR will develop (defined in our study as fetal abdominal circumference below the 5th centile with abnormal fetal umbilical artery Doppler requiring delivery before 37 weeks). Uterine artery Doppler was a useful tool in predicting which pregnancies were at particular risk of subsequent severe IUGR and associated pre-eclampsia and abruption. We agree that the referral population was likely to be biased to some degree, and in the discussion we highlight this: ‘One of the limitations of this study is that there may have been a degree of referral bias. This, in combination with the policy of first-trimester screening for chromosomal abnormalities, may change the relative proportions of pregnancy outcomes. However, the outcomes in each group will be similar…’. In other words, the proportion of isolated to non-isolated short femur may be higher, but the relative proportions of outcomes within these two groups should be similar to those that we report; this is of particular relevance in the isolated group. On the issue of normal ranges, we regret that Salomon and Bernard felt that these were discussed inadequately, and the reference for these is given (reference 7). Some light research would have shown that the population from which these normal ranges were constructed was from the same geographical area as that of our hospital (the two main hospitals are fewer than 10 km apart and have overlapping catchment areas2). We therefore believe that the reference charts used do fit our practice. We accept the importance of providing locally relevant normal ranges. However, one could question from how narrow a geographical area such ranges need to come to be sufficiently accurate, and whether using ranges derived from a very narrow segment of the population can be generalized sufficiently for use. Regarding identification of cases, as we explain in the methods (Page 508): ‘we performed a search of our computerized database in order to identify all cases of short femur diagnosed between 18 and 24 weeks of gestation during the study period’, and this is what was done. Given the likely appropriate charts, it is difficult for us to hypothesize why the number of pregnancies with a femur length < 5th centile was lower than expected. One possible explanation is that sonographers with ‘real time’ charts (i.e. when measurements are plotted on a chart at the time of the scan, as is the case in the referring units) may be more likely to re-measure and ‘normalize’ values that are borderline, when the finding is isolated. As our population was screened previously by first-trimester nuchal translucency measurement it is also likely that the most severe cases associated with chromosomal abnormalities or multiple abnormalities had undergone pregnancy termination before the time of the anomaly scan. Finally, we were impressed with the ability of the authors to back-calculate the number of scans needed, and were amused to find that we may be doing fractions of scans! A. T. Papageorghiou*, N. Fratelli*, A. Bhide*, B. Thilaganathan*, * St George's Hospital, Fetal Medicine Unit, Lanesborough Wing, Blackshaw Road, London SW17 0QT, UK

P36.06: Congenital heart disease confounding the diagnosis of severe intrauterine growth restriction: A case report

P36.06: Congenital heart disease confounding the diagnosis of severe intrauterine growth restriction: A case report

Congenital intrahepatic portosystemic shunt: prenatal diagnosis and possible influence on fetal growth

Congenital intrahepatic portosystemic shunts (IPSS) are abnormal vascular communications within the liver between branches of the portal vein and the hepatic veins. They have been recognized as an important disorder in children and should be differentiated from metabolic diseases, the symptoms of which may be similar. Several cases of prenatal diagnosis of abnormalities of the fetal venous system have been described in the literature, but the significance and prognosis of isolated congenital IPSS in prenatal life have not been reported and have only been derived from children. We present a case of congenital IPSS in which there was severe intrauterine growth restriction with a concomitant atypical fetal Doppler pattern. Findings on Doppler ultrasound indicate that the prenatal diagnosis of congenital IPSS is now feasible.

Outcome of Fetuses With Antenatally Diagnosed Short Femur

Short femur-below the fifth centile for gestational age might reflect inaccurate dating or may be a normal variant in a constitutionally small fetus, but it also has been associated with skeletal dysplasias and chromosomal abnormalities. Recent studies have reported an association between isolated short femur in the second trimester and delivery of a small-for-gestational age infant, possibly as the result of uteroplacental insufficiency. This retrospective study reviewed all pregnancies seen at a tertiary referral unit at 18-24 weeks' gestation with a fetal femur length below the fifth centile for gestational age. The gestational age and the size of the fetal nuchal translucency had been determined as part of a Down syndrome screening test at 11-14 weeks' gestation. Repeated fetal measurements identified 11 fetuses who did not have short femur. Of the 118 remaining cases, detailed ultrasonographic examination demonstrated associated abnormalities in 46, or 39%. Among these cases, the associated conditions were skeletal dysplasia (35%), chromosomal abnormalities (22%), and genetic syndromes (9%). In 35% of cases, the fetus had multiple anomalies without a specific diagnosis. In 72 instances, 61% of the total, short femur was an isolated finding. In 46% of isolated cases, evaluation revealed early, severe intrauterine growth restriction with abnormal umbilical artery Doppler findings, and delivery took place before 37 weeks' gestation. In 90% of these cases, abnormal uterine artery Doppler findings were apparent at the time of presentation. Preeclampsia developed in 36% of these pregnancies, and the rate of intrauterine death was 33%. Both of these events were considerably less frequent when uterine artery Doppler imaging was normal. In pregnancies with short fetal femur, the major determinants of outcome are the presence of other fetal abnormalities and abnormal uterine artery Doppler findings.

Cerebral venous blood flow in growth restricted fetuses with an abnormal blood flow in the umbilical artery before 32 weeks of gestation

Objective To evaluate the brain venous circulation in fetuses with severe intrauterine growth restriction (IUGR) before 32 weeks of gestation. Study design Fifty fetuses with severe IUGR diagnosed between 27 and 32 weeks of gestation and 50 appropriate-for-gestational age (AGA) fetuses matched by gestational age were evaluated. IUGR fetuses were classified according to their hemodynamic deterioration pattern in relation to the Doppler examination of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV). The fetal venous brain blood flow was evaluated in the vein of Galen (VG), superior sagittal (SS), straight and transverse venous sinuses. Results Only the transverse sinus (TS) showed a significant reduction in the pulsatility index (PI) values in IUGR fetuses. All other veins showed similar PI values between IUGR and AGA fetuses. All cerebral veins of IUGR fetuses showed significantly increased maximum and mean velocities. All these findings did not change in relation to the hemodynamic IUGR deterioration. In nearly all normal and all IUGR fetuses, a pulsatile blood flow pattern was observed in the straight and transverse sinuses, whereas an increased pulsatile pattern in the VG and in the SS was noted in IUGR fetuses. Conclusion Brain venous blood flow in IUGR fetuses shows an increment in the maximum and mean velocities of all veins and a reduction in the PI in the transverse sinus.

Sequence of cardiovascular changes in IUGR in pregnancies with and without preeclampsia

The aim of this study was to determine the cardiovascular changes sequence in intrauterine-growth-restricted (IUGR) fetuses using Doppler ultrasound. Sequential Doppler evaluations were carried out in 29 severe IUGR fetuses in pregnancies without maternal medical complications (group A) and in pregnancies complicated by preeclampsia (group B) delivered at < ort = 32 weeks. Nine fetal vessels and two cardiac valves were studied. One hundred and forty three Doppler studies were performed (median: five studies; range 3-9 per patient). There were 19 fetuses in the preeclamptic group and 10 fetuses in the second group. In group A IUGR fetuses, a progressive change was observed in the parameters studied more often than in group B IUGR fetuses (P < 0.05). In six cases, an abnormal tricuspid valve (TV) followed by an abnormal mitral valve (MV) Doppler was recorded prior to the occurrence of the intrauterine-fetal demise. Our data indicate that (1) in patients without preeclampsia a series of cardiovascular changes almost always occurs in severe IUGR fetuses; (2) the changes preceding intrauterine demise are right cardiac failure followed by left cardiac failure; (3) in patients with preeclampsia, the sequential Doppler changes are unpredictable and are seen in a few patients only.

Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis.

Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters. We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios. We identified 74 studies of pre-eclampsia (total 79,547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients. Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.

Spontaneous Intrauterine Umbilical Artery Thrombosis Leading to Severe Fetal Growth Restriction

Intrauterine thrombosis of umbilical cord vessels is a rare event (2.5–4.5/10,000) and usually followed by poor fetal outcome. We present the rare case of spontaneous intrauterine thrombosis of an umbilical artery leading to severe intrauterine growth restriction (IUGR) and provide clinical and pathological findings. A 28-year-old nulliparous third gravida was referred to our institution because of IUGR at 32 + 4 weeks of gestation. Fetal growth had been appropriate until the 31st week of gestation and had stopped thereafter. There were no signs of abruption of the placenta and no structural abnormalities except an absent paravesical colour Doppler flow in the region of the right umbilical artery. Other Doppler measurements, karyotype and TORCH serology were normal. Intermittent non-reassuring fetal heart rate led to cesarean section at 34 + 3 weeks of gestation. A healthy girl with measurements on the 3rd centile was born (weight of 1,590 g, length of 41 cm and head circumference of 29 cm). Gross examination displayed an elongated, highly twisted umbilical cord with a length of 70 cm, central insertion and three umbilical vessels. Microscopic examination confirmed the diagnosis of umbilical artery thrombosis along the entire length of the umbilical cord. Calcification within the thrombus and microcalcification in occluded chorionic vessels were observed as well as hemorrhagic endovasculitis and endangiopathia obliterans in the stem villi arteries. This fetal thrombotic vasculopathy (FTV) comprised about 40% of the parenchyma. The coagulation parameters and blood counts of the mother and the infant were normal apart from transient neonatal thrombocytopenia. The reason for thrombosis remained unclear but could be attributed to the elongated and highly twisted umbilical cord. Intrauterine arterial thrombosis may cause severe IUGR. This condition might be detectable by ultrasound in the course of an IUGR workup, especially when no other reasons can be found.

Ultrasound Detection of Placental Insufficiency in Women With Elevated Second Trimester Serum Alpha-Fetoprotein or Human Chorionic Gonadotropin

ObjectiveWe evaluated the role of placental morphology ultrasound and uterine artery Doppler in predicting adverse perinatal outcomes in women with unexplained elevated serum alpha-fetoprotein (AFP) or human chorionic gonadotropin (hCG) levels in the second trimester of pregnancy. MethodsWomen with a serum AFP > 2.0 MoM (n = 83) or serum hCG > 2.5 MoM (n = 68) had placental imaging at 19–23 weeks’ gestation. Abnormal placental morphology (i.e., a maximum thickness of > 4 cm or > 50%of length) and abnormal uterine artery Doppler [UTAD] (mean pulsatility index > 1.45) were related to placental complications of pregnancy. Relative risks were derived for all women. Likelihood ratios were derived for the subset (55/83) in the group with elevated AFP who had no medical and/or obstetrical risk factors. ResultsCompared with elevated serum hCG, an elevated serum AFP was associated with higher rates of perinatal mortality (15.6% vs. 4.3%), preterm birth at < 32 weeks’ gestation (26.5% vs. 7.3%), small-for-gestational age (SGA) birth weight < 10th centile (24.1% vs. 10.3%) and severe intrauterine growth restriction (IUGR) (8.4% vs. 2.8%). Thirty-seven (44.5%) women with elevated serum AFP had an adverse perinatal outcome, and 23 of these women (67%) had no prior medical and/or obstetric risk factors. Abnormal tests of placental function were more common in the elevated serum AFP group than in the hCG group (UTAD 30.1% vs. 11.6%; placental morphology 30.2% vs. 16.2%). Abnormal UTAD and abnormal placental morphology had similar positive likelihood ratios for a range of adverse perinatal events in the elevated AFP group (1.3–4.4) and were increased when both tests were abnormal (likelihood ratio 5.0 for preeclampsia, 4.5 for preterm delivery < 32 weeks, 4.9 for intrauterine fetal demise). In the elevated hCG group abnormal UTAD and abnormal placental morphology predicted SGA (likelihood ratios 5.2 and 4.9) and IUGR (likelihood ratios 4.7 and 7.3) but did not predict preeclampsia or preterm birth. ConclusionAssessment of placental function using either morphology or UTAD at 19–23 weeks’ gestation identifies a subset of women at increased risk of adverse perinatal events with an elevated serum AFP. These tests have more limited value in women with an elevated serum hCG because of the lower prevalence of adverse perinatal events.