The clinical significance of an estimated fetal weight below the 10th percentile: a comparison of outcomes of <5th vs 5th–9th percentile

Accepted Manuscript The Clinical Significance of an Estimated Fetal Weight Below the 10th Centile: A Comparison of Outcomes Between <5th versus 5th-9th Centile Malgorzata Mlynarczyk, MD PhD, Suneet P. Chauhan, MD, Hind A. Baydoun, PhD, Catherine M. Wilkes, MD, Kimberly R. Earhart, MD, Yili Zhao, MD, Christopher Goodier, MD, Eugene Chang, MD, Nicole M. Lee Plenty, MD, E Kaitlyn Mize, MD, Michelle Owens, MD, Shilpa Babbar, MD, Dev Maulik, MD PhD, Emily DeFranco, MD, David McKinney, MD, Alfred Z. Abuhamad, MD PII:

S0002-9378(17)30521-5

DOI:

10.1016/j.ajog.2017.04.020

Reference:

YMOB 11624

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 8 January 2017 Revised Date:

8 April 2017

Accepted Date: 11 April 2017

Please cite this article as: Mlynarczyk M, Chauhan SP, Baydoun HA, Wilkes CM, Earhart KR, Zhao Y, Goodier C, Chang E, Lee Plenty NM, Mize EK, Owens M, Babbar S, Maulik D, DeFranco E, McKinney D, Abuhamad AZ, The Clinical Significance of an Estimated Fetal Weight Below the 10th Centile: A Comparison of Outcomes Between <5th versus 5th-9th Centile, American Journal of Obstetrics and Gynecology (2017), doi: 10.1016/j.ajog.2017.04.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Mlynarczyk M et al The Clinical Significance of an Estimated Fetal Weight Below the 10th Centile: A Comparison

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of Outcomes Between <5th versus 5th-9th Centile

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Malgorzata Mlynarczyk, MD PhD1,

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Suneet P. Chauhan, MD2

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Hind A. Baydoun, PhD3,

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Catherine M. Wilkes, MD1,

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Kimberly R. Earhart, MD1,

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Yili Zhao, MD1,

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Christopher Goodier, MD4,

Nicole M. Lee Plenty, MD5,

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E Kaitlyn Mize, MD5

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Michelle Owens, MD5,

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Shilpa Babbar, MD6,

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Dev Maulik, MD PhD6,

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Emily DeFranco, MD7,

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David McKinney, MD7,

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Alfred Z. Abuhamad, MD1

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Eugene Chang, MD4,

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1. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA

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2. Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and

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Reproductive Sciences, UT Health - University of Texas Medical School at Houston,

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Houston, TX 3. Graduate Program in Public Health, Eastern Virginia Medical School, Norfolk, VA

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4. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC

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5. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,

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6. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Missouri-Kansas City, Kansas City, MO

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University of Mississippi Medical Center, Jackson, MS

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7. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,

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University of Cincinnati College of Medicine, Cincinnati, OH

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Contact information

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Malgorzata Mlynarczyk MD PhD

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Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 825 Fairfax Ave. Suite 310, Norfolk, VA 23507

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Telephone: (757) 446-7912; Fax: (757) 446-7464

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E-mail: [email protected]

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ACCEPTED MANUSCRIPT Mlynarczyk M et al Condensation

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The composite neonatal morbidity with sonographic estimated fetal weight <5th centile for

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gestational age is 1.4 fold higher than those at 5-9th centile and persists after adjustment for

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confounders (odds ratio 2.41).

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(Word count 31)

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ACCEPTED MANUSCRIPT Mlynarczyk M et al ABSTRACT

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Background: The association between small for gestational age (SGA; birth weight < 10th

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centile for gestational age) and neonatal morbidity is well established. Yet there is a paucity of

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data on the relationship between suspected SGA (sonographic estimated fetal weight <10th

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centile), at two thresholds and subsequent neonatal morbidity.

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Objective: The objective of this study was to determine the relationship between sonographic

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estimated fetal weight (SEFW) < 5th centile versus 5-9th centile and neonatal morbidity.

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Study Design: This retrospective study involved five centers and included non-anomalous,

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singletons, with SEFW <10th centile for gestational age (GA) who delivered from 2009 to 2012.

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Composite neonatal morbidity included respiratory distress syndrome, proven sepsis, IVH grade

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III or IV, NEC, thrombocytopenia, seizures or death. Odd ratios were adjusted (aOR) for center,

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maternal age, race, body mass index at first visit, smoking status, use of alcohol, use of drugs

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and neonatal gender.

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Results: Of 834 women with suspected SGA fetuses, 513 (62%) had SEFW <5th percentile and

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321 (38%) had SEFW of 5-9th percentile for GA. At delivery, 81% of women with suspected SGA

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had confirmed SGA. With SEFW <5th percentile group 59% of neonates had birthweight (BW)

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<5th centile; with SEFW 5-9th percentile, 41% had BW <5th percentile and 36% had weight at 5-

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9th centile. NICU admission differed significantly for those below 5th centile (29%) compared to

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those at 5-9th centile (15%; P < 0.001). The composite neonatal morbidity among the SEFW <5th

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centile group was higher than the SEFW of 5-9th centile group (31% vs. 13%; aOR 2.41, 95% CI

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ACCEPTED MANUSCRIPT Mlynarczyk M et al 1.53-3.80). Similar findings were noted when the analysis was limited to SEFW within 28 days of

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delivery (aOR of 2.22, 95% CI 1.34-3.67).

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Conclusions: Eight of ten suspected SGA had BW <10th percentile for GA with the prediction of

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actual birth weight being more accurate in <5th centile group. Neonates with SEFW of <5th

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percentile were more likely to be admitted to NICU, and have complications than those with

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SEFW of 5-9th percentile.

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ACCEPTED MANUSCRIPT Mlynarczyk M et al 70

INTRODUCTION Suspected small for gestational age (SGA) has been variably defined as sonographic

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estimated fetal weight (SEFW) below 10th centile for gestational age (GA) or less than 5th

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percentile for GA; as abdominal circumference <10th or <5th centile for GA; as flattening of the

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growth or as abnormal of umbilical artery Doppler; the categorization of growth has utilized

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population, customized or ethnic based nomograms.1-16 SGA at birth has been defined as birth

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below 25th, 15th, 10th, 5th, or 3rd percentile for GA. 17-24 Notwithstanding the various thresholds

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used to thus far, American College of Obstetricians and Gynecologists and Society of Maternal-

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Fetal Medicine characterize, suspected SGA as sonographic estimated fetal weight (SEFW)

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<10th percentile for gestational age (GA) and SGA, as birth weight below the 10th percentile for

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GA25,26.

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Pregnancies with suspected SGA are at increased risk of fetal death, medically indicated

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preterm birth, and cesarean delivery for non-reassuring fetal heart rate tracing 4, 7,9, 16, 27,28. SGA

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newborns are at increased risk of respiratory distress, intubation at term, proven sepsis,

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necrotizing enterocolitis, neonatal seizure, neonatal and infant mortality 20-23, 29-35. Moreover,

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they are also more likely to have neurologic sequelae, autism and later in life have adult-onset

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non-communicable diseases such as hypertension and diabetes 36-40.

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Despite the known association between SGA and poor outcomes4, 9, 16, 20-23, 27, 28-35 there

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are three important issues. First, the threshold of SEFW of sub-optimal growth is associated

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with adverse neonatal outcomes is a subject of debate. Some recommend suspected SGA if

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SEFW < 10th centile. McIntire et al23, however, reported that neonatal morbidity became 6

ACCEPTED MANUSCRIPT Mlynarczyk M et al significantly only when neonates were <3rd percentile of birth weight for GA. Second, despite

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the known inaccuracies of SEFW42-44, it is assumed that the morbidity and mortality associated

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with sonographic and actual BW are of similar magnitude2-6, 8, 25,26,41. Thirdly, unlike nomograms

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of birthweight for GA, 45,46 most of the regression equations that estimate fetal weight do not

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provide value to categorize them as < 3rd 47,48 and hence this threshold is difficult to utilize in

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daily clinical practice.

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An important study examined SEFW with perinatal morbidity and mortality was

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reported in Ireland (PORTO study)6. In over 1100 singletons with SEFW <10th percentile for GA,

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Unterscheider et al6 found that the adverse neonatal outcomes were related to SEFW <3rd

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percentile and abnormal umbilical artery Doppler velocimetry. These investigators cautioned

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that these results may not be generalizable to other countries with different demographics and

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obstetrics practice6. Thus, there is a need to determine the neonatal outcomes among those

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with SEFW <10th percentile and if it differs among those with estimated <5th vs. 5-9th centile for

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GA, in a US population.

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The primary objective of this study was to determine if the composite neonatal

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morbidity was significantly different in neonates with SEFW <5th vs. 5-9th percentile for

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gestational age in an US population. The secondary objective of this study was to compare the

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frequency composite neonatal with SEFW <5th vs. 5-9th percentile, if the last ultrasound for

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SEFW was performed within 28 days prior to delivery.44,49

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MATERIALS AND METHODS

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ACCEPTED MANUSCRIPT Mlynarczyk M et al This was a retrospective cohort study was which employed of the Fellows and Residents

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(FAR) Research Network affiliated with Central Associations of Obstetricians and Gynecologists.

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Five tertiary academic centers participated in this multicenter study: Eastern Virginia Medical

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School, University of Cincinnati, University of Missouri Kansas City, Medical University of South

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Carolina and University of Mississippi. Each participating center obtained approval from their

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respective institutional review boards (IRB). At each of the centers, either residents in an

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obstetrics-gynecology program or a maternal-fetal medicine fellow identified the pregnancies

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with SEFW < 10th centile and culled the data from the prenatal visits, sonographic exams,

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peripartum course, and neonatal outcomes. The cases were identified by querying the

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ultrasound database and labor and delivery log books. Only those with complete record of

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delivery at one of the participating institutions were included in the study.

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Using ultrasound database and labor and delivery log books, all pregnancies with the

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diagnoses of SGA were identified at the five centers. The inclusion criteria for the study were

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singleton gestation, no known anomalies (no abnormal karyotype and/or major anatomical

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deformity), early US before 22 weeks for confirmation of estimated due date (EDD), SEFW less

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than 10th percentile for GA at any time between 24 weeks and delivery, and live birth, defined

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by an Apgar score of at least one at 1 min of life. We excluded women with multiple gestation,

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SEFW <10th percentile before 22 weeks, late prenatal care (first ultrasound after 22 weeks),

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fetuses with known anomalies, stillbirths, delivery before 24 weeks and those that were

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transferred for delivery.

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ACCEPTED MANUSCRIPT Mlynarczyk M et al All women who met inclusion criteria had fetus with fetuses suspected to have SGA

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between 01/01/2009 and 12/31/2012 at participating centers were included in the study. At

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each center, the four biometric parameters—biparietal diameter, head and abdominal

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circumference, and femur length— used to derive the estimated fetal weight were measured

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according to the ACOG practice bulletin on ultrasonography in pregnancy. 44 Additionally at all

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centers, suspected SGA was defined as any SEFW, at 24 weeks or later, which was <10th

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percentile for GA, using Hadlock’s regression equation to estimate fetal weight47. A priori, we

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choose to compare SEFW <5th vs. 5-9th percentile for GA because these thresholds were noted

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in the ultrasound reports at all five centers, and because determination of whether the fetus

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was < or >3rd percentile was not available to clinicians at the centers. The first ultrasound

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detecting growth restriction was used to categorize the cohorts into the two groups. At birth,

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The Alexander’s nomogram was used to categorize newborns as <5th, 5-9th or 10th percentile or

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more.45

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Gestational hypertension, mild and severe preeclampsia were defined according to

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ACOG Practice Bulletin recommendations at the time of diagnosis50. The composite maternal

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morbidity (CMM) was defined as peripartum course complicated by any of the following:

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intubation, admission to intensive care unit, blood transfusion, pulmonary edema, amniotic

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fluid embolism, or cesarean hysterectomy. Composite neonatal morbidity was defined as the

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presence of any of the following: respiratory distress syndrome (RDS), proven sepsis,

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intraventricular hemorrhage (IVH) grade III or IV, necrotizing enterocolitis (NEC),

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thrombocytopenia, seizures and death. RDS was defined as a need for use of ventilator in the

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first 24 hours of life. Sepsis was diagnosed when a positive blood culture was documented.

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ACCEPTED MANUSCRIPT Mlynarczyk M et al Intraventricular hemorrhage was classified according to Papile’s criteria51. Necrotizing

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enterocolitis was diagnosed by neonatologists when more than one clinical sign and at least

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one radiographic finding were present. Clinical signs for NEC included: bilious gastric aspirate or

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emesis, fecal blood (occult or gross) and abdominal distention. Radiographic findings for NEC

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included pneumatosis intestinalis, hepatobiliary gas and pneumoperitoneum.

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Thrombocytopenia was diagnosed when platelets count was at or below the 5th percentile at a

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specific gestational age 52,53. Neonatal death was defined as the death within 28 days after

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birth.

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Our sample size calculation, based on the prior finding of composite neonatal morbidity

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of 30% among SGA54, indicated that 300 patients were needed in each group to show 10%

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difference in composite neonatal morbidity (from 30% to 20%) with power of 80% and two-

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tailed alpha of 0.05. Data are presented as mean ± standard deviation or nominal values (n and

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%) and were analyzed using Student t test for continuous variables and chi-square or Fisher

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exact test for categorical variables, respectively. A log-binominal regression model was used to

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estimate odds ratio (OR) and 95% confidence interval (CI). An adjustment for the following

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eight confounders was performed: center, maternal age, race, body mass Index (BMI) at first

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visit, smoking status, self-reported use of alcohol or drugs, and neonatal gender. We adjusted

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for BMI for it is associated with identification and peripartum outcomes with fetal abnormal

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growth 55,56. Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC,

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United States).

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RESULTS

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ACCEPTED MANUSCRIPT Mlynarczyk M et al Of 834 patients that met inclusion criteria, 513 (62%) had SEFW <5th percentile and 321

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(38%) had SEFW 5-9th percentile. The frequency of the estimated fetal weight being < 5th versus

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5-9th percentile did not differ among the centers (P = 0.343). Maternal demographics and

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clinical characteristics are presented in Table 1. The distribution by maternal age, nulliparity,

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BMI at the first visit, ethnicity, and use of alcohol and tobacco were similar between the two

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groups. There was no difference in clinical and demographics characteristics between the two

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groups except for drug use during pregnancy: 9.4% in <5th percentile group vs. 5.3% in 5-9th

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percentile group.

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There were no differences in the past medical or obstetrical (OB) history (Table 2). Both

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groups reported similar rates of prior preterm deliveries and the same incidence of SGA in prior

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pregnancies. The maternal antepartum complications for the two groups are noted in Table 3.

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Women with SEFW<5th percentile had a higher frequency of mild and severe preeclampsia

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compared to 5-9th percentile group. The GA at the diagnosis of severe preeclampsia was similar

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for both groups: 31.1 + 3.7 in those with fetuses estimate below 5th percentile versus 31.7 + 3.9

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weeks in those at 5-9th groups (P > 0.05). GA at diagnosis of cases with SEFW <5th percentile

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was approximately 2 weeks earlier than suspected SGA 5-9th percentile (30.5 ± 5.6 vs. 32.5 ±

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4.6 weeks) and was more likely to persist at the last ultrasound prior to delivery (97% vs. 80%;

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P<0.0001).

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The mean GA at delivery were similar (35.7 ± 3.6 vs. 35.6 ± 3.6 wks), though patients in

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SEFW <5th percentile group were more likely to deliver before 32 weeks (20% vs. 9%; Table 4).

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The route of delivery differed between the two groups; the majority of women with fetuses

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ACCEPTED MANUSCRIPT Mlynarczyk M et al SEFW < 5th percentile having a cesarean delivery. The CMM was similar for the two groups

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(Table 4). The mean time interval between the last ultrasound examination and delivery did not

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differ between groups (8.0 ± 12.1 days in <5th percentile group and 8.4 ± 8.9 days in 5-9th

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percentile group).

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Table 5 summarizes the neonatal outcomes. Among deliveries before 34 weeks,

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antenatal corticosteroids were administrated in over 90% cases. Most newborns (59%) with

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SEFW < 5th percentile had an actual birth weight < 5th percentile for GA; in contrast, about 40%

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of newborns with SEFW at 5-9th percentile had actual birth weight < 5th percentile for GA.

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Newborns with actual weight above 10th percentile were more common among pregnancies

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with SEFW 5-9th percentile vs. those in < 5th percentile (23% vs. 16%; P = 0.011). The frequency

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of Apgar score < 7 at 5 min and umbilical arterial pH < 7.00 were similar for the two groups.

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Admission to NICU differed significantly (29% vs. 15%; P < 0.001), but average length of NICU

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stay was comparable (Table 5).

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The composite neonatal morbidity for the two groups is provided in Table 6. Compared

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to those with SEFW at 5-9th percentile, the composite neonatal morbidity was significantly

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higher for those with estimate below 5th percentile for GA. At each centers the frequency of

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composite neonatal morbidity for those with SEFW below 5th percentile versus those at 5-9th

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percentile was similar (P = 0.185). In both groups, the most common morbidity was RDS (and

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the only one significantly different between the groups). Among women with SEFW within 28

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days of delivery, the composite neonatal morbidity differed significantly (Table 7) for those with

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SEFW < 5th percentile vs. 5-9th percentile for GA and the most common morbidity was RDS.

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ACCEPTED MANUSCRIPT Mlynarczyk M et al There were 19 deaths among the cohort, with 4 of them occurring after 28 days. The

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median GA for the diagnosis of suspected SGA among the 15 neonatal deaths was 24.6 weeks

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(range 20.6 to 31.0) and the median GA for delivery, 27.5 (range 24.6-31.1) weeks. Overall, the

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neonatal mortality was 18.0 per 1,000 live births (15/834). For newborns with SEFW < 5th

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percentile for GA, the mortality within 28 days was 25.3 / 1,000 live births (13/513) and 6.2 /

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1,000 (2/321) for SEFW at 5-9th percentile for GA. These results suggest a difference in neonatal

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mortality between groups, however, the comparison was not statistically significant.

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Comments:

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Principal findings of this study

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Compared to singletons with SEFW at 5-9th centile, those at < 5th centile had significantly

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higher composite neonatal morbidity. The adjusted odds of morbidity was over 2-fold higher

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among those with SEFW < 5th centile regardless of whether the suspected SGA was noted in

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early third trimester exam or on the ultrasound exam within 28 days of the delivery (Tables 6,

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7). This finding, though intuitive, differs from most publications on suboptimal fetal growth

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have linked birthweight < 10th percentile with adverse outcomes1,7,10-12,15,17,20,22-25,28-

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32,34,35,38,39,53,54,62-68

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pregnancies, publications linking SGA with adverse sequelae are not as suitable for

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management as those that correlate SEFW with peripartum morbidity2-4,6,9,18,27,57-59,61, 69-72.

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. Since the actual weight of the newborn is unknown to clinicians managing

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Of all patients that met inclusion criteria almost 2/3 (62%) had SEFW <5th percentile and

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1/3 (38%) had SEFW 5-9th percentile. As the uneven distribution of our study subject between

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groups is a little surprising, we hypothesize that it is due to the fact that suspected SGA is more 13

ACCEPTED MANUSCRIPT Mlynarczyk M et al likely to be detected by screening ultrasound than SEFW 5-9th percentile. Another possible

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explanation is that patients with more SEFW < 5th centile are more likely to be referred to

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tertiary centers where our study was performed.

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The observed discrepancy in detection of low birth weight between two groups is

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consistent with previous data published by Chauhan and colleagues54 indicating poor detection

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rate of growth restriction by prenatal ultrasound. Our findings suggest that the more severe

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SGA the better correlation with the actual birth weight.

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Our study shows that the composite neonatal morbidity is almost 1.4 fold higher when

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SEFW is below 5th percentile than those at 5-9th percentile (32% versus 13%) and differs

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significantly after adjustment for eight confounders (Table 6). The 8 confounders we adjusted

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for did not include gestational age. Although adjusting for gestational age may be clinically

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appealing, we believe that it introduces bias in the reported associations since it is in the causal

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pathway between the exposure (indication for delivery) and the outcomes (neonatal morbidity

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and mortality)53. Despite the fact that over 90% of newborns delivered before 34 weeks

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received antenatal corticosteroids (Table 5), RDS was the common morbidity among the two

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groups (Table 6). The association between growth restriction and respiratory morbidity has

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been reported24,29,33,74, with the putative etiology being reduced or impaired surfactant release

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or diminished response to glucocorticoids74. Quite elevated risk of RDS in 5-9th percentile group

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(13% of neonates) may be related to the fact that 33% of neonates form 5-9% percentile group

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have been born prematurely, before 37 weeks of GA. Further prospective studies with control

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group of normally grown fetuses are needed to clarify what neonates from 5-9th percentile

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ACCEPTED MANUSCRIPT Mlynarczyk M et al group are at risk of developing RDS and should be delivered at the tertiary centers. We

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speculate that pregnancies <37 weeks may be still referred to higher level of care hospitals,

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while those at term may be safely delivered in local hospitals.

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Though the most common morbidity was RDS, the high neonatal mortality among non-

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anomalous suspected SGA was notable. Overall, the corrected neonatal mortality among

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fetuses with SEFW < 10th percentile was 18.0 per 1,000 live births; 25.3 if the SEFW < 5th

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percentile and 6.2 if between 5-9th percentile. Such a high mortality within 28 days of birth

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among suspected SGA is remarkable considering that in the US, the neonatal mortality is about

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4.0 per 1,000 live births, which includes congenital malformations, the leading cause of

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mortality among newborns75. A comparison of neonatal mortality reported among fetuses with

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SEFW <10th percentile is notable for wide variation: 0 per 1,000 live births is reported in the

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randomized trial by Boers et al68 to 59.6 by GRIT trial70. The reasons for disparity in neonatal

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mortality among various reports are type of studies—retrospective versus prospective; single

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versus multiple centers; observational versus randomized trial—sample size, ethnicity,

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gestational age at recruitment, proportion of cohorts with absent or reverse umbilical diastolic

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flow and management schema once SGA is suspected2-4,6,9,18,25,27,28,57-59,61,69-72. A large

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prospective observational study is warranted to accurately assess the neonatal morbidity

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associated with suspected SGA and to identify the modifiable risk factors.

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In addition to the composite neonatal morbidity, our study provided nuanced

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information on SEFW < 10th percentile for GA, which can be used to counsel women and to plan

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randomized trials. For fetuses diagnosed as being growth restricted, 2 out of 3 had SEFW < 5th

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ACCEPTED MANUSCRIPT Mlynarczyk M et al percentile. About one-third of pregnancies with suspected SGA have medical complications.

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The frequency of SEFW being above 10th percentile in subsequent sonographic examinations—

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is significantly higher when the SEFW is between 5-9th percentile rather than < 5th percentile

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(Table 2). The route of delivery, especially cesarean for non-reassuring fetal heart rate tracing,

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differs on the threshold used to define suspected SGA The composite maternal morbidity,

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however, is similar for those with SEFW < 5th percentile vs. 5-9th percentile (Table 4). Among

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women with suspected SGA 81% (677/834) will deliver a newborn with actual weight < 10th

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percentile or SGA. For fetuses with SEFW at 5-9th percentile, about 40% will have actual birth

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weight below 5th percentile, the group at risk for composite neonatal morbidity (Table 5).

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We compared our study with the PORTO6 (Prospective Observational Trial to Optimize

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Pediatric Health in Intrauterine Growth Restriction), as they both are recently performed

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multicenter studies on SEFW <10th percentile and neonatal outcomes. The design of the PORTO

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study differs from ours in that it is prospective with pre-specified aims, trained sonographers at

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seven academic centers, and consistent management schema6. Despite these differences, we

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believe that our study is clinically useful for the population and pregnancy management differs

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between Ireland and US. These differences are best exemplified by the neonatal mortality with

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SEFW <10th percentile in PORTO (2.7 per 1,000 live births) versus our study (18.0 / 1,000 live

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births)6. As in our study, in the PORTO trial mortality among those with SEFW <5th percentile

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was higher than those with SEFW 5-9th percentile: 8 vs. 2.7 per 1,000 births. We agree with

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Unterscheider J et al6 that this discrepancy in neonatal mortality maybe in part explained by the

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variation in the ethnicity, the rate of obesity and the prevalence of medical and obstetrical

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complications, ante- and intra-partum management and GA at delivery.

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Limitations and strengths Limitations of our retrospective study should be acknowledged, including selection bias.

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It is notable that several publications on suspected SGA 2-4,9,27,61 from the US and on SGA are

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retrospective 7,10,11,15,17,20,22,23,24,28-35,38-40,53-57,62-68. Since this study was designed to assess the

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peripartum outcomes with suspected SGA in daily practice in the US, there was no pre-specified

306

training of the sonographers. Theoretically, we should have equal proportion of fetuses that

307

had SEFW <5th and 5-9th percentile for GA. Our ratio of fetuses with estimated weight <5th

308

percentile being 1.5-times more common than 5-9th percentile for GA, may indicate that

309

women managed tertiary centers have more comorbidity and “severe” SGA than those in

310

general obstetric population or that “severe” SGA are more likely to be detected than those

311

approaching 10th percentile. It is notable that in the prospective study6 of 1,116 with SEFW <

312

10th centile in Ireland, 94% (n = 1,047) were below 5th percentile for GA. Thus, indeed majority

313

of suspected SGA detected at academic centers are < 5%, be in the US or in Ireland6.

314

Notwithstanding the disproportionate fraction, providing the neonatal morbidity separately for

315

the two groups permits clinicians to use the data for counseling and management. Since all of

316

the SEFW and deliveries occurred in teaching centers the neonatal outcomes may differ in

317

community hospitals. The management of the women with suspected SGA was not pre-

318

specified but considering all centers are tertiary hospitals with graduate medical educations in

319

obstetrics-gynecology, the practice is assumed to be congruent with ACOG and SMFM

320

guidelines1, 16, 38.

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In the current report we did not segregate the outcomes based on the results of

321 322

Doppler but for our first report we wanted to focus just on the link with SEFW and neonatal 17

ACCEPTED MANUSCRIPT Mlynarczyk M et al outcomes. We also did not collect data on serial sonographic examinations and thus cannot

324

comment on growth velocity and adverse outcomes40,76. We did not collect any data for fetuses

325

with appropriate growth as a comparative group, which would have provided nuanced

326

knowledge of the morbidity and mortality with growth restriction. Consistent with national

327

guidelines25,26,41 we defined growth restriction as those below 10th percentile for GA and did

328

not account for growth potential which some investigators have utilized to characterize growth

329

restriction77,78. We excluded stillbirths from our study and focused on neonatal outcomes.

330

Although the stillbirth rate in the suspected SGA population does provide valuable information,

331

we do not have this information because the retrospective design of the study prevented us

332

from determining the time interval from death to delivery. A priori, we did not have an

333

algorithm estimating the percentile growth at the time of demise78 and most women with fetal

334

demise delivered at the hospital where they were referred from rather than at the academics

335

centers where the data was collected. Higher incidence of severe preeclampsia in patients with

336

SEFW <5th percentile may also be a subject of separate sub-analysis of the current study and

337

should be included in prospective study in order to better explain this finding. We did not use

338

the results of INTERGROWTH-21st study that prospectively collected data on fetal growth in

339

eight countries. Our reasons for not using the data from multicountry trial was it was these

340

measurements were not available for use at the centers which participated15,80,81. Lastly, we

341

used Hadlock et al47 equation to estimate fetal weight, which has been aptly criticized for being

342

a descriptive reference chart derived decades ago, based on a small sample size in Texas.82 Yet,

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it is remarkable that the suspected SGA did identify newborns at risk of morbidity.

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ACCEPTED MANUSCRIPT Mlynarczyk M et al The strengths of the study should be mentioned. This is one of the few studies on the

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topic with sufficient power, a pre-specified hypothesis and involves multiple centers with

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generalizable results. Our data reports on pregnancy and neonatal outcomes based upon SEFW

347

and not birthweight.

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In summary, compared to estimate between 5-9th percentile, sonographic estimated

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fetal weight <5th percentile is associated with a higher frequency of composite neonatal

350

morbidity. Our data provides clinically useful information to counsel women, albeit in academic

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centers, with a SEFW <5th versus 5-9th percentile for GA and is an impetus to design an

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interventional trial to mitigate the morbidity with suspected SGA.83,84

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1. Chang TC, Robson SC, Boys RJ, Spencer JA. Prediction of the small for gestational age infant: which ultrasonic measurement is best? Obstet Gynecol. 1992;80:1030-8. 2. O'Reilly-Green CP, Divon MY. Receiver operating characteristic curves of ultrasonographic estimates of fetal weight for prediction of fetal growth restriction in prolonged pregnancies. Am J Obstet Gynecol. 1999;181:1133-8. 3. Vergani P, Andreotti C, Roncaglia N, et al. Doppler predictors of adverse neonatal outcome in the growth restricted fetus at 34 weeks' gestation or beyond. Am J Obstet Gynecol. 2003;189:1007-11. 4. Chauhan SP, Cole J, Sanderson M, Magann EF, Scardo JA. Suspicion of intrauterine growth restriction: Use of abdominal circumference alone or estimated fetal weight below 10%. J Matern Fetal Neonatal Med. 2006;19:557-62. 5. Law TL, Korte JE, Katikaneni LD, Wagner CL, Ebeling MD, Newman RB. Ultrasound assessment of intrauterine growth restriction: relationship to neonatal body composition. Am J Obstet Gynecol. 2011;205:255.e1-6. 6. Unterscheider J, Daly S, Geary MP, et al. Optimizing the definition of intrauterine growth restriction: the multicenter prospective PORTO Study. Am J Obstet Gynecol. 2013;208:290.e1-6. 7. Carreno CA, Costantine MM, Holland MG, Ramin SM, Saade GR, Blackwell SC. Approximately one-third of medically indicated late preterm births are complicated by fetal growth restriction. Am J Obstet Gynecol. 2011;204:263.e1-4. 8. Buck Louis GM, Grewal J, Albert PS, et al. Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol. 2015;213:449.e1-449.e41. 9. Dahlke JD, Mendez-Figueroa H, Maggio L, Albright CM, Chauhan SP, Wenstrom KD. Early Term versus Term Delivery in the Management of Fetal Growth Restriction: A Comparison of Two Protocols. Am J Perinatol. 2015;32:523-30. 10. Gardosi J, Francis A. A customized standard to assess fetal growth in a US population. Am J Obstet Gynecol. 2009;201(1):25.e1-7. 11. Ego A, Subtil D, Grange G, Thiebaugeorges O, Senat MV, Vayssiere C, Zeitlin J. Customized versus population-based birth weight standards for identifying growth restricted infants: a French multicenter study. Am J Obstet Gynecol. 2006;194:1042-9. 12. Gardosi J, Francis A. Adverse pregnancy outcome and association with small for gestational age birthweight by customized and population-based percentiles. Am J Obstet Gynecol. 2009;201:28.e1-8. 13. Figueras F, Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol. 2011;204:288-300. 14. Kase BA, Carreno CA, Blackwell SC. Customized estimated fetal weight: a novel antenatal tool to diagnose abnormal fetal growth. Am J Obstet Gynecol. 2012;20:218.e1-5. 15. Anderson NH, Sadler LC, McKinlay CJ, McCowan LM. INTERGROWTH-21st vs customized birthweight standards for identification of perinatal mortality and morbidity. Am J Obstet Gynecol. 2016;214:509.e1-7.

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References

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16. Gordijn SJ, Beune IM, Thilaganathan B, et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016;48:333-9 17. Seeds JW, Peng T. Impaired growth and risk of fetal death: is the tenth percentile the appropriate standard? Am J Obstet Gynecol. 1998;178:658-69. 18. Crimmins S, Desai A, Block-Abraham D, Berg C, Gembruch U, Baschat AA. A comparison of Doppler and biophysical findings between liveborn and stillborn growth-restricted fetuses. Am J Obstet Gynecol. 2014;211:669.e1-10. 19. Chauhan SP, Magann EF. Screening for fetal growth restriction. Clin Obstet Gynecol. 2006;49:284-94. 20. Grisaru-Granovsky S, Reichman B, Lerner-Geva L, et al; Israel Neonatal Network. Mortality and morbidity in preterm small-for-gestational-age infants: a populationbased study. Am J Obstet Gynecol. 2012;206:150.e1-7. 21. Boulet SL, Alexander GR, Salihu HM, Kirby RS, Carlo WA. Fetal growth risk curves: defining levels of fetal growth restriction by neonatal death risk. Am J Obstet Gynecol. 2006;195:1571-7. 22. Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol. 2004;191:481-7. 23. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med. 1999;340:1234-8. 24. Mendez-Figueroa H, Truong VT, Pedroza C, Khan AM, Chauhan SP. Small-for-gestationalage infants among uncomplicated pregnancies at term: a secondary analysis of 9 Maternal-Fetal Medicine Units Network studies. Am J Obstet Gynecol. 2016;215:628.e1628.e7. 25. American College of Obstetricians and Gynecologist. Fetal Growth Restriction. ACOG practice bulletin No. 134. Washington, DC: American College of Obstetricians and Gynecologist; 2013. 26. Society for Maternal-Fetal Medicine Publications Committee, Berkley E, Chauhan SP, Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction. Am J Obstet Gynecol. 2012;206:300-8. 27. Chauhan SP, Taylor M, Shields D, Parker D, Scardo JA, Magann EF. Intrauterine growth restriction and oligohydramnios among high-risk patients. Am J Perinatol.2007;24:21521. 28. Rochelson BL, Schulman H, Fleischer A, et al. The clinical significance of Doppler umbilical artery velocimetry in the small for gestational age fetus. Am J Obstet Gynecol. 1987;156:1223-6. 29. Tyson JE, Kennedy K, Broyles S, Rosenfeld CR. The small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decrease survival? Pediatrics. 1995;95:534-8. 30. Trudell AS, Cahill AG, Tuuli MG, Macones GA, Odibo AO. Risk of stillbirth after 37 weeks in pregnancies complicated by small-for-gestational-age fetuses. Am J Obstet Gynecol. 2013;208:376.e1-7. 31. Gonzalez JM, Stamilio DM, Ural S, Macones GA, Odibo AO. Relationship between abnormal fetal testing and adverse perinatal outcomes in intrauterine growth restriction. Am J Obstet Gynecol. 2007;196:e48-51.

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32. Pilliod RA, Cheng YW, Snowden JM, Doss AE, Caughey AB. The risk of intrauterine fetal death in the small-for-gestational-age fetus. Am J Obstet Gynecol. 2012;207:318.e1-6. 33. Mendez-Figueroa H, Truong VT, Pedroza C, Chauhan SP. Morbidity and Mortality in Small-for-Gestational-Age Infants: A Secondary Analysis of Nine MFMU Network Studies. Am J Perinatol. 2016 Aug 17. 34. Chen HY, Chauhan SP, Ward TC, Mori N, Gass ET, Cisler RA. Aberrant fetal growth and early, late, and postneonatal mortality: an analysis of Milwaukee births, 1996-2007. Am J Obstet Gynecol. 2011;204:261.e1-261.e10. 35. Manogura AC, Turan O, Kush ML, et al. Predictors of necrotizing enterocolitis in preterm growth-restricted neonates. Am J Obstet Gynecol. 2008;198:638.e1-5. 36. Pallotto EK, Kilbride HW. Perinatal outcome and later implications of intrauterine growth restriction. Clin Obstet Gynecol. 2006;49:257-69. 37. Baschat AA. Neurodevelopment after fetal growth restriction. Fetal Diagn Ther. 2014;36:136-42. 38. Paulson JF, Chauhan SP, Hill JB, Abuhamad AZ. Severe small size for gestational age and cognitive function: catch-up phenomenon possible. Am J Obstet Gynecol. 2012;207:119.e1-5. 39. Moore GS, Kneitel AW, Walker CK, Gilbert WM, Xing G. Autism risk in small- and largefor-gestational-age infants. Am J Obstet Gynecol 2012;206:314.e1-9. 40. Barker DJ. The developmental origins of chronic adult disease. Acta Paediatr Suppl. 2004;93:26-33. 41. Green-top Guideline No. 31. London, UK: Royal College of Obstetricians and Gynecologists; February 2013, Minor revisions – January 2014. Available at: http://www.rcog.org.uk/globalassets/documents/guidelines/gtg_31.pdf Accessed March 20, 2016. 42. Chauhan SP, Charania SF, McLaren RA, Devoe LD, Ross EL, Hendrix NW, Morrison JC. Ultrasonographic estimate of birth weight at 24 to 34 weeks: a multicenter study. Am J Obstet Gynecol. 1998;179:909-16. 43. Chauhan SP, Hendrix NW, Magann EF, Morrison JC, Scardo JA, Berghella V. A review of sonographic estimate of fetal weight: vagaries of accuracy. J Matern Fetal Neonatal Med. 2005;18:211-20. 44. Abuhamad AZ; ACOG Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin, clinical management guidelines for obstetrician-gynecologists number 98, October 2008 (replaces Practice Bulletin number 58, December 2004). Ultrasonography in pregnancy. Obstet Gynecol. 2008;112:951-61. 45. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87:163-8. 46. Duryea EL, Hawkins JS, McIntire DD, Casey BM, Leveno KJ. A revised birth weight reference for the United States. Obstet Gynecol. 2014;124:16-22. 47. Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. Am J Obstet Gynecol. 1985;151:333-7.

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48. Anderson NG, Jolley IJ, Wells JE. Sonographic estimation of fetal weight: comparison of bias, precision and consistency using 12 different formulae. Ultrasound Obstet Gynecol. 2007;30:173-9. 49. Mongelli M, Ek S, Tambyrajia R. Screening for fetal growth restriction: a mathematical model of the effect of time interval and ultrasound error. Obstet Gynecol. 1998;92:90812. 50. American College of Obstetricians and Gynecologist. Diagnosis and management of preeclampsia and eclampsia. ACOG practice bulletin No. 33. Washington, DC: American College of Obstetricians and Gynecologist; 2002. 51. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92:529-534. 52. Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD: Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol. 2009;29:130-6. 53. Minior VK, Divon MY. Fetal growth restriction at term: myth or reality? Obstet Gynecol. 1998;92:57-60. 54. Chauhan SP, Beydoun H, Chang E, et al. Prenatal Detection of Fetal Growth Restriction in Newborns Classified as Small for Gestational Age: Correlates and Risk of Neonatal Morbidity. Am J Perinatol. 2014;31:187-94. 55. Monier I, Blondel B, Ego A, Kaminiski M, Goffinet F, Zeitlin J. Poor effectiveness of antenatal detection of fetal growth restriction and consequences for obstetric management and neonatal outcomes: a French national study. BJOG.2015;122:518-27. 56. Monier I, Blondel B, Ego A, Kaminski M, Goffinet F, Zeitlin J. Does the Presence of Risk Factors for Fetal Growth Restriction Increase the Probability of Antenatal Detection? A French National Study. Paediatr Perinat Epidemiol. 2016;30:46-55. 57. O'Dwyer V, Burke G, Unterscheider J et al. Defining the residual risk of adverse perinatal outcome in growth-restricted fetuses with normal umbilical artery blood flow. Am J Obstet Gynecol. 2014;211:420.e1-5. 58. Monteith C, Flood K, Mullers S, et al. Evaluation of normalizing cerebroplacental ratio as a potential predictor for adverse outcome in intrauterine growth restriction: results of the multicenter Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction (PORTO) study. Am J Obstet Gynecol. 2016 Nov 11. 59. Flood K, Unterscheider J, Daly S, et al. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. Am J Obstet Gynecol. 2014;211:288.e1-5. Erratum in: Am J Obstet Gynecol. 2015;213:88. 60. von Beckerath AK, Kollmann M, Rotky-Fast C, Karpf E, Lang U, Klaritsch P. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol. 2013;208:130.e1-6. 61. Maggio L, Dahlke JD, Mendez-Figueroa H, Albright CM, Chauhan SP, Wenstrom KD. Perinatal outcomes with normal compared with elevated umbilical artery systolic-todiastolic ratios in fetal growth restriction. Obstet Gynecol. 2015;125:863-9.

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62. Grobman WA, Lai Y, Rouse DJ, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. The association of cerebral palsy and death with small-for-gestational-age birthweight in preterm neonates by individualized and population-based percentiles. Am J Obstet Gynecol. 2013;209:340.e1-5. 63. Willinger M, Ko CW, Reddy UM. Racial disparities in stillbirth risk across gestation in the United States. Am J Obstet Gynecol. 2009;201:469.e1-8. 64. Bacak SJ, Baptiste-Roberts K, Amon E, Ireland B, Leet T. Risk factors for neonatal mortality among extremely-low-birth-weight infants. Am J Obstet Gynecol. 2005;192:862-7. 65. Minior VK, Shatzkin E, Divon MY. Nucleated red blood cell count in the differentiation of fetuses with pathologic growth restriction from healthy small-for-gestational-age fetuses. Am J Obstet Gynecol. 2000;182:1107-9. 66. Sciscione AC, Gorman R, Callan NA. Adjustment of birth weight standards for maternal and infant characteristics improves the prediction of outcome in the small-forgestational-age infant. Am J Obstet Gynecol. 1996;175:544-7. 67. Larkin JC, Chauhan SP, Simhan HN. Small for Gestational Age: The Differential Mortality When Detected versus Undetected Antenatally. Am J Perinatol. 2016 Sep 14. 68. Marrs CC, Mendez-Figueroa H, Hammad IA, Chauhan SP. Differential Morbidity in Preterm Small versus Appropriate for Gestational Age: Perhaps Unverifiable. Am J Perinatol. 2015;32:1251-6. 69. Boers KE, Vijgen SM, Bijlenga D, et al; DIGITAT study group. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ. 2010;341:c7087. 70. GRIT Study Group. A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. BJOG. 2003;110:27-32. 71. Lees CC, Marlow N, Arabin B, et al; TRUFFLE Group. Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound Obstet Gynecol. 2013;42:4008. 72. Sovio U, White IR, Dacey A, Pasupathy D, Smith GC. Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study. Lancet. 2015;386:2089-97. Erratum in: Lancet. 2015;386:2058. 73. Sharma KJ, Esakoff TF, Guillet A, Burwick RM, Caughey AB. Pregnancies complicated by both preeclampsia and growth restriction between 34 and 37 weeks' gestation are associated with adverse perinatal outcomes. J Matern Fetal Neonatal Med. 2016;10:1-4. 74. Malhotra A, Sasi A, Miller SL, Jenkin G, Polglase GR. The Efficacy of Surfactant Replacement Therapy in the Growth-Restricted Preterm Infant: What is the Evidence? Front Pediatr. 2014;2:118. 75. MacDorman MF, Hoyert DL, Mathews TJ. Recent declines in infant mortality in the United States, 2005–2011. NCHS data brief, no 120. Hyattsville, MD: National Center for Health Statistics. 2013.

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76. Hanson M, Kiserud T, Visser GH, Brocklehurst P, Schneider EB. Optimal fetal growth: a misconception? Am J Obstet Gynecol. 2015;213:332.e1-4. 77. Deter, RL Individualized Growth Assessment: Evaluation of growth using each fetus as its own control. Semin Perinatol 2004; 28: 23-32. 78. Deter RL, Spence L. Identification of macrosomic, normal and intrauterine growth retarded neonates using the modified Neonatal Growth Assessment Score. Fetal Diagn Ther. 2004; 19:58-67. 79. Bukowski R, Hansen NI, Willinger M, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network. Fetal growth and risk of stillbirth: a population-based case-control study. PLoS Med. 2014;11:e1001633. 80. Stirnemann J, Villar J, Salomon LJ, et al; for the International Fetal Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). International Estimated Fetal Weight Standards of the INTERGROWTH-21(st) Project. Ultrasound Obstet Gynecol. 2016 Nov 2. 81. Papageorghiou AT, Ohuma EO, Altman DG, et al; International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). International standards for fetal growth based on serial ultrasound measurements the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet. 2014;384:869-79. Erratum in: Lancet. 014;384:1264. 82. Villar J, Papageorghiou AT, Pang R, et al. Monitoring human growth and development: a continuum from the womb to the classroom. Am J Obstet Gynecol. 2015;213:494-9. 83. Chauhan SP, Rouse DJ, Ananth CV, et al. Screening for intrauterine growth restriction in uncomplicated pregnancies: time for action. Am J Perinatol. 2013;30:33-9. 84. Romero R, Deter R. Should serial fetal biometry be used in all pregnancies? Lancet. 2015;386:2038-40.

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Table 1. Maternal demographics of study population

< 30 ≥ 30

34 (11%) 252 (79%) 34 (10%) 125 (40%) 12.6 ± 5.1

28.7 ± 8.5

27.8 ± 9.0

257 (63%) 150 (37%)

183 (68%) 87 (32%)

p

RI PT

62(12%) 394 (77%) 57 (11%) 234 (46%) 12 ± 4.5

26.5 ± 5.9

OR (95% CI)

NS

1.16 (0.73-1.85) 0.89 (0.91-1.1) 1.1 (0.66-1.69) 1.3 (0.97-1.75)

SC

< 20 20-34 ≥ 35 Nulliparous GA at first visit (weeks) BMI at first visit (kg/m2)

SEFW 5-9th centile (N = 321)

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Maternal age (years)

SEFW < 5th centile (N = 513) 26.8 ± 5.9

NS NS NS NS NS

NS

0.82 (0.58-1.14) 1.78 (0.87-1.70)

NS NS

219 (69%)

0.84 (0.61-1.14)

NS

85 (27%) 8 (2%) 5 (2%)

1.06 (0.76-1.47) 1.55 (0.63-3.90) 1.96 (0.66-6.23)

NS NS NS

Ethnicity

African American

321 (65%)

Caucasian Hispanic Others

138 (28%) 19 (4%) 15 (3%)

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Social history

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Alcohol 12 (2%) 7 (2%) 1.08 (0.39-3.06) NS Tobacco 114 (22%) 78 (24%) 0.89 (0.64-1.26) NS Drugs 48 (9%) 17 (5%) 1.85 (1.01-3.41) 0.034 Data presented as mean ± standard deviation or % (N) SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; NS, not significant Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

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Table 2. Maternal obstetrical and medical history

Previous preterm birth Previous small for gestational age

71 (14%)

45 (14%)

Maternal Medical History

p

0.97 (0.69-1.37)

NS

1.02 (0.67-1.56)

NS

112 (35%)

0.99 (0.73-1.34)

NS

113 (28%)

59 (18%)

1.25 (0.87-1.81)

NS

Pregestational Diabetes

30 (6%)

24 (8%)

0.77 (0.43-1.39)

NS

Autoimmune disease

20 (4%)

10 (3%)

1.26 (0.55-2.93)

NS

SC

178 (35%)

M AN U

Composite maternal prepregnancy morbidity Chronic hypertension

OR (95% CI)

RI PT

SEFW < 5th SEFW 5-9th centile centile (N = 513) (N = 321) Obstetrical history 124 (24%) 79 (25%)

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Hemoglobinopathies 33 (7%) 21 (6%) 0.98 (0.54-1.79) NS Cyanotic heart disease 2 (0.4%) 2 (0.6%) 0.62 (0.06-6.21) NS Restrictive lungs disease 10 (2%) 12 (4%) 0.51 (0.2-1.28) NS IBD 5 (1%) 1 (0.6%) 1.57 (0.27-11.7) NS Thrombophilia 9 (2%) 12 (4%) 0.46 (0.17-1.18) NS Kidney disease 8 (2%) 1 (0.3%) 5.1 (0.64-108.6) NS Data presented as % (N) SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; NS, not significant; IBD, inflammatory bowel disease Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

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b

Anemia

74 (14%)

1.36 (0.63-2.86) 0.98 (0.63-1.54) 0.65 (0.33-1.27)

NS NS NS

1.0 (0.52-1.95)

NS

0.79 (0.54-1.18)

NS

164 (32%) 67 (21%) 1.78 (1.3-2.5) 17 (10%) 12 (18%) 0.5 (0.2-1.2) 27 (17%) 24 (36%) 0.4 (0.2-0.7) 120 (73%) 31 (46%) 3.2 (1.7-5.9) th SEFW < 10 percentile for gestational age

SC

Hypertensive disease GHTN Mild preeclampsia Severe preeclampsia

56 (17%)

p

M AN U

c

OR (95% CI)

RI PT

Table 3. Maternal antepartum complications of study population SEFW < 5th SEFW 5-9th centile centile (N = 513) (N = 321) Vaginal bleeding 25 (5%) 12 (4%) a Infectious disease 61(12%) 39 (12%) Spontaneous preterm 21 (4%) 20 (6%) labor PPROM 27 (5%) 17 (5%)

0.001 NS 0.003 < 0.0001

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GA at detection of SEFW 30.5 ± 5.6 32.5±4.6 < 0.0001 th < 10 percentile SEFW < 10th percentile 497 (97%) 257 (80%) 0.13 (0.07-0.24) <0.0001 persisted on the last scand Diagnosis to delivery 31.9±34.7 28.2±30.5 NS interval (days) Data presented as mean ± standard deviation or % (N) SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; NS, nonsignificant; PPRON, preterm premature rupture of membranes; GHTN, gestational hypertension; a Presence any of the following infections: CMV, toxoplasmosis, rubella, varicella-zoster, syphilis, listeria, tuberculosis, chlamydia, mycoplasma, herpes b Hemoglobin <11 g/dl c Percentage calculations within 3 subgroups of hypertensive disease spectrum refer to the total percentage of patients with hypertensive disease (164 patients in <5%ile and 67 patients in 59%ile groups) d On the last sonographic examination prior to delivery, the estimated fetal weight was > 10%ile for gestational age Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

SC

Table 4. Maternal intrapartum and postpartum complications

RI PT

ACCEPTED MANUSCRIPT

M AN U

SEFW < 5th SEFW 5-9th OR centile centile (95% CI) (N = 513) (N = 321) Gestational age (GA) at delivery 35.7 ± 3.6 35.6 ± 3.6 102 (20%) 29 (9%) 2.5 (1.6-3.9) 153 (30%) 78 (24%) 1.3 (0.9-1.8) 258 (50%) 214 (67%) 0.5 (0.4-0.7) Mode of delivery 277 (45%) 180 (56%) 0.63 (0.47-0.84)

Cesarean delivery Arrest of labor

AC C

NR FHRT Others VBAC

NS < 0.0001 NS < 0.0001 0.001

7 (1%)

5 (2%)

0.88 (0.25-3.22)

NS

273 (54%) 16 (6%)

129 (40%) 14 (11%)

1.72 (1.28-2.31) 0.49 (0.22-1.11)

< 0.0001 NS

1.78 (1.13-2.83) 0.71 (0.46-1.11) 1.18 (0.03-0.9)

0.01 NS 0.032

0.57 (0.28-1.14)

NS

0.84 (0.06-23.5) 0.49 (0.13-1.89) 0.77 (0.28-2.18) 0.42 (0.04-4.16)

NS NS NS NS ---

133 (48%) 43 (34%) 128 (46%) 69 (55%) 2 (0.4%) 7 (2%) Peripartum maternal morbidity 24 (5%) 17 (9%)

EP

Spontaneous vaginal delivery Operative delivery

TE D

GA at delivery (weeks) < 32 32-36 ≥ 37

p

Composite maternal morbidity Intubation 2 (0.5%) 1 (0.5%) ICU admission 6 (1%) 5 (3%) Blood transfusion 13 (3%) 7 (4%) Pulmonary edema 2 (0.5%) 2 (1%) Amniotic fluid embolism 1 (0.2%) 0 (0%) Cesarean hysterectomy 0 (0%) 2 (1%) Data presented as mean ± standard deviation or % (N)

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SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; NS, nonsignificant; GA, gestational age; NR FHR, non-reassuring fetal heart rate tracing; VBAC, vaginal birth after cesarean; ICU, intensive care unit

AC C

EP

TE D

M AN U

SC

RI PT

Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

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Table 5. Neonatal outcomes

2035 ± 692 131 (41%) 115 (36%) 75 (23%)

Apgar score <7 at 5 min Umbilical arterial pH

44 ( 9%) 366 (71%)

18 (6%) 190 (59%)

< 7.10

17 (4.6%)

4 (2%)

< 7.00

5 (1%)

p

1.62 (0.39-6.2)

NS

RI PT

2039 ± 690 302 (59%) 129 (25%) 82 (16%)

OR (95% CI)

NS < 0.0001 0.001 0.011

1.58 (0.87-2.89)

NS

0.93 (0.24-3.8)

NS

SC

SEFW 5-9th centile (N = 321) 39 (91%)

M AN U

ANCS if delivered < 34 weeks Birth weight < 5% for GA 5-9% for GA ≥ 10% for GA

SEFW < 5th centile (N = 513) 142 (94%)

0 (0%)

--

TE D

NICU admission 147 (29%) 49 (15%) 2.23 (1.01-3.25) <0.0001 Length of stay (days) 45.5 ± 48.02 47.4 ± 49.3 NS Data presented as mean ± standard deviation or % (N) SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; NS, nonsignificant; ANCS, antenatal corticosteroids; GA, gestational age; NICU, neonatal intensive care unit

AC C

EP

Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

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Table 6. Composite neonatal morbidity of study population

2.79 (1.84-4.24)

147 (29%) 11 (2%) 6 (1.2%) 16 (3%)

40 (13%) 5 (2%) 1 (0.3%) 6 (2%)

1.56 (1.27-1.92) 1.16 (0.63-2.13) -0.94 (0.55-1.61)

OR (95% CI) Unadjusted Adjusted*

SC

RDS Sepsis IVH NEC

SEFW 5-9th centile (N = 321) 42 (13%)

2.41 (1.53-3.80)

RI PT

Composite neonatal morbidity

SEFW < 5th centile (N = 513) 161 (31%)

1.43 (1.12-1.79) 0.9 (0.47-1.72) -0.84 (0.46-1.51)

AC C

EP

TE D

M AN U

Thrombocytopenia 23 (5%) 1 (0.3%) --Seizures 1 (0.2%) 0 (0%) --Death~ 13 (2.5%) 2 (0.6%) 4.05 (0.48-3.89) 4.17 (0.45-38.48) Data presented as % (N) SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis *Adjusted for center, maternal age, race, BMI at first visit, smoking status, use of alcohol, use of drugs, neonatal gender ~There were total of 19 deaths among the cohorts but 4 died 28 days after birth and are not included in the neonatal mortality calculations Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.

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Table 7. Composite neonatal morbidity with ultrasonographic examination < 28 days of delivery SEFW < 5%ile (N=474)

SEFW 5-9%ile (N=207)

OR (95% CI) Unadjusted Adjusted* 2.53 (1.57-4.06) 2.22 (1.34-3.67)

AC C

EP

TE D

M AN U

SC

RI PT

Composite Neonatal 159 (34%) 31 (15%) Morbidity RDS 147 (31%) 30 (15%) 2.42 (1.49-3.91) 2.13 (1.28-3.54) Proven sepsis 10 (2%) 5 (2%) 0.80 (0.23-2.78) 0.55 (0.13-2.39) IVH grade III/IV 7 (1.5%) 0 (0.0%) --NEC 15 (3%) 5 (2%) 0.83 (0.27-2.50) 0.83 (0.25-2.81) Thrombocytopenia 20 (4%) 1 (0.5%) --Seizures 1 (0.2%) 0 (0.0%) --Death 10 (2.1%) 2 (1.0%) 1.15 (0.22-6.02) 0.96 (0.17-5.45) Data presented as % (N) USE, ultrasonographic examination; SEFW, sonographic estimated fetal weight; OR, odds ratio; CI, confidence intervals; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis *Adjusted for center, maternal age, race, BMI at first visit, smoking status, use of alcohol, use of drugs, neonatal gender Total numbers in individual rows may not match column totals, as there were some patients with missing data and they were excluded from analysis.