Clinical trial NCT05043753: "Fetal GRowth AbnorMality DEtection Trial"
Official title: Department of Obstetrics and Gynecology Modena Policlinico Hospital Vial Del Pozzo 71, 41125 Modena
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Small for Gestational Age Infant
Large for Gestational Age Infant
Oligohydramnios
Polyhydramnios
Lead sponsor: University of Modena and Reggio Emilia
Sponsor class: OTHER
First posted: 2021-09-14
Enrollment: 1566
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: To compare the diagnostic accuracy of symphysis fundal height (SFH) as opposed to SFH combined with point of care ultrasound to measure the fetal abdominal circumference (POC-US-AC) in identifying small and large for gestational age infants (SGA and LGA infants) among low-risk pregnant women cared for by midwives after 35 weeks' gestation.

Low risk pregnancies will be evaluated at 35-38, 40, 41, and 41+ weeks' gestation by midwives trained in SFH measurement and POC-US. Formal obstetric US performed by a perinatologist (i.e high risk obstetrician) will be performed in case SFH and/or POC-US suspect fetal growth or amniotic fluid abnormalities. Prenatal evaluations will be compared to actual birthweights
Primary purpose: DIAGNOSTIC

Brief summary: The present trial intends to assess the diagnostic accuracy of symphysis fundal height (SFH) as opposed to SFH combined with point of care ultrasound to measure the fetal abdominal circumference (POC-US-AC) in identifying small and large for gestational age infants (SGA and LGA infants) among low-risk pregnant women cared for by midwives after 35 weeks' gestation.

Low risk pregnancies will be evaluated at 35-38, 40, 41, and 41+ weeks' gestation by midwives trained in SFH measurement and POC-US. Formal obstetric US performed by a perinatologist (i.e high risk obstetrician) will be performed in case SFH and/or POC-US suspect fetal growth or amniotic fluid abnormalities. Prenatal evaluations will be compared to actual birthweights.

Detailed description: Birthweight below the 10th (small for gestational age or SGA) or above the 90th (large for gestational age or LGA) percentile for gestational age has been associated with adverse maternal, fetal and neonatal outcomes. As birthweight reflects intrauterine development, accurate identification of abnormal fetal growth would allow obstetric providers to prevent adverse outcomes and mitigate complications associated with abnormal development.

Symphysis fundal height (SFH) measured in centimeters after 24 weeks of gestation is recommended as the standard of care to screen for fetal growth abnormalities among low-risk pregnancies. This method is low-cost, and easy to perform, but there is a lack of evidence supporting its effectiveness due to its poor sensitivity. Ultrasonography, the technique utilized to identify fetal growth abnormalities, is a costly procedure which involves the use of advanced equipment and providers, to perform and review the ultrasound, as well as a full examination with multiple measurements and images. Despite a few encouraging reports, insufficient evidence supports routine 3rd trimester ultrasound in low- risk pregnancies to improve detection of abnormal fetal growth.

Sonographic measurement of the abdominal circumference (AC) in the fetus was shown to be the single most useful indicator of fetal growth. Measurement of AC does not require extensive training, long time to acquire, or expensive ultrasound machines. It can be easily performed in the office by midwives who are specifically trained in obtaining the measurement. Therefore, we intended to evaluate if the use of bedside point of care ultrasound (POC-US) by midwives to evaluate fetal AC during routine antenatal visits in low-risk pregnancies would increase the accuracy of SFH in identifying fetuses with birthweight \< 10th or \> 90th, when compared to SFH alone.

This is an open label, investigator sponsored, two arms randomized controlled trial. Patients who satisfy all inclusion criteria, have no exclusion criteria, and have signed the written informed consent will be randomly assigned to screening of fetal growth abnormalities during routine antenatal appointments held by midwives according to SFH or SFH + POC-US-AC.

Low risk pregnant women are interviewed by a midwife at 35-38 weeks' gestation, who also reviews their medical and obstetrical history, prenatal labs and the ultrasound reports to discriminate between high and low-risk pregnancies. Patients who satisfy all inclusion criteria and do not have any exclusion criteria will be randomly assigned to one of two different approaches to identify fetal growth abnormalities and predict abnormal birthweight, after signing the written informed consent.

Screening test in the control group: Symphysis fundal height measurement. Fundal height is measured by trained midwives at each scheduled antenatal appointment from the pubis symphysis to the top of the uterine fundus, using a paper measuring tape in centimeters. Size greater than dates is suspected if the measurement is above the 90th gestational age specific percentile according to the Intergrowth 21 SFH references (Papageorghiu 2016). Similarly, size less than dates is recorded if the measurement is below the 10th percentile for age according to the Intergrowth 21 SFH references (Papageorghiu 2016). Formal obstetric ultrasound is requested if the SFH is \> 90th percentile, if it is \< 10th , or if it drops 50 growth centiles in two subsequent evaluations.

Screening test in the intervention group: Symphysis fundal height measurement + point of care ultrasound. After assessing SFH at each clinical encounter, the midwife will perform a POC-US to measure the fetal AC and evaluate the quantity of amniotic fluid. A positive screen for fetal growth restriction (indicative of a potential SGA infant) consists in a measured AC less than the 10th percentile for gestational age according to the standards defined by Nicolini et al in 1986 on an Italian population; instead, a positive screen for macrosomia (suggestive of a potential LGA infant) is an AC greater than the 90th percentile for gestational age according to the references set by Nicolini et al in 1996. Formal obstetric ultrasound is requested if the AC is \> 90th percentile, if it is \< 10th, or if it drops 50 growth centiles in two subsequent evaluations. Amniotic fluid volume will be evaluated determining the deepest vertical pocket (DVP).

A formal US is requested in case uterine size is measured as ≤ than the 10th or ≥ than the 90th percentile for gestational age according to Intergrowth 21, when POC - US reveals AC \< 10th percentile, AC \> 90th percentile according to Nicolini et al, in case DVP \< 2 x 1 cm, or DVP \> 8 x 1 cm, or also if SFH or AC drop \> 50 percentiles comparing two subsequent evaluations. Patients randomized to SFH + POC-US will have a formal US if either technique suspects abnormal fetal growth.

Formal US requested due to an abnormal screening test will be distinguished from scans ordered due to other indications, such as hypertensive disorders of pregnancy, or cholestasis of pregnancy diagnosed after enrollment. Hadlock' s references will be used to estimate fetal weight, and therefore to define FGR (i.e estimated fetal weight or AC \< 10th percentile) as well as macrosomia (i.e estimated fetal weight or AC \> 90th percentile).

Prenatal evaluation of fetal growth will be compared to the birthweight percentile according to the INeS neonatal charts (Bertino 2010) to identify SGA, LGA and AGA (appropriate for gestational age) infants.

After the initial evaluation low risk pregnancies are scheduled for antenatal appointments with a midwife at 40, 41 and 41+ weeks' gestation. All patients will have a POC-US by a midwife at 41, and 41+ weeks' gestation to screen for amniotic fluid abnormalities associated with protracted pregnancy, independently of the randomization arm. A midwife will perform SFH or SFH + POCT-US (according to randomization) at enrolment (35-38 weeks' gestation) and at 40 weeks. As sonographic assessment of fetal growth should not be performed more frequently than every 2 weeks due to the error associated with measurements; POC-US will only evaluate amniotic fluid volume at 41 and 41+3 weeks' gestation (unless the patient has missed a previous appointment), even among women randomized to SFH + POC-US.

The purpose of the study is to evaluate the most accurate approach to identify prenatally those pregnancies that will result in SGA or LGA infants. Prenatal evaluation consists in a universal screening test for fetal growth abnormalities (either SFH or SFH + POC US) followed by a confirmatory test (formal obstetric US) performed only when the initial screening test is positive. Fetal growth or amniotic fluid abnormalities are diagnosed in utero if confirmed by a formal obstetric ultrasound, and not when only suspected by a screening test; in fact, the study seeks to evaluate what is the most accurate combination of screening and confirmatory tests, and not the effectiveness of the screening test alone.

Eligibility criteria: Inclusion Criteria:

* Maternal age ≥ 18 years and ability to give informed consent.
* Singleton gestation
* Ultrasound examination that confirms or revises the EDD before 14 weeks of gestational age
* Gestational age ≥ 35 weeks' gestation
* Normal aneuploidy screening (1st trimester screening, 2nd trimester screening, integrated screening, NIPT) when performed
* Spontaneously conceived pregnancy (i.e the current pregnancy is not the result of in vitro fertilization)

Exclusion Criteria:

* Fetal chromosomal or genetic abnormalities if invasive prenatal diagnosis is performed
* Fetal malformations or soft markers identified on fetal anatomy survey
* Episodes of uterine bleeding after 24 weeks gestation. Unobserved self-reported bleeding with confirmed intact pregnancy on ultrasound after the bleeding episode is not an exclusion criteria.
* Uterine/placental abnormalities including uterine malformations (i.e bicornuate uterus, didelpus uterus), abnormal placentation (placenta previa, accreta, percreta), uterine fibroids.
* Cerclage in the current pregnancy
* History of intrauterine fetal demise
* History of fetal growth restriction or birth weight \> 4Kg in a previous pregnancy
* Fetal isoimmunization or alloimmunization
* Fetal demise in previous pregnancies
* Cancer (including melanoma but excluding other skin cancers). Dysplastic or pre-neoplatic conditions such as cervical intraepithelial neoplasia are admissible.
* Endocrine disease including thyroid disease (recently diagnosed or whose medication dose is not stable), adrenal disease, diabetes mellitus (pregestational and gestational).
* Renal disease with altered renal function (creatinine \> 0.9, proteinuria \> 300 mg/24 hour)
* Epilepsy or other seizure disorder
* Any collagen disease (lupus erythematosus, scleroderma, etc.)
* Active liver disease (acute hepatitis, chronic active hepatitis, persistently abnormal liver enzymes). Liver disorders accounting for cholestasis (including cholestasis of pregnancy) if diagnosed prior to enrollment.
* Hematological disorder including alloimmune and isoimmune thrombocytopenia but excluding mild iron deficiency anemia (Hb \> 9 gm/dl). Patients with sickle cell disease are excluded.
* Chronic pulmonary disease including asthma requiring regular use of medication and active TB. An asthma inhaler used on an as needed basis for a cold or an asthma attack is not considered regular use.
* Heart disease except mitral value prolapse not requiring medication
* Cardiovascular disorders: chronic hypertension, gestational hypertension or preeclampsia diagnosed prior to enrollment
* Infectious diseases: HIV, CMV, toxoplasmosis, parvovirus B19, HBV, HCV
* Chronic treatments with medications such as aspirin, steroids, anti-hypertensive agents, immunosuppressants, antineoplastic drugs.
* Prior laparoscopic or open uterine surgeries where the uterine cavity was entered (such as myomectomies)
* Resectoscopic myomectomies (prior resectoscopic polypectomies are not contraindications)
* Prior classical cesarean deliveries.

Primary outcomes:
measure: Number of prenatally identified fetuses that will be classified as small or large for gestational age as infants (SGA and LGA infants)
timeFrame: From enrollment through study completion, an average of 1 year. Prenatal evaluation of fetal growth and amniotic fluid volume will be performed at 35-38, 40,41, and 41+ weeks' gestation. Infants' weights will be evaluated at birth
Secondary outcomes:
measure: Number of formal obstetric ultrasound (US) requested due to abnormal fetal growth or amniotic fluid suspected prenatally
timeFrame: From enrollment through study completion, an average of 1 year. Formal obstetric ultrasound will be requested in case of suspicion of abnormal fetal growth or amniotic fluid on screening with symphysis fundal height associated or not to POC ultrasound
measure: Number of cases of oligohydramnios and polyhydramnios identified on formal obstetric US after being suspected on prenatal evaluation
timeFrame: From enrollment through study completion, an average of 1 year. Formal obstetric ultrasound will be requested in case of suspicion of abnormal fetal growth or amniotic fluid on screening with symphysis fundal height associated or not to POC ultrasound
measure: Number of deliveries indicated by amniotic fluid or fetal growth abnormalities detected on formal obstetric US
timeFrame: At the time of delivery, from enrollment through study completion, an average of 1 year
measure: Number of adverse neonatal outcome cases
timeFrame: At the time of delivery, from enrollment through study completion, an average of 1 year
measure: Number of adverse maternal outcome cases
timeFrame: At the time of delivery, from enrollment through study completion, an average of 1 year
Other outcomes:
Locations:
city: Cesena
country: Italy
facility: Cesena Hospital
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico di Modena
city: Monza
country: Italy
facility: Foundation MBBM at San Gerardo Hospital, University of Milan-Bicocca School of Medicine and Surgery, Monza, Italy.
Study officials:
affiliation: University of Modena and Reggio Emilia, Modena Policlinico Hospital, Department of Obstetrics and Gynecology
name: Giuseppe Chiossi, MD
role: PRINCIPAL_INVESTIGATOR
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