The NICHD Fetal Growth Study: Twin Gestations

NICHD Fetal Growth Study: Twin Gestations

Normal growth and development of twins are important for the long-term health of the children. The purpose of this study was to empirically define the trajectory of fetal growth in dichorionic twins using longitudinal two-dimensional ultrasonography and to compare the fetal growth trajectories for dichorionic twins with those based on a growth standard developed by our group for singletons. This knowledge may lead to interventions that could minimize or prevent pregnancy and newborn health problems in the future.

Study Overview

• Status: Completed
• Conditions: Fetal Growth Restriction; Growth Discordancy

Detailed Description

A prospective cohort of 171 women with twin gestations was recruited from eight U.S. sites from 2012 to 2013. After an initial sonogram at 11w0d-13w6d where dichorionicity was confirmed, women were randomized to one of two serial ultrasonology schedules. Ultrasound measurements at each follow-up visit included standard fetal biometrics ((BPD, HC, AC, FL); estimated fetal weight was calculated using a Hadlock formula. Growth curves and percentiles were estimated using linear mixed models with cubic splines. Percentiles were compared statistically at each gestational week between the twins and 1,731 singletons in the Fetal Growth Studies-Singletons cohort.

In addition to 2-D ultrasound measures for analyzing fetal growth, this study recorded maternal anthropometrics and a brief interview to capture changes in health status, stress and depression, and physical activity at each follow-up visit. Four blood draws at baseline and at targeted gestational ages for the eventual identification of biomarkers indicative of fetal growth were collected. After delivery, neonatal anthropometric measures were assessed for each twin, placental biospecimens were collected, and select information about the obstetrical course and newborn status were abstracted from medical charts. These exposures and outcomes provide opportunities to further compare singleton and twin gestations with respect to maternal biomarkers of fetal growth, well-being and maternal nutritional status using banked biospecimens to determine if the biomarkers ranges established for singletons are applicable to twin gestations.

Biospecimen Description:

• Maternal blood sample (serum, plasma, white blood cells, red blood cells and PAXgene RNA) at enrollment, 1st, 3rd, 5th follow-up visits, and delivery
• Cord blood and placentas for consenting women collected at delivery
• Placenta sample or buccal swab (determining zygosity by DNA probe for same sex pairs), collected at delivery

• Study Type: Observational
• Enrollment (Actual): 171

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University Of Alabama
  • California
    • Long Beach, California, United States, 90806
      • University of California-Long Beach
    • Orange, California, United States, 92668
      • University of California, Irvine Medical Center
  • Delaware
    • Newark, Delaware, United States
      • Christiana Care Health Services
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute of Child Health and Human Development (NICHD), 9000 Rockville
  • New York
    • New York, New York, United States, 10032-3784
      • Columbia University
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of S. Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Women with dichorionic twin gestations, irrespective of the mode of conception, maternal medical history or obesity status, were enrolled from eight U.S. clinical centers. Women were enrolled between 8w0d and 13w6d, and accurate dating was required for enrollment. A total of 171 women were recruited, with 152 gestations resulting in live birth.

Description

INCLUSION CRITERIA:

• Twin, viable pregnancy
• 8+0 13+6 weeks of gestation
• Maternal age 18 - 45 years
• Spontaneous pregnancy or pregnancy from ovulation induction or in-vitro fertilization with known date of transfer
• Pregnancy from egg donor or embryo donor (record if anonymous or known source)
• LMP-date and crown-rump length measurement match within certain number of days according to a standard scheme (for larger twin)
• Expect to deliver at one of the participating hospitals

EXCLUSION CRITERIA:

• Fetal reduction (medically induced only)
• Congenital anomalies (structural or chromosomal)
• Either twin with an increased nuchal translucency (>99th percentile for crown-rump length; i.e. 3.5 mm or more)
• Monochorionic twins
• Crown-rump length discordancy >10% in dichorionic twin pregnancies

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
NICHD Fetal Growth Study - Twin Gestations; Women with dichorionic twin gestations were enrolled between 8w0d and 13w6d and followed up to nine months (2012-2013) in this prospective cohort study. Intervention: No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fetal growth trajectories in dichorionic twin pregnancies	Fetal growth trajectories in dichorionic twin pregnancies were created using two- and selected three-dimensional ultrasound measures. Measures included maternal anthropometric measurements and 2D fetal biometry (BPD, HC, AC, FL) using standardized protocols. Women were recruited during the first trimester and followed until delivery. Each woman had seven scheduled ultrasound examinations, one at enrollment and six during follow-up visits. Women were randomized to receive sonograms according to one of the following two schedules: schedule A: 16, 20, 24, 28, 32 and 35 weeks or schedule B: 18, 22, 26, 30, 34 and 36 weeks.	3 years
Comparison of the fetal growth trajectories for dichorionic twins with singletons	The primary analysis compared fetal growth trajectories for dichorionic twins with 1,737 singleton gestations included in the NICHD Fetal Growth Studies - Singleton standard. For modeling twin trajectories, we used linear mixed models with a cubic spline mean structure and a random effects structure that included linear, quadratic, and cubic random effects for the twin pair and an intercept term for the individual fetus within twin pair. The linear mixed models were also used to test for overall differences (i.e., global tests) between the twin and singleton trajectories (for EFW and other measurements) using likelihood ratio tests of interaction terms between spline mean structure terms and twin-singleton indicator variables.	3 years
Incidence of fetal growth restriction (with small-for-gestational age as a proxy) in dichorionic twins (by zygosity)	Using small-for-gestational age as a proxy for growth restriction, we evaluated the percentage of dichorionic twins who would be classified below the 10th percentile using the study-generated singleton non-Hispanic white standard.	3 years
Comparison of singleton and twin gestations for maternal biomarkers of fetal growth	Longitudinal data will compare singleton and twin gestations with respect to maternal biomarkers of fetal growth, well-being and maternal nutritional status using banked biospecimens to determine if the biomarkers ranges established for singletons are applicable to twin gestations.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition	Pending the results of a validation study, measures of fetal fat and lean body mass from 2D ultrasound and/or fractional volumes from 3D will be assessed.	3 years
Genetic and environmental factors affecting fetal growth	Twin gestations offer an opportunity to differentiate genetic from environmental etiologies of developmental disorders, and to gain insight by investigating the role of shared factors versus factors affecting each of the twins independently. This involves comparing results of within cohort versus within twin pairs. The shared factors include maternal nutrition and gestational age, and the non-shared factors are those that affect each twin (e.g., placental placement, growth trajectory).	3 years
Biospecimen repository	The available bank of de-identified specimens will be used to add to our understanding of the determinants associated with fetal growth trajectories or adverse outcomes. The repository will be important for exploring possible epigenetic mechanisms and other specific hypotheses investigators may have.	3 years
Zygosity and growth trajectories	Placental samples for zygosity determination were obtained for all like-sex twin pairs. In the event that placental samples were not able to be obtained for like-sex twin pairs, a buccal swab from each infant was obtained prior to discharge, preferably in the first 48 hours of life. Both placenta zygosity samples and buccal swab samples were sent in real time to the Columbia Placenta Pathology Laboratory for zygosity testing. The research nurse provided women her with zygosity results when the information was available within three months following delivery.	3 years
Conception mode and growth trajectories	Information on mode of conception was collected during the enrollment interview.	3 years
Placental pathology and growth trajectories	The gross anatomy of the placentas (weight, cord length, diameter of the cord, and other gross morphology) were documented by the clinical site's participating pathologist. Photographs of placentas were taken by trained research personnel. Placental samples were obtained according to a standardized protocol. Eventual analysis may include proteomics, DNA analyses (e.g., comparative genomic hybridization, genomics, and assessment of the methylome), RNA expression, and microRNA levels. Also, analysis may include immunocytochemistry, histopathologic and biochemical / molecular studies. Once the research specimens were obtained, the remaining placenta was submitted to the clinical pathology department for processing and analysis.	3 years

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Grantz KL, Grewal J, Albert PS, Wapner R, D'Alton ME, Sciscione A, Grobman WA, Wing DA, Owen J, Newman RB, Chien EK, Gore-Langton RE, Kim S, Zhang C, Buck Louis GM, Hediger ML. Dichorionic twin trajectories: the NICHD Fetal Growth Studies. Am J Obstet Gynecol. 2016 Aug;215(2):221.e1-221.e16. doi: 10.1016/j.ajog.2016.04.044. Epub 2016 Apr 30.
• Amyx MM, Albert PS, Bever AM, Hinkle SN, Owen J, Grobman WA, Newman RB, Chien EK, Gore-Langton RE, Buck Louis GM, Grantz KL. Intrauterine growth discordance across gestation and birthweight discordance in dichorionic twins. Am J Obstet Gynecol. 2020 Feb;222(2):174.e1-174.e10. doi: 10.1016/j.ajog.2019.08.027. Epub 2019 Aug 24.

Study record dates

Study Major Dates

• Study Start: May 29, 2011
• Primary Completion (Actual): August 25, 2013
• Study Completion (Actual): September 30, 2014

Study Registration Dates

• First Submitted: June 8, 2011
• First Submitted That Met QC Criteria: June 8, 2011
• First Posted (Estimate): June 9, 2011

Study Record Updates

• Last Update Posted (Actual): September 5, 2017
• Last Update Submitted That Met QC Criteria: September 1, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Fetal Growth; Growth Discordancy; Twin Growth
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Fetal Growth Retardation
• Other Study ID Numbers: 999911178; 11-CH-N178