The NICHD Fetal Growth Study: Twin Gestations

Fetal growth is an important determinant of health and disease in the perinatal period,
childhood and adult life. NICHD is conducting an ultrasound study in singleton pregnancies to
establish a national standard for normal fetal growth by gestation and interval velocities.
Twins represent 3.2% of all births in the U.S, and these pregnancies are at increased risk
for fetal growth disorders, preterm and, most importantly, very preterm delivery. The rate of
small-for-gestational-age (SGA) defined as below the 10th percentile using a singleton birth
weight-for-gestational-age reference is 35%. Neonatal morbidity is higher in twin gestations
than in singletons (25.6 versus 4 per 1,000), and the infant mortality rate is also higher
(31 versus 6.4 per 1,000). Discrepancy in the sizes of twins at birth is a frequent
phenomenon, and is associated with an increased risk of perinatal morbidity and mortality.

The trajectory of fetal growth in twins throughout gestation has been observed and described
in a few studies, both using ultrasonography and ultrasonography combined with birth weight.
The findings suggest a slowing of growth for almost all twins after 28-30 weeks gestation,
and even twins who had been growing at rates similar to singletons before 28 weeks may show
slowed rates of growth in the third trimester. It has been hypothesized that this pattern of
growth for even well-growing twins is a normal down-regulation in response to a constricted
uterine environment and may underscore the need for a birth weight-for-gestational-age or
ultrasound reference that is specific for twins. As for singleton births, however, such
slow-downs later in pregnancy appear to be associated with earlier delivery and a greater
risk for morbidity associated with preterm birth. This would argue against a separate
reference for twins or, at least, for the development of a growth velocity standard for
singletons and twins to allow for the accurate assessment of interval growth to better manage
these cases.

We propose to conduct the NICHD Fetal Growth Study Twin Gestations, which is a prospective
cohort study with longitudinal measurement of fetal growth conducted in nine clinical
centers. Overall, there are four main research objectives: 1) to describe fetal growth
trajectories in twins using two- and selected three-dimensional ultrasound measures; 2) to
compare and contrast fetal growth trajectories for twins with the newly established fetal
growth standard developed for singletons to determine its applicability for monitoring the
growth of twin fetuses and discordant growth of the pair; 3) to estimate the incidence of
growth restriction (with SGA as a proxy) in singleton and twin gestations (by zygosity),
however, growth restriction may be defined by the new growth standard; and 4) to 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.

This study will recruit 350 pregnant women with a twin gestation from nine clinical centers.
The study is designed to enroll approximately 350 dichorionic twin pairs based upon incidence
figures for twinning at the population level. Women will be recruited during the first
trimester and followed until delivery. Serial ultrasound assessments of fetal growth are the
standard of care for twin pregnancies, and we will coordinate the timing of research
ultrasounds to the fullest extent possible with clinical scans to minimize exposure as
further described in this protocol. Each woman will have seven scheduled ultrasound
examinations, including fetal biometry at all visits, fetal Doppler studies, and four blood
draws at baseline and at targeted gestational ages for the eventual identification of
biomarkers indicative of fetal growth. After delivery, neonatal anthropometric measures will
be assessed for each twin, and select information about the obstetrical course and newborn
status will be abstracted from medical charts.

- 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 pregnancies74