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BACKGROUND: Of all babies that die after 25 weeks gestation, 40% are small-for-gestational-age (SGA). Although there is no evidence that routine third trimester ultrasound screening (US) leads to better perinatal outcomes, it is increasingly used in the Netherlands to detect SGA. This leads to a considerable rise in health care costs.

Therefore, before routine third trimester US screening is implemented it is essential to evaluate its clinical effectiveness and cost-effectiveness. If effective, this intervention may lower the relatively high perinatal mortality rate in the Netherlands.


DESIGN: Nationwide cluster randomised controlled trial. Primary care midwifery practices will be randomised. Included women will be followed through if they are referred to specialist care.


INTERVENTION AND CONTROL: In all practices, growth will be monitored using standardised symphysis fundal height measurement and US will be performed if clinically indicated. A protocol will be developed with experts across the country in a Delphi study, to ensure consistent management of suspected SGA. Additionally, in intervention midwifery care practices, routine US examinations will be performed between 28 to 30 weeks and 6 weeks thereafter between 34 and 36 weeks.


PRIMARY OUTCOMES: The primary outcome for the main study is a composite of severe adverse perinatal outcome before neonatal discharge, defined as one or more of the following: perinatal death, Apgar score below 4 at 5 minutes after birth, coma, stupor, neonatal seizures, need for assisted ventilation for more than 24 hours, asphyxia, septicaemia, meningitis, broncho-pulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia or necrotizing enterocolitis. Costs will also be part of the primary outcome for the economic evaluation.


MAIN SECONDARY OUTCOMES: Separate types of severe adverse perinatal outcomes mentioned in the primary outcome, number of ultrasound scans, consultations, referrals, pain medication, place of birth, operative delivery, birth weight, gestatonal age, premature birth, non-cephalic presentation at birth, neonatal intensive care unit admission. In a subsample: women’s positive and negative experiences with the approach to fetal growth monitoring in the third trimester, ethical dilemmas, clients’ costs.


SAMPLE SIZE: 15,000 women in 60 midwifery practices, 7,500 in each arm.



Long term infant follow-up is an invaluable part of the study. Personal data are collected from all women so that they can be contacted for follow-up. In case of significant neonatal morbidity, infant data will be collected up to 6 months after birth. The project group is searching for funds to be able to do follow-up evaluations on at least 3000 children up to two years and if possible longer.

The aim of the follow-up is to study growth and health, cognitive and social emotional development and parenting attitudes among children in the routine US group in comparison with children in the control group and of SGA children versus non-SGA children.

Budget required: €200,000.



Analyses in the main study will be by intention to treat and logistic regression techniques will be used. The economic evaluation will be performed from a societal perspective.


DURATION: 48 months.




ADDITIONAL STUDY OBJECTIVES: If extra budget is available, the following studies will be conducted in addition to the follow-up study:

(a) RNA-sequencing in maternal plasma.

The central question is: are the changes in gene expression as defined in a genome-wide manner by RNA-sequencing of maternal plasma RNA predictive for intrauterine growth restriction (IUGR) and/or discriminative for IUGR with different etiology?

This project will be integrated into the NITRO study and consists of RNA-sequencing of maternal plasma RNA isolated from pregnant women with pregnancies complicated by IUGR (n=20) and matched controls (n=20). Required external funding: € 20,000.

(b) Predictive value of ‘phase rectified signal averaging’ (PRSA).

In total, 1000 term fetuses with biometry and/or estimated fetal weight < P10 in the 10 Dutch tertiary perinatologic centres will be included. Noninvasive transabdominal fetal heart rate registration, will be performed during routine CTG surveillance with the Monica AN24 or Nemo Puretrace fetal heartrate monitor. The main outcome is the predictive value of PRSA and spectral analysis of the fetal heart rate, to identify term SGA-fetuses at risk of severe adverse perinatal outcome. Required external funding: € 70,000.

(c). Value of individualised growth curves for monitoring postnatal growth.

In a retrospective analysis, the use of individualised growth charts will be compared with conventional growth charts in terms of predicting actual birth weight, incidence of SGA and perinatal outcomes. Required external funding: € 15,000.

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