Long-term Follow-up of Children Born in the PETN Studies (LOOP)

Langzeiteffekt Einer Pentaerithrityltetranitrat (PETN)-Behandlung in Der Schwangerschaft - Nachbeobachtung Der Kinder Der PETN-Studien

In every 10th pregnancy, the child in the uterus is insufficiently nourished, a so-called growth retardation. This occurs when the child cannot reach its growth potential due to an undersupply in the uterus. This inadequate supply is considered a developmental cause for the later development of physical diseases like cardiovascular diseases, sugar metabolism disorders and obesity as well as mental developmental problems (for example problems in cognitive skills, deficits in language development, concentration and attention).

From 2002 to 2008, 111 patients with impaired placental blood flow were included in a small study and treated with Pentalong or placebo. From 2017 to 2022, the positive effects of the study treatment were tested on a larger number of patients. A total of 317 pregnant women were included at 14 participating study centers in Germany.

In this follow-up study, the development of the children born in the two studies will be examined. The study consists of two independent parts: firstly, questionnaires are answered by the former participants and secondly, an on-site visit is carried out to check the physical and mental health of the child.

Study Overview

• Status: Recruiting
• Conditions: Intrauterine Growth Restriction; Pentaerithrityl Teratnitrate in Pregnancy; Long-Term Effects to Children
• Intervention / Treatment: Behavioral: Questionnaire Child Behaviour Checklist; Behavioral: Questionnaire Young Self Report; Diagnostic test: physical examination; Diagnostic test: metabolic examination; Behavioral: Questionnaire Reynolds Intellectual Assessment Scales and Screening; Diagnostic test: electroencephalogram; Other: Questionnaire Movement Assessment Battery for Children; Other: Questionnaire Continuous Performance Test; Other: Questionnaire Diagnostic System for Mental Disorders; Diagnostic test: kidney function tests; Other: Questionnaire Five to Fifteen; Diagnostic test: cardiovacular examination

Detailed Description

Pregnancies in which impaired uterine blood flow is detected by Doppler measurements during routine examinations in the second trimester are at high risk of developing fetal growth restriction (FGR). FGR affects 10% of pregnancies and is the leading cause of perinatal mortality and morbidity. In addition, intrauterine growth restriction places a lifelong burden on the physical and mental health of affected children. Epidemiological studies have shown that children with FGR have an increased risk of developing type 2 diabetes mellitus, hypertension, dyslipidemia and a high BMI. In addition, the affected children show disorders in hormonal balance and pubertal development as well as specific impairments of various cognitive and neurocognitive functions. There is also a link between FGR and lower cognitive ability in preschool children, school-age children and young adults, as well as lower communication, language and reading skills in school-age children. Neuronal development (e.g. EEG frequency spectra, resting-state networks) and executive functions are also impaired by FGR.

In the follow-up study, the children will be examined from the age of 6. Here, the effects of PETN on the development of children of women with high-risk pregnancies can be further investigated and a comparative study of growth-retarded and normal-growth children can also be carried out.

• Study Type: Observational
• Enrollment (Estimated): 228

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Not yet recruiting
    • Berlin Charité Campus Mitte
    • Contact: Stefan Verlohren, PD Dr.
  • Berlin, Germany, 12351
    • Not yet recruiting
    • Berlin Vivantes Klinikum Neukölln
    • Contact: Wolfgang Schlembach, PD Dr.
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Not yet recruiting
      • Universitäts-Frauenklinik Tübingen
      • Contact: Karl O Kagan, Dr.
      • Contact: Harald Abele, Prof. Dr.
    • Ulm, Baden-Württemberg, Germany, 89075
      • Not yet recruiting
      • Universitatsklinikum Ulm
      • Contact: Ulrike Friebe-Hoffmann, PD Dr.
  • Bayern
    • München, Bayern, Germany, 81377
      • Not yet recruiting
      • Klinikum der Universität München
      • Contact: Christoph Hübener, Dr.
    • München, Bayern, Germany, 81545
      • Not yet recruiting
      • Städtisches Klinikum München
      • Contact: Laura de Vries, Dr.
      • Contact: Ninette Scharle
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Not yet recruiting
      • Medizinische Hochschule Hannover
      • Contact: Constantin von Kaisenberg, Pr. Dr.
      • Contact: Matthias Jentschke, Dr.
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Not yet recruiting
      • Universitätsklinikum Bonn
      • Contact: Mateja Condic
      • Contact: Julia Welz
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Not yet recruiting
      • Universitätsklinikum Dresden
      • Contact: Matej Komar, Dr.
      • Contact: Jennifer L Winkler, Dr.
    • Leipzig, Sachsen, Germany, 04103
      • Not yet recruiting
      • Uniklinikum Leipzig
      • Contact: Anne Tauscher, Dr.
      • Contact: Susanne Schrey-Petersen, Dr.
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06110
      • Not yet recruiting
      • Krankenhaus St. Elisabeth und St. Barbara
      • Contact: Sven Seeger, Dr.
      • Contact: Yvonne Jäger, Dr.
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Not yet recruiting
      • Universitatsklinikum Schleswig Holstein
      • Contact: Ulrich Pecks, PD Dr.
      • Contact: Christel Eckmann, Prof. Dr.
  • Thüringen
    • Jena, Thüringen, Germany, 07747
      • Recruiting
      • Universitatsklinikum Jena
      • Contact: Tanja Groten, Prof. Dr.; Phone Number: 0361 9 32 92 01; Email: Loop@med.uni-jena.de
      • Contact: Ekkehard Schleußner, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

all live born children from participants of the PETN-studies

Description

Inclusion Criteria:

• mothers participation in one of the PETN studies
• age above 5 years
• completion of questionnaires for self reported data
• written consent for physical examination

Exclusion Criteria - only physical examination:

• physical and mental states preventing physical examination

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Placebo; children of mothers that have been taken placebos during participation of PETN study	Behavioral: Questionnaire Child Behaviour Checklist; The Child Behavior Checklist comprises items assigned to 8 subscales describing various behavioral areas. These subscales can be summed up to scores for internalizing and externalizing problems as well as a total score. Checklist scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean higher amount of problems.; Other Names: CBCL/6-18R; Behavioral: Questionnaire Young Self Report; The Questionnaire Young Self Report comprises items assigned to 8 subscales describing various behavioral areas. These subscales can be summed up to scores for internalizing and externalizing problems as well as a total score.; Other Names: YSR/11-18R; Diagnostic test: physical examination; physical development examination including height (in cm), weight (in g) and tanner states; Diagnostic test: metabolic examination; metabolic development using blood analysis including blood components, metabolic parameters (Glucose, HbA1c, cholestrol); Behavioral: Questionnaire Reynolds Intellectual Assessment Scales and Screening; The RIAS is standardized intelligence test. The RIAS provides an "Total Intelligence Index" (GIX, estimate of the general intelligence/g-factor), Verbal Intelligence Index (VIX) and the Nonverbal Intelligence Index (NIX). Test scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean better cognitive performance.; Other Names: RIAS; Diagnostic test: electroencephalogram; neurocognitive development; Other Names: EEG; Other: Questionnaire Movement Assessment Battery for Children; The M-ABC-2 is an standardized test to assess the motoric development. Adding up subscores addressing manual dexterity, aiming and catching, and balance delivers a total score of the motoric performance. Test scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean better performance.; Other Names: M-ABC-2; Other: Questionnaire Continuous Performance Test; The CPT measures selective attention, sustained attention as well as impulsive behavior. Checklist scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean worse performance.; Other Names: CPT; Other: Questionnaire Diagnostic System for Mental Disorders; The FBB-ADHS assesses a total score for ADHD-like behavior and subscores for the symptom trias of ADHD (attention deficit, motoric hyperactivity as well as impulsive behavior, Questionnaire scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean higher amount of symptoms.; Other Names: FBB-ADHS; Diagnostic test: kidney function tests; urine examination (proteomics, cytokines, lipidomics); Other: Questionnaire Five to Fifteen; The FTF 5-15R is a questionnaire to evaluate the child's developmental outcome in different areas of everyday life (cognition, language, and motor impairment as well as social, emotional, and behavioral problems). Individual item scores are added up per area and divided by the number of items. This results in a common scale value. Range of Percentile scores from 0 to 100 (0-90: no developmental problem; 90 and higher: hint for developmental problem). Higher scores mean worse developmental outcome.; Other Names: FTF 5-15R; Diagnostic test: cardiovacular examination; measurement of pulse wave velocity; Other Names: Arteriograph
PETN; children of mothers that have been taken in PETN during participation of PETN study	Behavioral: Questionnaire Child Behaviour Checklist; The Child Behavior Checklist comprises items assigned to 8 subscales describing various behavioral areas. These subscales can be summed up to scores for internalizing and externalizing problems as well as a total score. Checklist scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean higher amount of problems.; Other Names: CBCL/6-18R; Behavioral: Questionnaire Young Self Report; The Questionnaire Young Self Report comprises items assigned to 8 subscales describing various behavioral areas. These subscales can be summed up to scores for internalizing and externalizing problems as well as a total score.; Other Names: YSR/11-18R; Diagnostic test: physical examination; physical development examination including height (in cm), weight (in g) and tanner states; Diagnostic test: metabolic examination; metabolic development using blood analysis including blood components, metabolic parameters (Glucose, HbA1c, cholestrol); Behavioral: Questionnaire Reynolds Intellectual Assessment Scales and Screening; The RIAS is standardized intelligence test. The RIAS provides an "Total Intelligence Index" (GIX, estimate of the general intelligence/g-factor), Verbal Intelligence Index (VIX) and the Nonverbal Intelligence Index (NIX). Test scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean better cognitive performance.; Other Names: RIAS; Diagnostic test: electroencephalogram; neurocognitive development; Other Names: EEG; Other: Questionnaire Movement Assessment Battery for Children; The M-ABC-2 is an standardized test to assess the motoric development. Adding up subscores addressing manual dexterity, aiming and catching, and balance delivers a total score of the motoric performance. Test scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean better performance.; Other Names: M-ABC-2; Other: Questionnaire Continuous Performance Test; The CPT measures selective attention, sustained attention as well as impulsive behavior. Checklist scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean worse performance.; Other Names: CPT; Other: Questionnaire Diagnostic System for Mental Disorders; The FBB-ADHS assesses a total score for ADHD-like behavior and subscores for the symptom trias of ADHD (attention deficit, motoric hyperactivity as well as impulsive behavior, Questionnaire scores are reported on a T-scale. Range of T-scale from scores 20 to 100 (average performance between scores 40 and 60). Higher scores mean higher amount of symptoms.; Other Names: FBB-ADHS; Diagnostic test: kidney function tests; urine examination (proteomics, cytokines, lipidomics); Other: Questionnaire Five to Fifteen; The FTF 5-15R is a questionnaire to evaluate the child's developmental outcome in different areas of everyday life (cognition, language, and motor impairment as well as social, emotional, and behavioral problems). Individual item scores are added up per area and divided by the number of items. This results in a common scale value. Range of Percentile scores from 0 to 100 (0-90: no developmental problem; 90 and higher: hint for developmental problem). Higher scores mean worse developmental outcome.; Other Names: FTF 5-15R; Diagnostic test: cardiovacular examination; measurement of pulse wave velocity; Other Names: Arteriograph

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
childrens behaviour	total score of either CBCL/16-18R or YSR/11-18R	up to 2 years after study inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
physical development height	height of the child in cm	up to 2 years after study inclusion
physical development weight	weight of the child in kg	up to 2 years after study inclusion
age appropriate development	age appropriate development documented as "yes or no" question in german routine examination plan ("Kinderuntersuchungsheft") in the last 6 years at caregivers	up to 2 years after study inclusion
cognitive, motoric, and exectuve function	scores of the eight domains of the FTF 5-15-R	up to 2 years after study inclusion
physical development	self reported tanner states	age above 10 years
cardiovascular development	pulse wave velosity	age of 6 to 8 years
IQ development	scores of RIAS test	age of 6 to 8 years
motoric development	total score of M-ABC-2	age of 6 to 8 years
attention behaviour	scores of the four domains of the cpt	age of 6 to 8 years
symptoms of attention and activity disorders	total scores of DISYPS-III	age of 6 to 8 years
neurocognitive development	results of EEG power measurement in alpha band	age of 6 to 8 years
neurocognitive development	results of EEG power measurement in beta band	age of 6 to 8 years
neurocognitive development	results of EEG power measurement in gamma band	age of 6 to 8 years
neurocognitive development	results of EEG power measurement in delta band	age of 6 to 8 years
neurocognitive development	results of EEG power measurement in theta band	age of 6 to 8 years
epigenetic analysis	DNA-methylation	age of 6 to 8 years

Collaborators and Investigators

• Sponsor: Jena University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2024
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: May 14, 2024
• First Submitted That Met QC Criteria: August 1, 2024
• First Posted (Actual): August 2, 2024

Study Record Updates

• Last Update Posted (Actual): August 2, 2024
• Last Update Submitted That Met QC Criteria: August 1, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Growth Retardation
• Other Study ID Numbers: ZKSJ0133

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No