The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

During pregnancy, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child’s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.


Summary
The biggest fraction of mortality and morbidity in newborn children in Germany is caused by diseases in a small subgroup of children: preterm deliveries with a birth weight below 1,500 g. The most important goal for all persons in care of preterm babies is the undisturbed physical and cognitive development of these children, which usually is assessible at the age of 5-6 years. Unfortunately, in Germany no neonatological network exists to systematically analyze the determinants of the longterm development of preterm babies. Hence, the main aim of this study protocol is the establishment of such a German neonatal network (GNN), that Our study group has since than more than 10 years been working on describing genetic risk factors for neonatal pathologies. Our DNA data base comprises mote that 10,000 DNA samples of preterm babies with a birth weight below 1,500 g. It is one of the largest of its kind world-wide.
We expect that environmental factors (such as different treatment regiments in different neonatal departments, social background etc.) will have stronger effects on the long-term development of preterm babies than genetic determinants. Within the framework of this protocol we not only aim at studying the genetic regulation, but also the influence of center-specific treatment paradigms, of social environments and of novel therapeutic approaches -such as the application of surfactant without intubation -on the long-term development of preterm babies.
The main aim of the study is the prospective documentation of clinical data of 20,000 preterm babies with a birth weight of below 1,500 g starting from birth on and including the collection of DNA samples and the assessment of physical and cognitive development at the age of 2 to 6 years.

Hypotheses and aims
The main goal of the study is the establishment of a German Neonatal Network (GNN) that analyses

State-of-the-art, own preliminary work, and perspectives of the study
In all populations about 1% of all newborns are born pretermly and with a birth weight below 1,500 grams. In Germany, these preterm infants are all treated in tertiary level neonatal intensive care units, and their course and outcome data are very accurately recorded. In 2005, the Joint Committee of the Federal Government obliged all neonatal departments of the highest care level to include developmental neurological follow-up examinations of all preterm babies with a birth weight below 1,500 grams. In contrast to many other countries, such as the US, there is no neonatological research network in Germany that collects and analyzes these data and examines the short-term and, in particular, the long-term effects of preterm birth (and associated therapies). The treatment effects of certain forms of therapy in preterm babies -unlike in many other patient groups -can be evaluated only years later by assessing the successful physical and mental development of these children.
Therapies that have been introduced because of a short-term improvement of surrogate parameters have repeatedly proven to be harmful in the long term, especially in neonatology. As a recent example, the postnatal use of dexamethasone for the prophylaxis and treatment of bronchopulmonary dysplasia 8 should be mentioned. Until a few years ago, dexamethasone was used in a large proportion of preterm babies with bronchopulmonary dysplasia for its short-term positive effects on gas exchange. Careful follow-up studies in preterm babies in infancy and school age showed that preterm infants treated in randomized trials with dexamethasone showed a lower intelligence quotient and a higher rate of cerebral palsy. Today, dexamethasone is only used occasionally in preterm babies. The aim of the present protocol is to establish a nationwide network with a special focus on studying the long-term development of preterm babies. The following preliminary data and perspectives exist:

Influence of preclinical and social factors
It is well-known that certain preclinical (e.g. birth due to an amniotic infection syndrome) and social factors (e.g. origin, maternal education) have a major impact on the long-term development of preterm babies. We expect that these factors -which are often very difficult to influence -have a greater impact on the long-term development of preterm infants than the genetic factors described above and have a similar impact as the center-specific therapies described below. So far there are no studies investigating the combined effects of genetic, social and clinical factors.

Center-specific therapies
With regard to the frequency of the above-mentioned endpoints, there are great differences between individual neonatal departments. Special emphasis was therefore placed on analyzing these differences and providing feedback to the participating study centers. We expect center-specific factors to have approximately the same impact on the short-and long-term development of preterm infants as preclinical and social factors. They, however, can be much better influenced (see below). 9

Benchmarking
All clinics participating in the study receive center reports after each monitoring, comparing their own center's clinical data with data from all other centers and data from the most successful centers (in relation to the short-and long-term outcomes mentioned above). Since we also collect a variety of treatment data, centers with unfavorable outcomes can quickly find out about differences in therapy compared to centers with good outcomes (always based on the respective outcome). We will also give the centers the ability to perform specific searches for their own records compared to all other records.
We know from ongoing projects that the center reports we have prepared by many hospitals are already being used as quality indicators for their daily work.

Clinical studies
Furthermore, the goal of the preterm neonatal network described here is to promote the planning and

Study type
The GNN is a prospective cohort study in which approximately 25% of all preterm babies born in Germany with a birth weight below 1,500 grams are included and followed up over a period of 6 years with respect to their physical and neurological development. 10 Inclusion criteria: -Birth <= 36 + 6 weeks gestation -Birth weight <1,500 g Exclusion criterion: -Transfer of the infant from another hospital.

Endpoints
Data on each individual patient are collected at 3 times: 1.
During the immediate postnatal stay in the clinic.

2.
During an outpatient re-appointment, at the age of 2 years.

3.
During an outpatient re-appointment, at the age of 6 years.
The following relevant endpoints are analyzed:

During the primary stay in hospital:
-

Collection of data with potential impact on endpoints
In addition to these endpoint assessment tools the study collects a wealth of data that could potentially affect the endpoints.

Proposed sample size
Since we expect the lowest effect sizes for genetic risk factors, the cohort size calculation for our study is based on the numbers required for the identification of genetic risk factors. Genome-wide studies in adults indicate that 500-2,000 affected patients are needed to identify genetic risk factors for a single disease. Since the incidence of the outcomes described above is between 3 and 20% in preterm babies with a birth weight below 1,500 grams, a number of 20,000 prospective children enrolled in the study is necessary to identify genetic risk factors. Thus, the final aim of the present study is to enroll and follow up 20,000 preterm babies with a birth weight below 1,500 grams over a 12-year period. For such a high case number, the permanent participation of about 50 large neonatal departments in the study is planned. We are aware that the participation in this study for the participating centers means additional expenses. From the very beginning, we therefore paid attention to making the study as easy as possible to implement in everyday clinical practice. There are also the following benefits for participating centers: -Regular reports allow to compare therapy and outcome data with other centers.
-Participation in the study fulfills the legal requirements given by the Federal Joint Committee on "Measures to ensure the quality of care for preterm babies and newborns" of Sept. 20, 2005.
-For the tracking of patients, we will set up an address database maintained by the study center.
The participating centers will be informed about address changes of their preterm babies. This greatly simplifies the communication for organizing the obligatory examination of preterm babies at 2 years.
-In order to relieve the participating centers and to enable a more objective assessment of the long-term course (reduce inter-observer variability) , the 6-year study is carried out by one study team of the study center in Lübeck. As with the short-term outcome data, the centers receive feedback on their patients as compared to those of all other centers.
-For the documentation of the data up to the 2-year examination, a lump-sum remuneration is paid per completed patient to the participating centers.

Study conduct
13

Inclusion of study centers
Due to the high number of cases required, the study was planned as a multi-center nationwide study.
Since the study center invests considerable resources into the coordination of the individual centers, our goal is to get as large neonatological departments as possible to participate in this study, as this will not only increase the number of necessary patients more quickly, but also the resources of the patients study center can be used more targeted. Neonatological departments with less than 40 preterm infants <1,500 g per year should be included in this study only in exceptional cases. The admission of study centers is carried out by the study director.

Training of employees at the centers
Before the inclusion of a patient at the respective center, a staff training in the participating center is carried out by a doctor of the study center covering the objectives and course of the study. As part of this training the participating center is provided with 50 pre-packaged envelopes for patient inclusion and 50 containers for the asservation of umbilical cord samples.

Inclusion of patients and documentation of clinical data
In addition to a detailed information form, a consent form and a questionnaire on the preterm basic clinical data, the study center's patient inclusion set contains 4 sterile smear tubes for collecting 2 oral mucosal swabs each from the preterm infant and the baby's mother. The basic clinical data questionnaire (Documentation Sheet 1 of 3) will be sent to our laboratory along with the oral mucosal swabs. Furthermore, a short piece of umbilical cord (collected immediately after birth) is frozen at minus 20 °C from each preterm infant participating in the study. Once the child has been discharged, data collection forms 2 and 3 (one of which is identical to the neonatal questionnaire) are completed and sent to the study center or faxed. The flow chart on the following page summarizes the inclusion of patients.

Inclusion criteria met
Hand over the information and consent form to the parents Consent given 2 oral mucosal smears are taken from mother and preterm infants

Shipping of oral smears and data collection sheet 1/3
In data collection sheets 2/3 and 3/3, at first only the name of the child and the date of birth are entered. The sheets are included in the child's file and sent to the study center after he/she has been discharged.
In addition to the oral mucosal smears, a short piece of umbilical cord of each infant (obtained, for example, when shortening the umbilical cord as part of primary care) is frozen at minus 20 °C as soon as possible after birth.
The stored umbilical cord samples are collected by a doctor of the study center as part of the monitoring, so they do not have to be sent. At six-monthly intervals, the data collected will be reviewed by the coordinating study center in Lübeck and all participating centers will receive a written report commenting on both the clinical procedures and outcome data compared to the other centers participating in the study.
The detailed collection of drugs administered and procedures performed (data collection questionnaire 2/3) allows us to study the interplay between exogenous factors and specific genetic predispositions. A major benefit for the participating centers is a regular report of their performance which is provided by the coordinating study center and can provide important suggestions for the standard management of individual centers and the resulting clinical outcome. However, data comparability requires regular monitoring of data quality. Patient inclusion and documentation of the clinical data is the task of the respective centers; the data is entered into a database (double-checked) at the study center.

Data bases and data protection
In order to be able to follow the preterm infants over a period of 6 years, a comprehensive tracking system is established by the study management. Two databases are created for the entire study. The For the maintenance of the address database parents of all preterm babies participating in the study will be contacted by the study center with a greeting card for the child's birthday and informed about the course of the study. In the case of undeliverable cover letters, an address is determined via the supervising clinic or the communal registration offices.

Documentation of the follow-up examinations
Due to the commitment of the Joint Federal Committee for the Care of Preterm Infants, all preterm babies aged 18-24 months will be re-examined by the participating centers. The recommended method of investigation is the Bayley II scores, which is applied by the centers. Furthermore, the

Monitoring and quality control
Since the study described here is intended to obtain data for the conduct of prospective clinical trials, the study design follows the recommendations for "Good Clinical Practic ". This requires appropriate monitoring of the participating centers.

Monitoring procedures prior to inclusion of a study center
Prior to the inclusion of a center in the study, hospitals that are interested in participating will be interviewed. This serves to ensure a sufficient center size. With regard to a clinical drug study, important center properties (e.g. possibility of carrying out ultrasound examinations, X-rays, laboratory examinations) are also requested.

Monitoring during the study
All study centers are visited by a doctor from the study center every six months. The monitoring is verifying the completeness of the clinical data on the basis of the source data (patient records), the inclusion rate of patients who fulfill the inclusion criteria of the study based on the source data (usually ward book) as well as a numerical collection of the parameters death, delivery mode, ventilation, laseror cryocoagulation ROP, NEC or ileum perforation requiring surgery, VP shunt, gestational age, birth weight, sepsis with positive blood culture, surgery of a persistent ductus arteriosus, IVH grade, PVL, BPD and pathological hearing test for all preterm infants that met the inclusion criteria, but were not enrolled in the study. The documentation of these data takes place in the form of a counting list and serves to make the individual centers as comparable as possible. For each visit, a written report is provided by the respective monitor, which is filed in the study folder of the participating center and in the study center. The monitoring of the follow-up data at the age of 2 is carried out analogously by employees of the study center. After monitoring the data, all complete data sets and the associated DNA samples are pseudonymized.

Sample processing and laboratory tests
For each patient participating in the study 5 DNA samples will be taken: 2 oral mucosa smears each from mother and child are sent to the study center as part of the submission of the first documentation sheet, and a short piece of frozen umbilical cord is stored at the participating centers and collected by the doctor of the study center during the monitoring visit. Since the quality and quantity of umbilical cord DNA is much higher than that of oral mucosal DNA, only one maternal DNA sample is initially isolated from the oral mucosal specimens. The remaining oral mucosa smears remain frozen. After the monitoring visits DNA is isolated from the deep-frozen umbilical cord samples for each preterm baby and divided into 3 portions (1 sample for genome-wide investigations, 1 sample for the selective examination of interesting polymorphisms, 1 sample as reserve and control). Should for individual patients no umbilical cord be preserved, the DNA will be isolated from the buccal swab and frozen as a sample for examination of interesting polymorphisms. Genome-wide studies only make sense from a very high number of cases of about 500 preterm babies affected by a specific disease (e.g. sepsis), so that we are planning first genome-wide examinations only from the second year of study on. Prior to these genome-wide studies, we will investigate candidate gene polymorphisms that were predictive of preterm disease in adult genome-wide studies (e.g. risk genes for diabetes mellitus and their impact on the incidence of postnatal insulin therapy in preterm babies) or in premenstrual candidate gene studies.

Genetic and risk factors
The following endpoints are planned for the first genome-wide investigations: For all these outcomes, we expect a frequency of at least 20% on the basis of preliminary examinations, so that we are very likely to be able to identify valid genetic risk factors for these diseases already after 6 years. Sufficiently large number of cases for rare diseases of prematurity (e.g. necrotizing enterocolitis, ductus arteriosus requiring surgery, retinopathy requiring laser-or cryotherapy, a pathological hearing test in the neonatal period etc.) are expected after about 8-10 years. Genetic risk factors for mental retardation or disability, which can reliably be determined only during the follow-up at the age of 6 years, we expect after 9-12 years project duration. As a control group, we will select a group of preterm infants with genome-wide examinations who did not experience any complications during the clinical course, and who show normal physical and mental development at the age of 2, despite having extremely low birth weight (<1,000 g) and low gestational age (<29 weeks). From all preterm infants who meet these criteria, a control group of 1,000 children is randomly chosen for genome-wide examinations. Background of the creation of such a group of "resilient preterm infants" (i.e. no disease despite extremely high disease risk) is the expectation that in this group risk alleles are rare and protective alleles for diseases of preterm infants occur more frequently than in the normal population, whereas in the group of preterm infants with certain diseases (e.g. sepsis) we expect an accumulation of risk alleles and a rarer occurrence of protective alleles compared to the normal population. Overall, this results in a higher difference of allele frequency, so that predictive polymorphisms can be detected more easily. Comparisons with published genome-wide health records are also planned.

Ethics
The study protocol is advised by all institutional review boards of those sites participating in the study.
The study center is the Department of Pediatric and Adolescent Medicine of the University of Lübeck.
The vote of the ethics committee of the medical faculty of the University of Lübeck is attached.

Costs
All our investigations and data collections are free of charge for the participating study centers as well as for the patients participating in the study.

Information sheet for parents Dear parents,
Your child was born with a birth weight below 1,500 grams and well before the expected date of birth. We know that most preterm babies, even those born with such low birth weight, can be released from the hospital after a period of time that seems very long to their parents. Unfortunately, there is little data on the long-term development of very small preterm infants in Germany. In particular, it is not known what influence the preterm birth itself, but also the therapy in the hospital, the genetic predisposition of the individual child and subsequent environmental factors have on the long-term physical and mental development of preterm babies.
What is the purpose of this study?
The most important goal of our study is to find factors that have a positive influence on the long-term development of preterm babies. Only if one knows which form of therapy, which genetic peculiarity and which environmental factors have a favorable influence on the long-term development of the preterm infants, one can use these therapies and environmental factors purposefully and develop perhaps also medicaments, which mimic particularly favorable genetic characteristics. Conversely, one can of course avoid unfavorable factors. Our study thus serves the future better treatment of very small preterm babies. The data registered in the study will only be collected and used for this purpose.

How is the study conducted?
Of all preterm babies participating in our study, data are collected at three time points: during inpatient stay after birth, at the age of 2 and at the age of 6. During your inpatient stay, your child's essential clinical data (e.g. birth and discharge weight) will be registered by the physicians. In order to be able to investigate possible genetic influences on the development of preterm babies, we need 2 oral mucosal smears each of mother and child and a short remainder of the child's umbilical cord. The smears are made with a sterile cotton swab and are not a burden even for very young children. The umbilical cord sting is taken when the umbilical cord is shortened at the first treatment of the child and would otherwise be discarded. No other research is done on the material used and privacy is respected. At no time will blood samples be taken for the study. At the age of 2 years, your child's motor development will be tested. This study is recommended for all preterm babies with a birth weight below 1500 grams; it is not an investigation that is done extra for our study. Finally, at the age of 6, an examination of mental and physical development (including an eye test) is planned. The follow-up examinations at the age of 2 and 6 take place in the clinic where your child was cared for right from the beginning, so you do not have long journeys. The result of the follow-up examination will be discussed with you immediately. We will also send you a parent questionnaire at all three times (i.e. while your child is still in the hospital, at the age of 2 and at the age of 6). This parent questionnaire was already answered by more than 17,000 parents whose children are not preterm infants. Thus, this study will enable us to find out whether preterm babies differ in terms of their diet, the frequency of visits to a doctor etc. from children who are not pretermly born. So that you can complete these questionnaires in peace, we will send them as pseudonymized (i.e. only with a number) sheets directly to your home address.

Who participates in the study and how long will the data be stored?
Our study is the largest study to date in Germany on the long-term development of preterm babies. 50 neonatal departments throughout Germany participate in our study. We plan to include approximately 20,000 preterm infants in our study over a 10-year period and expect to store the anonymized data for at least 18 years, when the last children included in the study will be re-examined.
How are the data protected?
Protecting the personal data of the preterm babies participating in the study is particularly important to us. For this reason, we will store all data in a pseudonymised way (i.e. all personal data such as name and address of the participating children will be replaced by a number). Therefore, we cannot tell you any individual results of genetic testing. In order to be able to invite you in time for the follow-up examinations, we would like to ask you for permission to save your address. We will only match your address with the pediatric clinic or the registration office and will not pass it on to any third party. Both the address file and the clinical data files are protected by special passwords and programs so that nobody has access to your data. It is particularly important to us to inform you about the progress of our study. We would therefore like to ask you for your consent that we send you a short information letter once a year (for the birthday of your child). After the examination at the age of 6 years, all data will be completely anonymized, i.e. your personal data will be completely deleted. Participation in this study is, of course, voluntary, and if you do not participate in the study, you or your child will not experience any disadvantages. You can, of course also withdraw your participation in the study. In this case, all data (personal and clinical) will be deleted and all samples will be destroyed. However, this is only possible until the examination at the age of 6 years, because at this time all personal data will be deleted anyway. If you would like to withdraw your participation in the study please write to the "German Neonatal Network, Department of Pediatrics of the University of Lübeck, 23538 Lübeck".

How are the results of the study published?
Basically, no data on individual clinics or individual children are published or passed on to third parties. All clinics participating in the study receive regular reports on their preterm babies. In order to inform as many interested physicians as possible, but also other interested parties, about the results of our work, we will publish the overall results of the study in scientific journals and on the internet.

How is the study funded?
The study is funded exclusively by public funding from the Federal Ministry of Education and Research. It is possible that in the future there will be commercial exploitation of the research results to which the researchers and universities participating in the study will contribute. In this case, you give up with your consent to any financial claims that could possibly result from the marketing of the test results.
Who is responsible for the content and conduct of the study? I have been informed that the samples taken are only used anonymously for the investigation of influencing factors for preterm birth and preterm birth and that a report of the genetic data cannot be sent to me or to the doctors treating my child.
I / we had the opportunity to ask all my / our questions, these were answered satisfactorily and completely.

Education Sheet for Parents
Dear parents, your child was born prematurely, and small for date-with a birth weight less than 1,500 g. We know that many babies can be discharged from hospital, even if they have been born small for date, albeit after an amount of time which appears excessive to the parents. Unfortunately, there is very little valid data, available in Germany, regarding the development of these small-for-date and premature babies in the long-term. The effect of prematurity and low birth weight on the long-term physical and mental development of these babies is particularly unclear. Apart from the low birth weight and prematurity itself, the influence of other factors; such as currently available therapeutic treatments, the genetic constitution and environmental factors on the development of these children is also not known.

What is the purpose of the survey?
The main objective of our survey is to determine the factors, which influence positively the long term progress and development of these babies. This is possible only if we are aware of the exact nature of the treatment, environmental factors and genetic imprinting, which affect the long term growth and development of premature babies. If these are known, it is possible to implement these treatment methods and environmental factors systematically and specifically. This may lead to the future creation of drugs, which simulate particularly favourable genetic characteristics as well as make it possible to eliminate the factors which have an adverse effect. Finally, our survey aims to discover improved treatment modalities, in order to improve the outcome of underweight and premature babies.
In order to maintain confidentiality, the data is collected and used exclusively for this survey.

How is the survey carried out?
The data will be collected at three key stages: 1. During the baby's stay in hospital immediately following birth During the stay at hospital all the essential clinical data of your child (e. g. birth weight and weight at discharge from hospital) will be recorded by the physicians. In order to also examine and analyse the possible genetic influence on the development of the baby, we request your permission to collect two smears of the oral mucosa (the inside of the mouth) of both mother and child, as well as a short piece of the umbilical cord. The smears are taken with a sterile cotton pad and the procedure doesn't cause pain or distress, even to the small baby. The piece of the umbilical cord is obtained while cutting it during the initial medical care of the premature baby. The cord would otherwise be discarded. The human material will not be used for any additional tests and all data protection requirements will be adhered to strictly. We will not ask for blood collection at any point during the survey.

At the age of two years
At the age of two years, the motor and neuro development of your child is tested. This examination is recommended anyway for all babies weighing less than 1.500 g at birth; i.e. this is not an examination specially carried out for the purpose of this survey. Englisch

At six years of age
At six years of age, we plan to examine the mental, intellectual and physical developmental progress (including visual tests).
The follow-up examinations at the age of two and six years will take place in the hospitals where your child has been medically supervised from birth; meaning that you do not have to travel long distances in order to participate in the survey. The results of the follow-up examinations will be discussed immediately afterwards.
Furthermore we will forward to you a questionnaire for parents at all three stages of the survey (during the child's initial hospital stay and at the age of two and six years). These parents' questionnaires have already been answered by more than 17,000 parents, whose children were not born prematurely. As a result, this survey will enable us to find out if the prematurely born infants differ from those born at term; regarding their nutrition, the frequency of consultations etc. We will forward the pseudonymised (i. e. only identified by a number) sheets directly to your private address so that you may complete the questionnaire at your own convenience.

Who takes part in the survey? Data storage
Currently, our survey is the largest one on the long-term development of premature babies that has been conducted in Germany. 50 neonatal departments throughout the country are involved in our survey; and we intend to include about 20.000 neonates over a period of 10 years. We plan on storing the anonymised data over a period of at least 18 years, until the data from the follow-up examinations of the last child enrolled in the survey are completed.

Data protection
It is particularly important for us to protect the personal data of the children participating in the survey.
All data will therefore be stored in a pseudonymised format (i. e. all personal data, such as the name and address of participating children are substituted for by a number). We will thus not be in a position to communicate individual results of the genetic examinations to you.
In order to invite you to the follow-up examinations in good time, we request permission to store your address. This address will be verified only with your respective mentoring paediatric clinic and with the registration office; without it being passed to a third party. Both the address data file and the data file including clinical data are protected by extra passwords and encryption, in order to ensure that there is no unauthorised access. It is very important to us to keep you informed about the progress of our survey, and we would therefore ask for your approval to send you a brief report, informing you of the study's progress once a year (on your child's birthday).
All data are completely anonymised immediately after the examination at 6 years of age, i. e. any personal data are completely deleted.
It must be clarified, that participation in this survey is entirely voluntary: no disadvantage, neither to you nor to your child will result from not taking part in it. It will also be possible to withdraw your participation at any point prior to the examination at six years of age, resulting in the destruction of all Englisch data (personal and clinical), and all samples. After the final examination, all personal data will anyway erased.
In the case that you wish to withdraw your participation in this survey, please write to: The "German Neonatal Network, GNN (Deutsches Frühgeborenen Netzwerk), Klinik für Kinder-und Jugendmedizin der Universität Lübeck, 23538 Lübeck".

Publication of the results of the survey
By principle, no data about clinics or individual infants will be published, or passed on to a third party.
All clinics participating in the survey will receive regular reports on the development and progress of the premature infants that they are caring for. In order to inform as many medical scientists and professionals in the field, as well as others with interest in the results of our assignment, overall conclusions and results will be published in scientific journals, or on the internet.

Financing of the survey
This study is funded exclusively by public subsidies from the Bundesministerium für Bildung und Forschung (German Federal Ministry for Education and Research). It may the case, that in the future, the results of the survey will have a commercial use; wherein any profits are reserved for the use of the researchers/scientists and university participating in the survey. Your written consent agrees that any financial demands/claims, resulting from the potential commercialisation of the research will be refrained from.

Who is responsible for the content and carrying out of the survey?
Many medical professionals have taken an active role in this survey. The topic has been discussed with representatives from the professional associations for Neonatology, Perinatology and Social Paediatrics respectively; as well as numerous experts for statistical data evaluation. Prior to commencing with the survey, many parents with premature children had been interviewed; and the survey itself has been cleared by "Das frühgeborene Kind e. V." (German Federal Association), the largest association for parents with premature infants. Prof. Dr. Wolfgang Göpel (Klinik für Kinder-und Jugendmedizin, Universität Lübeck, 23538 Lübeck), the executive of the survey, is responsible for its implementation and realisation. Should the case be that any damages are inflicted upon a participant of the survey-during its progress, and on account of the behaviour of an employee of the Universitätsklinikums Schleswig-Holstein (UK S-H), the UK S-H will be held liable for any such issues.
By carrying out this survey, we hope to better support small-for-date and premature infants in the future. In the case that there remain any questions regarding this survey, please do not hesitate to contact the physician treating your child, or one of the physicians responsible for the survey.

Declaration of Consent
Herewith I/we give my/our agreement to the participation of my/our child/children _________________________________________ born on ___________________ at the survey "Deutsches Frühgeborenen-Netzwerk (German Neonatal Network)" I have received, read and understood the written information for patients about the survey mentioned above. Purpose and issue of the survey where explained to me in detailorally and written.
It was pointed out to me that the participation of my child is voluntarily. I have the right to stop/cease the participation at any time and without giving reasons devoid of disadvantages for me or my child.