Medical School Hotline

“The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary artery disease.”¹ The Developmental Origins of Adult Disease Hypothesis, proposed by DJ Barker, describes the development of adult disease in terms of fetal exposures and growth. Multiple large epidemiologic studies have confirmed events prior to birth are significant in child development and subsequent adult health.^2–4 Adult morbidities that potentially occur secondary to small size at birth can be split into two groups: metabolic and non-metabolic. Metabolic morbidities include hypertension, dyslipedemia, coronary artery disease and insulin resistance; non-metabolic morbidities include attention deficit hyperactivity disorder, neurodevelopmental delay and Schizophrenia.⁵

It is theorized that fetal adaptations to intrauterine conditions affects the shape and development of fetal structure and organs. Certain exposures could cause abnormalities to the process of fetal organ development. The alterations in fetal organ development and subsequent organ function are thought to be responsible for the development of adult disease. Though the intrauterine environment plays a role in the development of adult disease, postnatal exposures are also important. For example, the highest risk of adult coronary artery disease occurs in individuals who were small at birth but who became heavy in childhood.⁶ Individuals who are small at birth and remain lean have a much lower rate of coronary artery disease. The causal association between low birth weight and overweight in childhood with subsequent development of coronary artery disease holds across diverse populations and sexes; thus this observation is robust and is of importance.⁶ To study the complex interrelationships between genetics, psychosocial, and pre- and postnatal environmental exposures and adult disease, a large, representative cohort of maternal-child pairs needed to be established.

The National Children's Study (NCS) is underway. In excess of 100,000 maternal-child pairs will be recruited into the sample from 105 different areas across the United States. Broad environmental and cultural exposures and health status will be assessed longitudinally throughout the life of the child, during various developmental stages (pregnancy, at birth, infancy, childhood, adolescence and adulthood). Genetic and epigenetic studies will be performed upon biologic samples that will be collected and stored. Interactions between genetic predisposition and the environment will be studied in a cohort of adequate size. The NCS will provide a superb opportunity to study maternal genetics and pre- and postnatal environmental exposures on fetal and subsequent child health.

The NCS is a dynamic, evolving research project. Many of the specific measures that will be obtained throughout the life of the child have yet to be determined. The potential information that it will yield regarding genetics, psychosocial and environment exposures and child health is amazing. It is anticipated that this information will help to improve the care provided for children, and their children's children.

The University of Hawai‘i National Children's Study center will be enrolling over 1000 children into the national cohort. For the pilot study, factors affecting recruitment of participants and operational activities are being studied. In the main study, the study design will become increasingly complex. Some of the childhood conditions that will be evaluated include childhood accidents, obesity, autisim and attention deficit hyperactivity disorder. An environmental concern of particular interest for Hawai‘i will be the effect of environmental air exposures like volcanic emissions and smoking on pregnancy outcomes, particularly small for gestational age at birth.

The causative factors for small gestational age at birth are diverse, and include intrauterine infection, fetal chromosomal abnormality, multiple gestation, maternal medical diseases like diabetes, substance abuse, hypertension, malnutrition, and abnormal placental development resulting in increased placental resistance. The most significant modifiable risk factor for small for gestational age at birth is smoking. When compared to non-smokers, smokers are 3.5 times more likely to have an infant that is small at birth.⁷

In 2004 and 2006 the US Surgeon General summarized the evidence regarding the adverse effects associated with maternal smoking. Outcomes attributed to smoking during pregnancy include premature birth, delivery of a small for gestational age infant and childhood obesity and behavioral disorders like attention deficit hyperactivity disorder.^8–9 These documents included a firm recommendation to stop smoking during pregnancy. However, though public health efforts in this area have been quite successful,¹⁰ and overall rates of smoking during pregnancy have decreased, up to 10% of all pregnant women will continue to smoke throughout gestation.⁷

Large epidemiologic studies of smoking exposure and pregnancy outcomes support a causal relationship between smoking and small for gestational age infants.¹¹ There is a correlation between maternal smoking and both small for gestational age infants and childhood obesity,⁶ a phenotype that can result in increased risk of coronary artery disease as an adult. Proposed mechanisms underlying impaired fetal growth secondary to smoking include decreased uterine blood flow and abnormal placental development with increased resistance resulting in chronic hypoxia. Smoking also affects maternal appetite and food consumption. This may also play a role in maternal and fetal nutrition. There is also substantial epidemiologic data suggesting a causal relationship between maternal smoking and childhood obesity. A recent meta-analysis of 14 studies, comprised of 84,563 children, confirmed children whose mothers smoked during pregnancy are at increased risk to be overweight (odds ratio 1.5).¹² The mechanism underlying this observation is unclear.

The study will be particularly interested in looking at the efficacy of public health and local community and provider based programs and process to encourage smoking cessation. The sample size of the study will be large enough so that subgroups of participants will be identified with similar lifestyles, as the effect of societal burden on health is clear, and this factor must be considered. The study could also provide the opportunity to identify factors that optimize pregnancy outcomes in women who continue to smoke. Much of the epidemiologic work regarding the effects of smoking in pregnancy is dependent on patient recall of smoking exposure. In the NCS, information regarding smoking during pregnancy can be collected prospectively, eliminating recall bias. Additionally, biologic samples that are being collected could be assayed for cotinine levels, as a biologic marker for smoking exposure, allowing for more accurate correlations between smoke exposure and pregnancy outcome. Genetic variations in enzymes metabolizing the products in tobacco smoke cause variations in serum levels of cotinine thus measuring the biomarker not only quantifies exposure but allows for an assessment of the effect of genetic variation on pregnancy outcomes.¹²

The potential benefit of the NCS for the children of Hawai‘i is clear. In addition to the data that will be obtained, University infrastructure has been expanded to support the contract particularly in the area of information technology and data storage. Finally, because the University received this contract, several additional projects have been awarded in biotechnology development, dietary assessment, health literacy, and in evaluating factors affecting recruitment and retention in the study.

To study the potential affects of diet on child growth and development in Hawai‘i, and in particular childhood obesity, dietary instruments utilized in the NCS must reflect the local diet. Dietary instruments that have been developed to study dietary intake across populations are awkward and time consuming to use, and do not include many of the food items commonly consumed in Hawai‘i. Terminology utilized in the surveys is also inconsistent. For example, malassadas and lau lau are not listed, and Ahi and Aku are just listed as tuna. Dr. Rachel Novotny^* has been awarded a project to look at utilizing the internet to improve the quality of data collected and the ease of use of dietary instruments.

A major barrier to success of the project in Hawai‘i is recruitment and retention of participants. Thus far, the people of Hawai‘i have been welcoming and most have been interested in participating in this landmark study. However, study participation is a significant long-term commitment, as the children will be followed for 21 years. If 3% of participants drop out of the study each year, and this drop out rate is commonly seen in prospective observational studies, by the end of the 21st year only 37% of the original cohort will remain in the study for the final assessment of health as a young adult. Clearly, the more participants that can be retained in the study for the entire 21 years, the better the data and study conclusions. Dr. Rosanne Harrigan^** and Dr. Beatriz Rodriguez*** will be studying the factors that affect recruitment and retention in the local populations, focusing on the Pacific Islander and Filipino cultures. It is hoped that this research will retain the majority of the participants in the study for the entire 21 years, ensuring the results are representative of the population of Hawai‘i.

Conducting a study of this magnitude and with this longitudinal study design is a challenge. In addition to concerns about dietary assessment and participant retention in Hawai‘i, it will be a challenge to track the participants as they move. The significant population of military personnel will result in participants moving all around the world. However, understanding how the movement of military families and deployment of parents overseas affects child health and development is crucial to optimizing the health of these families. We are working with Dr. Parnell Mattison**** at Triple Army Medical Center to ensure we capture and appropriately follow our military population. The goal is to provide the best for all children, regardless of race, ethnicity, socioeconomic status, parental employment, or location of residence. It is anticipated that the people of Hawai‘i will support and participate in the National Children's Study.