The History of Preconception Care: Evolving Guidelines and Standards

This article explores the history of the preconception movement in the United States and the current status of professional practice guidelines and standards. Professionals with varying backgrounds (nurses, nurse practitioners, family practice physicians, pediatricians, nurse midwives, obstetricians/gynecologists) are in a position to provide preconception health services; standards and guidelines for numerous professional organizations, therefore, are explored. The professional nursing organization with the most highly developed preconception health standards is the American Academy of Nurse Midwives (ACNM); for physicians, it is the American College of Obstetricians and Gynecologists (ACOG). These guidelines and standards are discussed in detail.
Introduction
From the earliest recorded time, women have been advised to increase their level of wellness and to avoid hazardous substances before becoming pregnant. Plutarch wrote that the ancient Spartans: “...ordered the maidens to exercise themselves with wrestling, running, throwing the quoit and casting the dart, to the end that the fruit they conceived might, in strong and healthy bodies, take firmer root and find better growth” [1]. In the Old Testament [2], the following passage appears: “And the angel of the Lord appeared unto the woman, and said unto her, ‘Behold now thou art barren, and bearest not: but thou shalt conceive and bear a son. Now, therefore beware, I pray thee, and drink not wine and strong drink, and eat not any unclean thing.’ ”
As the modern practice of obstetrics evolved, it became a specialty that separated women’s prepregnancy wellness from prenatal care, but in the last quarter century this has begun to change. The dominant model of prenatal care as the main perinatal prevention strategy has been reexamined, and recognition of the importance of the prepregnancy period has emerged. Today the general public and health care professionals could easily be overwhelmed by the amount of information available which promotes prepregnancy or preconceptional health. A Google search (conducted April 25, 2005) of the term “preconception health” identified 630,000 hits. On the same day a search of the National Library of Medicine’s PubMed found 338 entries for “preconception health” with the earliest published in 1978, and 103 articles for “preconceptional” with the earliest published in 1982; in addition, most of the articles identified through the two search terms were unique. The nation’s approach to women’s health care may well be at the tipping point of redefining the perinatal period to include women’s wellness across the reproductive life span as an appropriate and favored approach to impacting reducing poor pregnancy outcomes.
Stimulated by research findings which underscored the limitations of traditional prenatal care on decreasing the incidence of congenital anomalies, leaders in the health community, professional organizations, advocacy groups and federal government began actively encouraging redefinition of the United States’ perinatal prevention paradigm in the early 1980s. Because the usual pathways to impact on perinatal outcomes (prenatal and neonatal care) often start too late to achieve primary prevention, the need to reach women with prevention opportunities before prenatal care was recognized and the concept of preconceptional health promotion emerged. This article explores the history of the preconception movement in the United States and the current status of professional practice guidelines and standards.
The decade of the eighties
One of the first federal position papers to acknowledge the need to change the nation’s approach to prevention appeared in 1979; while focused on the need to develop a continuum of child health care, it included the concept of prepregnancy care [3]. The programmatic elements in the proposed comprehensive package of integrated services were identified as:Interconceptional carePrenatal carePerinatal careChild Health careServices for handicapped childrenAdolescent services
Interest in moving away from categorical care to more integrated and comprehensive services has subsequently become a hallmark of current efforts to redefine the perinatal prevention paradigm. Why the list employed the word “interconceptional” rather than preconceptional is not clear. Since 1979, “interconceptional” care has come to represent efforts to address health status between pregnancies, birth spacing and intendedness of subsequent conceptions; “preconceptional” generally refers to the woman’s health status and risks before the first pregnancy and her health status shortly before any conception. “Periconceptional” usually refers to the time immediately before conception through the period of organogenesis. It is important to note that this nomenclature is inconsistently applied and not universally accepted. In England, for instance, “preconceptional” is referred to as “preconceptual.”
By 1985, the concept of preconceptional care and its potential advantages began to gain momentum. In that year, the Institute of Medicine published Preventing Low Birthweight [4] and noted that numerous opportunities exist before pregnancy to reduce the incidence of low birth weight, but that they are too often overlooked in favor of interventions during pregnancy. The Committee emphasized the importance of prepregnancy risk identification, counseling and risk reduction; health education related to pregnancy outcome in general, and to low birthweight, in particular. The Committee supported restructuring the perinatal prevention paradigm by noting:“Much of the literature about preventing low birthweight focuses on the period of pregnancy—how to improve the content of prenatal care, how to motivate women to reduce risky habits while pregnant, how to encourage women to seek out and remain in prenatal care. By contrast, little attention is given to opportunities for prevention before pregnancy. Only casual attention has been given to the proposition that one of the best protections available against low birthweight and other poor pregnancy outcomes is to have a woman actively plan for pregnancy, enter pregnancy in good health with as few risk factors as possibly, and be fully informed about her reproductive and general health.” (p. 119)
The IOM Committee advocated that family planning services be positioned as an essential component of effective preconceptional initiatives, thereby supporting the integration of services rather than reinforcing firm boundaries of categorical programs. It also recommended that the content of reproductive health education, particularly in schools and family planning settings, be expanded to introduce concepts of prepregnancy wellness. The third recommendation of the Committee was to develop the notion of preconceptional consultation to identify and reduce risks associated with poor pregnancy outcomes, particularly for women who had already experienced a poor outcome.
In 1989 another federally appointed committee, The Expert Panel on the Content of Prenatal Care, gave a strong endorsement to preconceptional health when it recommended that the preconception visit may be the single most important health care visit when viewed in the context of its effect on pregnancy [5]. The Panel went on to suggest that the last family planning visit should be the preconception visit and that the concept of preconception care should become a routine part of prenatal care with accompanying reimbursement and coverage included in all health insurance plans. However, the Panel indicated that preconception care is likely to be most effective when services are provided as part of general preventive care or during primary care visits for medical conditions. This approach has come to be referred to as “opportunistic care” because it takes advantage of the opportunities afforded by visits for other reasons.
Specific components of preconception care were identified by the Panel as (1) risk assessment, (2) health promotion and (3) intervention and follow-up. The Panel advocated that the preconception assessment include a holistic range of investigations including: individual and social conditions, adverse health behaviors, medical, psychological and environmental conditions and barriers to family planning and early prenatal care enrollment.
In 1983, the American Academy of Pediatrics (AAP) and the American College of Obstetrics and Gynecologists (ACOG) in partnership with the March of Dimes Birth Defects Foundation published the first Guidelines for Perinatal Care [6]. Appendix C of those first guidelines notes that “Preparation for parenthood should begin prior to conception. At the time of conception the couple should be in optimal physical health and emotionally prepared for parenthood” (p. 257). The Guidelines indicated that when pregnancy is contemplated, the preconception visit should be part of a comprehensive gynecologic examination, and the history should include a detailed family history including ethnic background as well as investigation of lifestyle issues, religion, the home and work environments, hobbies, pets, immunizations, medications and dietary habits. The guidelines recommended use of an extensive checklist to systematically explore areas of potential significance. Based on the patient’s history, the “counseling and instruction session” could be focused in a variety of directions including testing for genetically transmitted diseases and the parent’s carrier status, as well as counseling regarding potential teratogenic exposures, exploration and interventions to address medical problems prior to pregnancy, interconceptional care to address the likelihood of recurrence of any complications experienced in previous pregnancies, including congenital anomalies, and the importance of recording menstrual dates to allow the earliest possible initiation of prenatal care.
In 1985, ACOG provided a small grant to Moos and Cefalo to develop and test a checklist which came to be known as the preconceptional health appraisal [7, 8]. The appraisal was designed to aid providers in conducting comprehensive screening for preconceptional risks in a time-efficient manner and employed a self-assessment tool with built-in educational feedback. First introduced into local health department family planning clinics in North Carolina, it was adopted over the next several years by numerous state health departments across the country as well as private providers, large health maintenance organizations and several Canadian provinces. The commitment of public health organizations to introduce women to the concepts of preconceptional health during routine family planning visits placed the public sector in the position of being a leading innovator in the preconception movement. One state that demonstrated particular commitment to changing the perinatal prevention paradigm was Wisconsin. By the mid-1980’s, the Wisconsin Association for Perinatal Care was calling for redefinition of perinatal care to include the preconceptional period [9], and it has been unwavering in its commitment to improve pregnancy outcomes through preconceptional health promotion strategies ever since.
Concurrent with the above noted activities, additional credence to the benefits of preconceptional health promotion and primary prevention was provided when two nationally recognized obstetrician-gynecologists published books on the topic, one for the professional community and one for the consumer market [7, 10].
The decade of the nineties
Healthy People 2000, the national health promotion and disease prevention objectives for the United States, published in 1990, moved preconceptional care into a standard expectation within the health care system when it defined it as a one of its service and protection objectives. The specific objective reads:Increase to at least 60% the proportion of primary care providers who provide age-appropriate preconception care and counseling (p. 199)
Supporting rationale for the objective states that “the purpose of preconception care and counseling is to ensure that couples are healthy prior to pregnancy and prepared to assume the responsibilities of parenthood, thereby reducing the risk of poor pregnancy outcomes” (p. 199). The remainder of the rationale not only echoes the position of the earlier 1989 Expert Panel on the Content of Prenatal Care regarding the opportunities of preconception care to address many medical conditions, personal behaviors and environmental conditions [5] but also stresses preconceptional health promotion as an opportunity to educate young people about the risks of sexual activity, including unintended pregnancies, disease-related infertility and cancers [11]. In 1993, the March of Dimes Birth Defects Foundation published Toward Improving the Outcome of Pregnancy: The 90s and Beyond which introduced the concept of “reproductive awareness” as the basic health promotion strategy needed to improve pregnancy outcomes [12]. The document, often referred to as TIOP, reflects the position of the March of Dimes’ Committee on Perinatal Health. Because awareness of reproductive risks, healthy behaviors and family planning options is essential to improving the outcome of pregnancy, the committee declared that “a society-wide change in reproductive awareness is needed in the United States” (p. 12) and called for “a new strategy to reach each woman of childbearing age with reproductive awareness messages at every health encounter”(p. 12). The committee called upon health care providers to move away from the expectation that the prevention of poor pregnancy outcomes is only the professional responsibility of obstetrical providers by noting:“A woman’s health status in relationship to pregnancy usually is not considered until the first prenatal visit, and prenatal care often is segregated from other health care by provider type and by payment mechanism. Yet women of childbearing age have many encounters with the health care system. These include visits to gynecologists, pediatricians, internists, family physicians, nurse midwives and nurse practitioners, in settings such as public health, school health, women’s health, substance abuse treatment, family planning, and sexually transmitted disease clinics and private offices (p. 13).”
TIOP goes on to call for professional standards, structures and financing to be set in place to ensure an annual preconception or interconception risk reduction visit for every woman from menarche to menopause and that a prepregnancy planning visit become a standard component of maternity care, routinely available to all women and integrated into the perinatal care delivery system. TIOP also stressed that reproductive awareness is not sex or gender specific and that the need to reach out to males, especially during the preconception and interconception periods, requires thoughtful and innovative strategies.
ACOG published its first technical bulletin on preconception care in May, 1995 [13] The bulletin called for thorough and systematic identification of risks, the provision of education individualized to the patient’s needs, and the initiation of any desired interventions. Risk identification was broadly defined to include the areas of medical, reproductive, and family histories, nutritional habits, drug and environmental exposures and social issues and these efforts were to be targeted at improving outcomes for both the mother and the fetus ACOG took the position that rather than ensuring healthy pregnancy outcomes as suggested by other position papers, preconception care allows the woman and her partner, if so desired, to make informed-decisions. It states:“Once information is available, the patient can be informed about the certainty or limitations of available information, what the risks of pregnancy may be, and precautions that may be beneficial. After women have been informed of the increased risks pregnancy may pose to their health or the health of a fetus or both, they can accept the increased risks, choose to modify their risks or opt to avoid childbearing (p. 2).”
ACOG cautioned against over promising the benefits of preconceptional care to both providers and patients by specifically noting that preconceptional services do not guarantee good pregnancy outcomes. It noted that placing emphasis only on women who are planning their next conception or women who have been identified as high-risk will result in a significant number of missed opportunities for primary prevention. Women who experience an unintended pregnancy are at least as likely to have risk factors for poor pregnancy outcomes as women who consciously plan the timing of their pregnancy. Therefore, ACOG recommended that routine visits by women who may, at some time, become pregnant are important opportunities to emphasize the importance of preconceptional health and habits and the advantages of planned pregnancies. Finally, ACOG called for a coordinated multispecialty effort directed by the obstetrician-gynecologist as a means to provide a comprehensive framework for preconceptional health care for all women of childbearing potential.
The current decade
In 2002, the fifth edition of the AAP/ACOG Guidelines for Perinatal Care was published [14]. In the preceding editions, preconception care had moved from an appendix item to the main text in preceding editions. This latest edition, however, reflects a shift away from framing preconceptional care as appropriately targeted toward prospective parents who are contemplating pregnancy to an emphasis on integration of preconceptional health promotion into all health encounters during a woman’s reproductive years.
While some efforts to operationalize a redefined perinatal prevention paradigm grew, others dropped back. For example, Healthy People 2010 eliminated preconceptional health as a specific objective [15]. Except for the objective, “Increase the proportion of pregnancies begun with an optimum folic acid level” (target: 80%), the relevance of a woman’s health status at the time of conception to pregnancy outcomes is not referenced in the document, and reliance on prenatal and neonatal care to impact on pregnancy outcomes is reinforced as the preferred strategy to meet the perinatal objectives.
Evolving standards and guidelines from professional organizations
As the concept of preconception care has evolved in the health care community, several professional organizations have addressed its importance for their members, and some have developed specific guidelines or standards for preconception care.
Nursing organizations
In nursing, there are several professional organizations whose members care for reproductive age women. The AANP (American Academy of Nurse Practitioners) is the largest national professional organization for nurse practitioners of all specialties, with 15,000 members. While many nurse practitioners might be delivering preconception health services, AANP has not developed specific educational standards specific to this topical area, nor do their generic practice standards include preconception health. According to AANP Executive Director Dr. Judith Dempster (personal communication, April 11, 2005), members with questions about preconception health standards would be referred to specialty organizations such as AWHONN.
AWHONN (Association of Women’s Health, Obstetric and Neonatal Nurses) is the official professional organization for women’s health and obstetric nurses, and is comprised of 22,000 nurses whose goals are to promote excellence in nursing practice. While AWHONN does not have specific standards of care for women during the preconception period, they do offer many products to their members which discuss preconception health, including a practice monograph which outlines the importance and components of preconception care [16]. They also publish a Clinical Position Statement which states that AWHONN supports legislation and policies that encourage women of childbearing age to consume 400 micrograms of synthetic folic acid every day [17]. In addition, AWHONN is also a member of the National Council on Folic Acid (NCFA), a partnership of over 80 national organizations and associations, state folic acid councils and government agencies. While not strictly a preconceptional project, AWHONN developed a specific Clinical Position Statement on Smoking and Childbearing, urging nurses to screen women for tobacco use and help women stop smoking [18]. Although nurses initiated this program during pregnancy, it had major interconceptional ramifications for the women involved, and has added to the literature on smoking cessation for women of reproductive age [19].
ACNM, the American College of Nurse Midwives is the professional organization for all nurse midwives in the United States, and represents over 7,000 nurse midwives who are providers of comprehensive women’s health. In their Core Competencies for Basic Midwifery Practice (www.acnm.org/prof/display.cfm?id=137) they have specific educational and practice standards for preconception health for women. These standards are:“V. Components of Midwifery Care: The Primary Health Care of WomenB. Applies knowledge of midwifery practice in the preconception period that includes, but is not limited to, the following:1. Assessment of individual and family readiness for pregnancy, including emotional, psychosocial and sexual factors2. Impact of health, family and genetic history on pregnancy outcomes3. Influence of environmental and occupational factors, health habits, and behavior on pregnancy planning4. Health and laboratory screening to evaluate the potential for a healthy pregnancy” (p. 3)
NAPNAP (the National Association of Pediatric Nurse Practitioners) does not publish any guidelines or standards for preconception care. Their members provide services for adolescents, but the organization has not yet addressed preconception care in a structured manner (personal communication Dr. Karen Kelly Thomas, Executive Director NAPNAP, April 13, 2005). They have, however, published at least one article in their official journal on the topic [20].
In terms of general nursing education, the AACN (The American Association of Colleges of Nursing) does not offer specific guidelines for what is to be taught to student nurses about preconception health, but rather sets standards for overall educational goals.
Organizations for all professionals
The March of Dimes, while not an organization which targets just one type of professional, has been producing numerous materials for health care professionals about preconception health for many years. Materials and products that the March of Dimes produces for providers of care include: their nursing module Preconception Health Promotion: A Focus for Women’s Wellness [21], a Preconception Curriculum consisting of power point slides for Obstetricians, Family Medicine specialists, Pediatricians, and Internists which suggests that every visit to a health care provider should include elements of preconception care, a Preconception Screening and Counseling Tool, grants to the March of Dimes Chapters for preconception services, an educational program called Genetics and Your Practice (CD and online), and a Genetic screening pocket guide. Many of these can be found on their website www.marchofdimes.com, and their Spanish language website www.nacersano.org. They also produce an e-preconception newsletter (Spanish), an education program for Spanish women called Comenzando Bien, and pamphlets for patient education such as Are You Ready?, Think Ahead for a Healthy Baby, Folic Acid brochures, and Pre-Pregnancy Planning Fact Sheet.
The CDC, the March of Dimes, and the National Council on Folic Acid (NCFA) have organized a national folic acid promotion effort for the prevention of serious birth defects of the brain and spine (neural tube defects or NTDs). The goal of the effort is to teach all women about the importance of getting enough folic acid every day. The effort aims to reach every woman who could possibly become pregnant, as well as teach health care professionals and community advocacy groups about the importance of folic acid. The CDC, the March of Dimes, and NCFA have created messages, materials, websites, and other tools to reach providers and women with the folic acid message. In 2005, the CDC and March of Dimes collaborated to develop a national summit on preconception care in order to bring together all the stakeholders in the subject; this supplement issue of Maternal Child Health is one of the many consequences of these efforts by CDC/MOD.
Physician organizations
The American Academy of Pediatrics represents 60,000 pediatricians, many of whom provide adolescent services to young women of reproductive age. They publish, along with the American College of Obstetricians and Gynecologists, Guidelines for Perinatal Care, the document which is generally accepted to be the outline for acceptable care during the perinatal period for women and infants. In the current edition, 5 pages are devoted to preconception care, which is described as “the identification of those conditions that could affect a future pregnancy or fetus, and that may be amenable to intervention (p. 73)” [14]. The Guidelines note that all encounters with women of reproductive age should include counseling about health which could optimize pregnancy outcome. AAP is also a member of the National Organization on Fetal Alcohol Syndrome, which addresses medical school curriculum for fetal alcohol syndrome, and AAP supports numerous state-wide programs to enhance adolescent health before childbearing. In the American Board of Pediatrics study guide for the certifying examining for Adolescent Medicine certification, materials included are prevention of pregnancy, prevention of substance use, and general reproductive health care, all of which contribute to better preconception health (www.aap.org/sections/adol/adol.pdf).
The American Academy of Family Physicians (AAFP) represents 94,000 family physicians, residents and medical students in the United States, and sets the professional standards for care delivered by family physicians. While no specific guidelines or standards for preconception health services developed by AAFP could be located, AAFP addresses the issue of preconception care in many articles in their official journal, and in other practice venues such as suggestions to increase use of folic acid [22, 23].
CREOG is the Council on Resident Education in Obstetrics and Gynecology, and is charged with setting the educational standards for obstetricians and gynecologists in training. CREOG’s Educational Objectives are contained in its core curriculum [24]. Regarding preconception care, CREOG’s core curriculum states: “In evaluating patients for preconceptional care, obstetrician gynecologists must assess those factors of the history, physical examination, and diagnostic studies that pregnancy would alter; assess the patient’s access to and compliance with a plan of prenatal care; and consult with or refer her to other experts on specific conditions that may arise during the pregnancy.”(p. 39). Its standards are as follows:“ II. Antepartum Care—Preconceptional Care1. Perform a thorough history, assessing historical and ongoing risks that my affect future pregnancy2. Counsel a patient regarding the impact of pregnancy on maternal medical conditions.3. Counsel a patient regarding the impact of maternal medical conditions on pregnancy4. Counsel a patient regarding appropriate lifestyle modification conducive to favorable pregnancy outcome.5. Counsel a patient regarding appropriate preconception testing.6. Counsel a patient regarding pregnancy associated risks and conditions, such as advanced age, hypertension, diabetes, genetic disorder, prior aneuploid or anomalous fetus/newborn” (p. 49)
ACOG, the American College of Obstetricians and Gynecologists represents 46,000 obstetricians and gynecologists in the United States, and in 2005 celebrated its 50th anniversary. ACOG has advocated for preconception care for several decades, and offers the most detailed guidelines for the provision of preconception services. ACOG’s acknowledges that while ideal health prior to pregnancy does not guarantee a perfect or uncomplicated pregnancy, women who are considering pregnancy should undergo comprehensive preconception evaluation, examination, and counseling. However, preconception care is best when it is provided as part of primary health care, rather than as a discrete new category of health care, particularly since almost one-half of all pregnancies in the United States are unintended [25, 26].
Components of preconception care—ACOG
In examining multiple documents produced by ACOG in recent years, certain components of preconception care can be delineated.
Periodic assessments
Preconception counseling should occur at periodic assessments for all reproductively capable women. These assessments may be yearly or as appropriate [27]. Counseling should include discussions about the likelihood of pregnancy (planned or unplanned), counseling on appropriate medical care and behavior to optimize pregnancy outcomes, specific health risks the woman has that may predispose her to an adverse pregnancy outcome if not addressed, and how to either effectively prevent an unplanned pregnancy or to maximize her physical and emotional health prior to a planned or even unplanned event. Even clinicians that do not provide prenatal care should be able to provide preconception counseling and screening to their reproductively capable patients.
The patient’s history should be reviewed and updated on an annual basis or more often if appropriate. The history should include a review of any medical conditions and medications the patient may be using. It is important to ask about prescription as well as over the counter drugs, herbs, and supplements. Inquiries about occupational and hobby exposures to chemicals, solvents, or heavy metals should be made. In this manner, potentially teratogenic agents may be identified.
The patient’s reproductive history may provide important clues about future pregnancy risks. Recurrent miscarriages should raise suspicion of a possible genetic or chromosomal problem. The neonatal outcome of previous pregnancies should be noted but it is equally as important to ask women about the current health of any children they have as some congenital disorders do not become manifest until several months or even years after birth and may not be considered by the family to represent a congenital defect.
Genetic disorders and genetic screening
The woman’s family history and ethnicity for genetic disorders and malformations should be obtained. Carrier screening for Tay-Sachs disease is recommended for individuals of Eastern European (Ashkenazi) Jewish, French Canadian and Cajun descent [28]. ACOG recommends offering cystic fibrosis screening to individuals with a family history, reproductive partners of persons with cystic fibrosis, and to couples in whom one or both partners are Caucasian and are planning pregnancy [29].
Carrier screening for Tay-Sachs, Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals during preconception screening. These same individuals may be offered or may request screening for Gaucher disease, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, or mucolipidosis IV as well. Carrier screening should be offered to any individual with a positive family history of one of these disorders; the screening should be for the specific disorder. When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. Except for Tay-Sachs and cystic fibrosis, the carrier frequency and detection rate for the other disorders is unknown.
If an individual is found to be a carrier for Tay-Sachs or one of the other aforementioned diseases, their relatives are at risk for carrying the same mutation; carriers are encouraged to inform their relatives of the risk and availability of carrier screening [28].
Other screening tests exist for genetic disorders with an increased incidence in specific ethnic groups, e.g., alpha or beta thalassemia screening in Orientals, beta thalassemia screening for those of Mediterranean descent, and sickle cell disease screening for African-Americans.
Women who have had a previous pregnancy complicated by autosomal trisomy, a sex chromosome aneuploidy, or if either partner has a chromosome translocation or inversion or aneuploidy should be given education about their increased risk of recurrence in future pregnancies and a referral for pre-pregnancy genetic counseling should be offered [30].
Immunizations and infectious diseases
The woman’s immunization status, history of childhood diseases, and risk for exposure to hepatitis, HIV, or other sexually transmitted infections needs to be updated at least annually. When practical, preconceptional immunization of women to prevent disease in the offspring is preferred to vaccination of pregnant women with certain vaccines [31].
Approximately 30% of US adults have serologic evidence of prior exposure to toxoplasma gondii, a known teratogen. Screening for Toxoplasma gondii is controversial because evidence that treatment prevents congenital disease is lacking. All reproductively capable women should be advised to avoid eating undercooked or raw meat, wear gloves when working with soil, and practice safe-handling techniques when changing cat litter [32].
Congenital cytomegalovirus (CMV) infection occurs in 1% of all live births in the United States and causes major neonatal illness in 5% to 10% of these cases. Women with young children or those who work with young children may be counseled about reducing the risk of CMV through universal precautions, e.g. the use of latex gloves and rigorous hand-washing after handling diapers or after exposure to respiratory secretions. There are currently no other specific recommendations as there is no evidence that screening and/or treatment programs prevent infection [32, 33].
All women should be kept current with age-appropriate vaccines. Reproductive aged women should be asked about previous infection with varicella and offered vaccination if they report no known history of chickenpox. Conception should be delayed until 1 month after the second injection is given. Women who expect to be at least 3 months pregnant during the influenza season (November to April) should be vaccinated.
Behavioral/psychosocial factors
A woman’s lifestyle and social behaviors should be reviewed and updated frequently. The use of alcohol, smoking, or other substances may have significant effects on pregnancy. Smoking during pregnancy is associated with low birth weight, abruptio placenta, preeclampsia, and preterm labor [34]. A woman’s personal situation has a significant effect on her health and often changes over time. Clinicians should ask all women about intimate partner violence and women should be aware that it may escalate during pregnancy. In addition, a woman’s mental health history may provide clues about recurrence risks either during or after a pregnancy.
A woman’s dietary habits should be reviewed. Daily folic acid intake of 0.4 mg should begin at least 1 month before pregnancy and continue through the first trimester. For women who have had a child with a neural tube defect, a higher dose of folic acid (4.0 mg/d) is recommended and has been shown to decrease the recurrence rate of neural tube defects [35]. Women who may become pregnant—planned or unplanned—should be aware of recent FDA warnings to avoid specific types of fish as they may be high in methyl mercury—a known neurotoxin to a developing fetal nervous system. Women should also be questioned about the need for any dietary restrictions they may have required in childhood. Women with PKU in childhood may not currently be adhering to a phenylalanine free diet but hyperphenylananinemia is associated with neurological impairment in a developing fetus.
Maternal prepregnancy weight is associated with several adverse outcomes. Women weighing more than >300 lbs (>136 kg) prior to pregnancy have a markedly increased risk for developing gestational diabetes, preeclampsia, and requiring a cesarean delivery compared with women weighing 100–149 lbs (45–67 kg). In one study, even among a subsample of women who did not have any diabetic or hypertensive diseases, excess weight significantly increased the likelihood of macrosomia and NICU treatment [36]. The relationship between maternal obesity and perinatal outcomes is necessary when discussing routine care as well as specific preconception planning.
Medical history and conditions
While most reproductive aged women are healthy, there are specific medical conditions associated with adverse pregnancy outcomes if untreated or treated poorly. Some medical conditions are contraindications to pregnancy. Hypertension should be under control prior to initiation of a pregnancy and women using angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists who are considering pregnancy should be switched to other agents and adjusted on these medications prior to conception. Certain cardiac disorders, such as primary pulmonary hypertension, place women at a very high risk for morbidity or mortality during pregnancy [37]. There is an increased risk (3–10%, depending on the parent’s condition) of congenital heart disease among children born to women who have a history of a congenital heard defect [38].
Women with a history of thromboembolism have an increased risk of recurrence during pregnancy. Women with a history of thrombosis should be offered testing for inherited or acquired thrombophilias, particularly if the results of the testing would affect the management of future pregnancies. Testing may be considered in women with a family history of thrombosis or a first degree relative with a specific mutation [39].
It is very important that women receive a thorough work-up and evaluation prior to being diagnosed with a seizure disorder and started on medication. Women diagnosed with seizures of unknown etiology should be told that even if they are on no medications at all, they have a two-fold higher risk for congenital malformations in their offspring than individuals without seizures. Anticonvulsant therapy use during pregnancy, particularly hydantoin or valproic acid, is associated with an increased risk for specific congenital defects. It is important to determine if anticonvulsant medication can be safely discontinued or to initiate therapeutic changes before pregnancy occurs. Women should be told that enzyme-inducing antiepileptic drugs may lower the efficacy of combination oral contraceptives, so an oral contraceptive containing a higher estrogenic concentration may be necessary. For women taking antiepileptic drugs who are considering a pregnancy, folic acid supplementation 5 mg/day is recommended for one month prior to conception and until the end of the first trimester [40].
Women with poorly controlled asthma before pregnancy tend to have increased difficulty with asthma during pregnancy [41]. Severe, poorly controlled asthma may have an adverse effect on fetal outcome as a result of chronic or intermittent maternal hypoxaemia [42].
Women with quiescent autoimmune disease or a distant history of disease should be carefully evaluated and counseled about maternal and fetal risks. Patients should be counseled that the best time to attempt conception is during periods of inactive disease.
Women should be made aware of the deleterious effects of hypothyroidism in pregnancy, including an increased incidence of abortion, obstetric complications and fetal abnormalities in untreated women [43, 44]. Women being treated for hypothyroidism will require increased doses of thyroxine early and throughout pregnancy in order to maintain adequate levels; this is especially important during the first trimester [45]. Low maternal thyroxine concentrations may lead to impaired neurodevelopmental outcome in the neonate and child. Routine assessment for the presence of subclinical hypothyroidism is not recommended. ACOG recommends testing of thyroid function only in women with a personal history of thyroid disease or symptoms of thyroid disease [46].
Diabetes mellitus represents a medical condition where preconception control has been proven to translate into improved maternal-fetal outcomes. Patients with poor glucose control during the first 8–10 weeks of pregnancy have a 2–3 fold higher risk of birth defects in their offspring than patients without diabetes. Good glycemic control before conception diminishes the risk of birth defects to a level comparable to that of the normal population [47].
Women should be asked about any ongoing dermatologic therapy she may be receiving. Isotretinoin (Accutane) is used for a variety of skin conditions and is a known teratogen. Some anti-psoriasis treatments (Acetretin X and methotrexate) are known teratogens, while some antiviral medications (podophyllum) are contraindicated in pregnancy.
Table 1 includes suggestions for the clinician during routine or periodic health assessments to optimize possible future pregnancy outcomes for all reproductively capable women.
Table 1Suggestions for the clinician during routine or periodic health assessments to optimize possible future pregnancy outcomes for all reproductively capable women• Determine if the woman suffers from any undiagnosed or uncontrolled medical problems. If she does, provide recommendations for treatment of these conditions and when it would be best to attempt pregnancy.Make sure the patient is aware of any associations between the medical condition(s) and medications(s) she is taking and their impact on pregnancy outcomes.Ask the woman about her reproductive intentions at every visit, ascertain what her risk of an unplanned pregnancy may be; for women not actively seeking to become pregnant, discuss her current contraceptive method and any concerns or problems she may be having with it.Review the woman’s family history—including new births among family members—annually as things change over time. Discuss any familial conditions that may herald an increased risk of adverse pregnancy outcome for the woman.Discuss the significance that nutrition can have on maternal fetal outcomes,e.g., the impact of 0.4 mg folic acid per day on neural tube defects in women with no family or previous history of a neural tube defect), the need to avoid excessive vitamin usage, especially vitamins A and D, and the additional measures women on restricted diets may need to take to optimize their health and the health of the developing fetus.Review the patient’s social behaviors or lifestyle patterns—such as smoking, alcohol, or other substance use or abuse—that may affect pregnancy adversely and offer treatment options.Ascertain the immunity status of woman to rubella, hepatitis, and varicella. Ensure she is up to date on immunizations.
Conclusion
The concept of preconception care has gained momentum over the past two decades, and health care providers are increasingly being urged to provide such care by their professional organizations. It is hoped that, with its stated goal of improving birth outcomes, preconception care could help insure that the health status of all reproductively capable women would be optimized. In examining available standards and guidelines for preconception care, the professional nursing organization with the most highly developed preconception health standards is the American Academy of Nurse Midwives, and for physicians is the American College of Obstetricians and Gynecologists [48]. Other professional organizations examined did not have specific care standards for comprehensive preconception health, but have educated their members about one or more aspects of preconception health (smoking cessation, folic acid awareness).

guidelines and standards
preconception health
women’s health


Heritability of a skeletal biomarker of biological aging

Changes in the skeletal system, which include age-related bone and joint remodeling, can potentially be used as a biomarker of biological aging. The aim of the present study was to investigate the extent and mode of inheritance of skeletal biomarker of biological aging—osseographic score (OSS), in a large sample of ethnically homogeneous pedigrees. The investigated cohort comprised 359 Chuvashian families and included 787 men aged 18–89 years (mean 46.9) and 723 women aged 18–90 years (mean 48.5). The TOSS - transformed OSS standardized in 5-year age groups for each sex, was analyzed as a BA index. We evaluated familial correlations and performed segregation analysis. Results of our study suggest the familial aggregations of TOSS variation in the Chuvashian pedigrees. In a segregation analysis we found a significant major gene (MG) effect in the individual’s TOSS with a dominant most parsimonious model (H2 = 0.32). Genetic factors (MG genotypes) explained 47% of the residual OSS variance after age adjustment and after including sex-genotype interaction, they explained 52% of the residual variance. Results of our study also indicated that the inherited difference in the skeletal aging pattern in men lies mostly in the rate of aging, but in women in the age of the onset of the period of visible skeletal changes.
Introduction
Biological age (BA) estimates the functional status of an individual in reference to his or her chronological peers on the basis of how well he or she functions in comparison with others of the same chronological age (Borkan and Norris 1986). Changes in the skeletal system, which include age-related bone and joint remodeling, can potentially be used as a biomarker of BA. Skeletal aging measures are strongly correlated with the status of the vital health systems (Gabriel et al. 1999; Kiel et al. 2001, Kadam et al. 2004, Kalichman et al. 2006b) and ultimately with survival rates (Johansson et al. 1998; Haara et al. 2003). The rate of degenerative changes in the skeleton may reflect an individual’s biological resistance, immunity, functional or health status in reference to his or her chronological age. Therefore, age-related skeletal changes can possibly be used as an index of BA.
Roentgenography is one of the common methods used to assess health status and age-related changes in bones and joints (Plato 1987; Plato et al. 1994). Previously, Kobyliansky et al. (1995) reported an osseographic scoring (OSS) system that uses hand radiographs to assess skeletal aging. OSS is a synthetic measure for assessing skeletal aging based on radiographic features of the hand, combining both osteoporotic and osteoarthritic changes of hand bones and joints. This system was originally suggested by Pavlovsky (1987) and has been used in BA evaluations in population studies (Kobyliansky et al.1995; Livshits et al. 1996; Pavlovsky and Kobyliansky 1997). Importantly, OSS has been shown to highly correlate with chronological age in adults of different ethnic groups (Karasik et al. 1999, Kalichman et al. 2002).
Accumulating research shows that single gene changes in yeast, worms, and rodents can significantly alter life span (Kenyon et al. 1993; Kaeberlein et al. 1999; Cheng et al. 2003; McBurney et al. 2003). The observation that the first-degree relatives of human centenarians are both disease resistant and have longer than average life spans implies a genetic component to human longevity (Perls et al. 2002; Atzmon et al. 2004). Current estimates based on twin studies indicate that the human life span is 25% heritable (McGue et al. 1993; Herskind et al. 1996; Gudmundsson et al. 2000; Perls et al. 2002). Genetic factors may also significantly contribute to interindividual differences in BA (Karasik et al. 2004, 2005). In variance component genetic analysis, performed in Karasik’s study (2004), genetic factors explained 57% of the total variance of the BA index based on OSS measurements.
The aim of our study was to investigate the extent and mode of inheritance of a skeletal biomarker of biological aging (OSS) in a large sample of ethnically homogeneous pedigrees.
Materials and methods
Sample
The population sampled consisted of native Chuvashians residing in numerous small villages in the Chuvashia and Bashkartostan Autonomies of the Russian Federation. The data were gathered in three field studies during August/September of 1994 (555 individuals), May/June of 1999 (715 individuals), and September 2002 (240 individuals) by investigators from the Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University (Israel), and the Institute of Anthropology, Moscow University (Russia). The expeditions were part of a Chuvashia Skeletal Aging Study (ChuSAS) project whose main aim was to investigate the different aspects of skeletal aging within the Chuvashia population. All information collected and measurements taken during all expeditions were done by the same team of investigators. The investigated cohort comprised 359 families and included 787 men aged 18–89 years (mean 46.9) and 723 women aged 18–90 years (mean 48.5).
The Chuvashian population is characterized by a stable family structure with traditional relationships. For generations the Chuvashians have resided under the same environmental conditions and have not been exposed to an outside genetic flow (El’chinova et al. 2003). In the present study, we collected data from residents of a number of small villages (with a predominant Chuvashian population) located in the Volga region. A rural population is more homogeneous than urban in terms of ethnicity, occupation, and physical activity. The study participants shared similar living, economic, and professional conditions with most individuals employed in agriculture or in other occupations involving physical labor. Data from 80% to 90% of the families (including all family members who were living in the area at the time of the expedition) were obtained. Since almost every individual was related to one of the families, we were able to collect data on up to 90% of the population in each village. Data obtained from self-completed questionnaires and confirmed during the interview included sex, age, age at menarche, age at menopause and occupation. Menopause was defined as >12 months without menstruation. Age at last menstruation was considered as menopausal age. In order to minimize the possible recall bias, the investigators excluded from the analyses all women who had doubts about their age at menarche. The anthropometrical measurements (weight, stature, etc.) were also collected using standard methodology. In the studied sample, there were no individuals with known rheumatoid or psoriatic arthritis or users of steroid medication. Subjects with post-traumatic hand osteoarthritis were excluded from the study. All procedures involved were consensual. The subjects signed an informed consent form, and the entire project was approved by the Helsinki Ethics Committee of Tel-Aviv University.
Additional information about the studied population can be found in our previous publications: sex- and age-related variations of the somatotype (Kalichman and Kobyliansky 2006), reproductive indices, such as age at menarche and at menopause (Kalichman et al. 2006 a, 2007a) and sex- and age-related variations of OSS (Kalichman et al. 2007b).
Hand radiographs
Single plain radiograms of both hands were taken from each study participant in the postero-anterior position with the X-ray source located 60 cm above, using a standard radiographic technique, as described in detail by Livshits et al. (1996). Hands were placed on the same film-containing plate to avoid any film or development variation. It was exposed for 5–10 s at 100–150 mA without intensifying screens at 50 kV.
OSS evaluation
An individual’s OSS was determined by the occurrence of the following: (a) bone proliferations (spurs), including apiostoses (tufting of distal phalangeal tuberosity), osteophytes, enthesophytes of the juxta-articular area and at midshaft; (b) manifestations of bone porosity, such as resorption of trabeculae, development of lacuna (juxta-articular osteopenia) and erosion of cortex; (c) loci of osteosclerosis, defined as enostosis and sclerotic nuclei; and subchondral sclerosis; and (d) non-traumatic joint deformities, defined as narrowing of joint cavities and periarticular bone corrosion (Kobyliansky et al. 1995; Pavlovsky and Kobyliansky 1997; Karasik et al. 2005; Kalichman et al. 2007b). Phalanges of the 2nd to 5th fingers of the left hand were examined. The first finger (thumb) does not directly project in a standard X-ray and was therefore not utilized. The presence of a given feature, but not its level of development, was documented for each OSS estimate. The overall number of those skeletal aging features was used as an OSS.
Each radiograph was read by an experienced skeletal researcher according to the accepted protocol of OSS evaluation. Ten X-rays were read and then re-read by the investigator to estimate the intra-observer reliability of the readings. All discrepancies were reviewed for systematic errors. This exercise continued until the reliability was high (k > 0.8). Afterwards, the investigator read the remaining X-rays, still blinded to patient identifiers. Before reading each batch of X-rays one re-read 5 X-rays, which had been previously read, to “calibrate” one’s readings to a standard. The intra-observer reliability (kappa statistics) was 0.82 (P < 0.01). The intraclass correlation for the OSS was 0.92 (P < 0.01).
OSS reflects amount of skeletal changes occurring stochastically during the life-span, and therefore it is characterized by strong increase of trait variance with age (Kalichman et al. 2007b and Fig. 1). It is reasonable to assume that not the deviation of OSS from the age-group mean, but only relative rate of OSS accumulation with age can be inherited. Consequently we constructed a trait using the standardization in age-sex groups to equalize the means and variances in the whole age range for both sexes. The resulting trait, TOSS (transformed OSS) was further analyzed. The biological meaning of this trait is the relative position of individual (higher or lower than average values of OSS) in his/her age-sex group expressed in the units of SD specific for each group. This accurately fit the definition of BA as the functional status of an individual in reference to his or her chronological peers (Borkan and Norris 1986).
Fig. 1Mean OSS values and standard deviations (SD) in age groups of 5 years for men and women
Statistical and genetic analysis
Prior to any other evaluations, the descriptive statistics reflecting the basic characteristics of the studied sample were computed in the whole sample and within age groups of 5 years.
At the first stage we computed familial (spouses, parent-offspring and sib-sib) correlations between the corresponding TOSS levels to examine the potential genetic effect on the skeletal biomarker of BA.
The segregation analysis, as implemented in the statistical package MAN (Malkin and Ginsburg 2003), was utilized in this study to test a mode of inheritance of the skeletal biomarker of BA—TOSS. Only individuals older than 29 were included in the analysis, since the high prevalence of zero OSS values in younger individuals make the standardization approach unacceptable. More precisely, in two 5-year age groups younger than 30 years the distribution of TOSS significantly deviated from normal (Chi-squareχ2-test for frequencies gave P < 10–6), whereas in all older age groups did not (P > 0.01). Only pedigrees having at least one measured pair of relatives were included in the analysis. The mixed model of inheritance (Morton and MacLean 1974; Elston 1981; Lalouel 1983; Beaty 1997; Ginsburg and Livshits 1999) estimates the effects of a potential major gene and possible multifactorial effects, and is described in detail in numerous publications, including the aforementioned. The parameters that had been estimated in the general model are defined as follows: p—the population frequency of allele A1 (assuming diallelic gene locus); μgs—the average genotypic value of individuals having genotype g and sex s (g = 1, 2, and 3 corresponds to genotypes A1A1, A1A2, and A2A2, respectively); σ2g—the trait variance in individuals having the same major gene genotype g, it estimates the trait variation resulting from the effect of all possible environmental factors and potential minor genes; τg—the transmission probability parameter, which estimates the probability that a parent of genotype g transmits allele A1 to the next generation; ρ, β, and ε are partial correlations between the trait’s residuals adjusted for a major gene effect, in spouses, parents/offspring, and the siblings, respectively. A transmission probability test, described by Ginsburg and Livshits (1999), was used to estimate the significance of the major gene (MG) effect. A best-fitting and most parsimonious Mendelian model was established after dropping all non-significant parameters.
Using the procedure implemented in the package MAN (Malkin and Ginsburg 2003) and parameters estimated for the most parsimonious model, we determined the most likely MG genotype combination for each pedigree. We divided our sample into groups according to sex and the determined individual genotype of putative BA-related MG for genotypes having distinguishable genotypic values.
To analyze the age dependence of OSS, as a primary (directly measured) BA-related index, in groups of potentially different inherited BA, we used the stochastic model, described in detail by Kobyliansky et al. (1995). We estimated for each group the following aging population parameters: t0—the earliest age at which the first signs of OSS can be found, q—the individual probability of revealing the first signs of OSS changes per chronological time unit, assuming an individual’s age ≥t0, and B—the coefficient characterizing the rate of OSS changes per time unit (per year) after the process of aging has started. Next, we built the age-dependent expectation of the mean OSS level for each group according to sex and predicted MG genotype. Using the likelihood ratio test, we compared the extent of stochastic model approximation, both accounting for the MG genotype group and without it. Eventually we used ANOVA as implemented in STATISTICA 6.0 (StatSoft 2000) to test the differences between parameters of female organism development such as age at menarche and age at menopause in MG genotype groups.
Results
Figure 1 shows the OSS mean values and SD in age groups of 5 years. Up to age 45, men have higher OSS scores than women. After age 45 OSS in women was higher, compared with men and the sex difference in the OSS scores increases up to the end of the age range. The OSS variance in age groups increases rapidly up to age 50.
Familial correlations of TOSS (Table 1) showed no significant correlation for spouses, but parent-offspring and sibling correlations were significant. This indicates the existence of a clear familial aggregation of TOSS variation in the Chuvashian pedigrees, which cannot be explained by pure common environmental effects. We investigated the nature of TOSS inheritance later using segregation analysis. Because of the method by which TOSS was constructed (standardization within each sex-age group), in the segregation model the sex effects were not significant. The other results are presented in Table 2 and support the MG hypothesis regarding trait inheritance. The most parsimonious Mendelian model was dominant. The recessive allele with a population frequency of 0.6 corresponded to relatively slow aging. For the most parsimonious Mendelian model, H2 = 0.315; total proportion of TOSS variance explained by the model was 0.349. Using this model, we predicted the most likely MG genotype combination for each pedigree included in the analysis. Because of the dominant nature of the most parsimonious model, we divided all individuals into two groups with potentially different genotypic values: (1) homozygous on allele A1 and (2) all the rest. Using a stochastic model of aging (Kobyliansky et al. 1995), we constructed the model of age dependence of directly measured OSS for a whole sample and for each predicted genotype group separately with and without considering the effects of sex. Table 3 presents the parameters of four resulting models and a comparison between them. According to the likelihood ratio test (LRT), Model 1, which included only the effect of age, has a significantly worse extent of approximation than both Model 2, which included the effect of genotype-age, and Model 3, which included the effect of sex-age. The extent of approximation was significantly higher for the effect of genotype-age, which explained 47% of the residual OSS variance after only adjustment for age, and lower for the effect of sex-age (5%). Model 4, which includes all age-sex-genotype effects, showed a significantly higher extent of approximation in comparison with other models and explained 52% of the residual OSS variance after adjustment for age. After adjustment for age and sex, the residual parent-offspring correlation of OSS was significant, but became non-significant after adjustment for the sex-age-genotype.
Table 1Familial correlations of TOSSRelativesRN of pairsPSpouses0.083330.15Parent-offspring0.127550.002Sib pairs0.311890.0008Table 2Segregation analysis for TOSS (OSS standardized in age groups of 5 years for each sex)ParameterMain modelsRestricted modelsGeneralMendelianEqual τ-sArbitrary τ-sMendelian most parsimoniousEqual τ-s123456P0.6000.6280.2520.5580.598 ± 0.0330.563μ1−0.727−0.724−1.080−0.758−0.729 ± 0.057−0.702μ20.4810.525−0.3290.3800.429 ± 0.0610.362μ30.3620.3850.3830.380!0.429!0.362!σ120.2990.3250.0740.2550.303 ± 0.0450.289σ221.0740.9880.5041.1651.067 ± 0.103 1.181σ320.2050.2321.0490.255!0.303!0.289!ρ0.0850.1040.099[0.000][0.000][0.000]β0.006−0.0290.033[0.000][0.000][0.000]ε0.3250.2280.3110.3270.249 ± 0.0670.327τ10.910[1.000]0.2720.916[1.000]0.614τ20.632[0.500]0.272!0.618[0.500]0.614!τ30.001[0.000]0.272!0.020[0.000]0.614!Log LH−1425.66−1428.27−1435.91−1427.29−1429.61−1440.51χ2−5.22 NS (1)20.5** (1)1.63 NS (1)4.64 NS (4)26.44** (4)NS—P > 0.05; ** P < 0.01Number in parentheses in the χ2—row specifies a comparative columnConstraints denotation: [ ]— parameter is fixed to shown value; !— parameter is constrained to be equal to the parameter above in the tableTable 3Parameters of stochastic aging models estimated for OSS data without grouping (1) and grouped according to predicted genotype (2), sex (3), or both sex and predicted genotype (4)ParameterAllA1A1A1A2 or A2A2Allt021.223 ± 0.93321.705 ± 0.88422.225 ± 1.179q0.118 ± 0.0150.077 ± 0.0100.217 ± 0.044B0.552 ± 0.0040.518 ± 0.0040.600 ± 0.004TM29.68934.61926.838Model 1 (3 d.f.)Model 2 (6 d.f.)R2=0.838R2=0.915Log LH=−3476.8Log LH=−3065.5–χ2= 822.6 (1)Ment020.524 ± 1.23121.573 ± 1.14221.886 ± 1.683q0.127 ± 0.0240.098 ± 0.0140.233 ± 0.071B0.501 ± 0.0050.449 ± 0.0050.556 ± 0.005TM28.40031.74026.182Woment022.078 ± 1.34221.840 ± 1.16922.623 ± 1.601q0.107 ± 0.0190.057 ± 0.0000.187 ± 0.046B0.617 ± 0.0070.629 ± 0.0080.657 ± 0.007TM31.40039.37327.979Model 3 (6 d.f.)Model 4 (12 d.f.)R2=0.846R2=0.923Log LH=−3443.3Log LH=−3000.7χ2= 67.0 (1)χ2= 952.2 (1); 129.6 (2); 885.2(3);A1A1— genotype corresponding to lower values of TOSS in segregation analysis; t0— the minimal age at which initial bone changes occurred in a group; q—the group probability that an individual will first develop involutive bone change after age t0; B—the group rate of aging (bone change) per time unit; TM—the expected mean age in a group in which the first bone change occurred; number in parentheses indicates the comparative model for LRT; all LRT values are significant with P < 10−6
Figure 2 shows a scatterplot of OSS-age for the predicted genotypes in both sexes and the corresponding curves of age-dependent OSS expectation given by the stochastic model. For women in the group of genotype A1A1 (with slow skeletal aging), the age at menarche was significantly higher (P = 0.012) than in the group of genotypes A1A2 or A2A2; the group mean difference was 0.45 year. The difference in the age at menopause was in the same direction, but not significant for the whole sample. Note that our sample includes women strongly influenced by difficult life conditions during World War II. In these women the variance in the age at menopause is increased in comparison with the normal population. For women whose year of birth ≥1937 (the normal part of the population), the age at menopause was higher in group A1A1 than in other group (P = 0.054); the group mean difference was 1.6 year.
Fig. 2OSS values for predicted genotype groups: black—A1A1, gray—A1A2 or A2A2
To compare our findings with results of other authors, we quantitatively analyzed the similarity of differently constructed BA indices. The correlation between the BA index proposed by Karasik et al. (2004) and TOSS was 0.82 in the Chuvashian population. The correlations between the BA index, used by Livshits et al. (1996), versus the BA of Karasik et al. (2004) and TOSS were estimated as 0.80 and 0.89, correspondingly. Though the resemblance of the indices may be influenced by population type, the aforementioned BA indices are sufficiently similar.
Discussion
In the present study, we evaluated the extent and mode of inheritance of a skeletal biomarker of BA. We constructed this biomarker (TOSS) to be maximally fitted according to the BA definition; it reflects the intensity of an individual’s skeletal changes in relation to its coevals of the same sex, and the range of the index does not depend on the age cohort.
We previously evaluated the association between OSS, as an index of BA, with morbidity in a general Chuvasha population (Kalichman et al. 2006b). Statistically significant association was found in the present study between age-adjusted OSS and rheumatic morbidity. Morbidities such as ischemic heart disease, pulmonary diseases, traumatic brain injuries and gynecological diseases also showed differences between mean values of OSS in affected vs. non-affected individuals. However, after correction for multiple testing, the statistical significance was insufficient. The association between OSS and diabetes mellitus was close to significant (P = 0.07) and we surmise that with a larger sample of diabetic individuals, a clear-cut association will be confirmed.
It is well-established that genetic factors play an important role in an individual’s BA (Karasik et al. 2005). Our finding suggests the familial aggregations of TOSS variation within the Chuvashian pedigrees. The evaluation of heritability of the skeletal biomarker of BA in segregation analysis suggested the existence of a MG effect with a most parsimonious dominant model. A number of BA indices, based on age-related skeletal changes, were previously proposed and analyzed in different populations. Livshits et al. (1996) analyzed the OSS measurement in the Turkmenian population. They used the age-adjusted OSS values as a BA index. This index showed a significant familial parent-offspring correlation of 0.1 ± 0.09, which is approximately the same as for TOSS in our study (0.12). Nevertheless, in their segregation analysis of the age-adjusted OSS, the Mendelian model was rejected. A possible reason is that a simple age adjustment does not equalize the residual variance of OSS, which significantly increases with age. As a result, parents and offspring received a BA index with different amplitude and this difference probably prevented establishing MG inheritance in segregation analysis. Other phenotypes of BA, as well, are characterized by substantial heritability. Thus, functional age (other term for BA) has been assessed by a general linear regression model of many biomarkers in Minnesota twins (27–88 years old). A subset of these biomarkers (mostly physiological variables) identified by a factor analysis had heritability of ∼59% (Finkel et al. 1995). Duggirala et al. (2002) have reported that BA, measured according to Uttley and Crawford (1994), had a substantial genetic component (heritability ranging from 0.27 ± 0.11 in one Mennonite geographical subsample to 0.47 ± 0.18 in the other).
Karasik et al. (2004) studied a sample that included 1,402 members of 288 pedigrees from the Framingham Heart Study; the log-transformation was used to reduce the growth of OSS variance with age. A special BA index was constructed by adjusting the individual’s age for log-transformed OSS with cubic polynomial. The log-transformation automatically excludes from the analysis all individuals with zero OSS (note that for ages >30, the zero OSS value is meaningful and denotes a low BA). For the resulting trait, the genetic variance component analysis showed that sex, height, the body mass index, and, in women, menopausal status and estrogen use, jointly explained approximately 6% of the total variance of BA index. Genetic factors explained an additional 57%. The genome search for this BA index revealed a number of potential chromosomal regions in the two-point analysis, but for multipoint, only the region on chromosome 21 remained significant.
The variance component analysis, used by Karasik et al. (2004), a priori assumes a polygene mode of inheritance. Our segregation analysis results confirm the findings about a significant genetic effect and furthermore suggest the existence of a MG effect in an individual’s TOSS with a dominant most parsimonious model. The MG hypotheses may be, to some extent, supported by the fact that in the multipoint variance component linkage analysis by Karasik et al. (2004) only one chromosomal region showed a significant LOD score >3 (likelihood ratio greater than 103). We found that genetic factors (MG genotypes) explained 47% of the residual OSS variance after adjustment for age, and after including the sex-genotype interaction, they explained 52% of the residual variance. For TOSS the MG effect was 32%.
Additionally, we compared the age dependence of OSS by directly measuring the individual’s skeletal health index in predicted MG genotype groups. Kobyliansky et al. (1995) proposed a two-stage stochastic statistical model of the population aging pattern for OSS. The implied stages are as follows: (1) the period of life between birth and the apparent onset of skeletal changes (t < ti), defined as the latent period, and (2) the period of visible changes beginning after ti (which is not the same in different individuals), when involutive changes occur continuously throughout the remaining life. Applying this model separately in predicted genotype groups, we compared their aging features by means of model parameters (t0, q, B). The earliest age of the first visible changes, t0, was almost the same in all sex-genotype groups, about 22 years. The probability per year of transition from the latent to the visible changes period, q, was for genotype A1A1 about 1/3 of probability for other individuals. This was especially expressed for women and it results in greater values of the average transition age TM (39.3 years in A1A1-group and 31.7 for the others). The rate of aging, B, was also significantly different in the predicted genotype groups, but this difference was expressed more for men. Thus, we can conclude that the inherited difference in the aging pattern lies in men, mostly in the rate of aging, but in women, it is in the age of onset of the period of visible changes.
An additional finding was that in the group A1A1 (slow aging), for women, the age at menarche was significantly greater (P = 0.012) than in the group {A1A2 OR A2A2}. For women born after 1937 (those whose maturation period was not influenced by WW II or the subsequent rehabilitation period), the age at menopause was also greater in the group A1A1 (P = 0.054). Thus, there is a positive relation between the rate of sexual development and the rate of aging, characterized by degenerative skeletal changes. The rate of sexual development is positively associated with intensity of normal metabolism, which also may lead to accelerated aging. Early onset of menarche is also known to be linked to other aging conditions such as elevated blood pressure and glucose intolerance, compared with later maturing girls, independent of body composition (Remsberg et al. 2005).
The main molecular characteristic of aging is the progressive accumulation of damages in macromolecules that result on macro level in heterogeneity of tissues and degenerative changes. Rattan (2006) pointed out three major sources of this damage: (1) reactive oxygen species (ROS) and free radicals formed due to external inducers of damage (for example ultra-violet rays), and as a consequence of cellular metabolism; (2) nutritional glucose and its metabolites, and their biochemical interactions with ROS; and (3) spontaneous errors in biochemical processes, such as DNA duplication, transcription, post-transcriptional processing, translation, and post-translational. Bessenyei et al. (2004) reviewed data concerning SNPs associated with life span positioned in a variety of genes regulating metabolic processes, apoptosis, stress response (see also Singh et al. 2006) and immune response. Several polymorphisms in ER-alpha (estrogen receptor that are known to play significant role in skeletal development) were reported to be associated with life span (Bessenyei et al. 2004) and with both osteoarthritis (Jin et al. 2004) and osteoporosis (Albagha et al. 2005) related phenotypes. The VDR (vitamin D receptor) gene is also known to be associated with both types of degenerative changes in certain skeletal sites (Uitterlinden et al. 1997; Yue et al. 2005). A great number of genes with significant association signals were cited in recent reviews of Loughlin (2005) (osteoarthritis) and Liu et al. (2006) (osteoporosis). de Boer et al. (2002) described studies of mice with a mutation in XPD, a gene encoding a DNA helicase that functions in both repair and transcription. Mice with mutation were found to exhibit many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. So OSS, the index comprising various accumulated degenerative skeletal changes, despite to different molecular mechanisms, which are involved in bone loss, cartilage loss and other OSS components, may be under genetic control of some polymorphic genes taking part in DNA repair pathways, transcription and translation control and/or some polymorphic genes controlling intensity of normal metabolism, that influence the rate of molecular damage (Kirkwood and Austad 2000). This supports the assumption that OSS as a skeletal biomarker of BA can be used to evaluate the organism’s general aging status.

heritability
biological aging
osseographic score
chuvashia
skeletal aging


Transient caloric restriction and cancer risk (The Netherlands)

Over the past century, many animal experiments have shown that caloric restriction can reduce the risk of cancer, a finding that proved to be highly reproducible. Many papers have been published on its potential for human health, but until know little evidence is available on its actual effects in humans. In Utrecht, The Netherlands, we have been investigating the effects of the 1944–1945 Dutch famine on breast cancer risk factors and breast cancer risk, and paradoxically the relatively short-term famine seemed to be related to increased breast cancer risk in later life. One of the differences between the famine situation and the large body of evidence from animal experiments is the duration of caloric restriction. Almost all animal experiments investigated sustained caloric restriction and information on the effects of short-term transient caloric restriction is very scarce. A search in the literature identified some animal experiments on short-term transient caloric restriction and these seemed to be at least supportive to the famine findings. Because caloric restriction in humans for preventive health measures would be mostly short-term, it is important to extend animal research on short-term caloric restriction.
During the 20th century, a large body of experimental evidence has been accrued signifying that caloric restriction protects against cancer. Rodent data are abundant and consistently show (i) that caloric restriction lowers the incidence of a variety of spontaneous as well as induced or transplanted tumours; (ii) that this effect is directly proportional to the amount of caloric restriction; (iii) that the effects can largely be ascribed to caloric restriction per se, and not merely to the decrease in one or more dietary components; (iv) that caloric restriction initiated in early life as well as in later life is effective in cancer prevention; (v) that caloric restriction prolongs life [1–5]. A pooled quantification of the inhibitory effects of caloric restriction on spontaneous mammary tumour incidence in mice showed that caloric restriction lowered the incidence with 55% [6].
Preliminary reports on energy restriction in non-human primates appear to be consistent with findings in rodents [7, 8]. What about humans? Obviously, this is difficult to investigate, but can lead to important insights in cancer aetiology and to opportunities for prevention. The 1944–1945 Dutch famine, a relatively short severe famine during World War II [9, 10], could shed some light on this issue, and has been used before as an “experiment of history” [11–13].
During the past years, we have conducted several studies on the effects of the 1944–1945 Dutch famine on breast cancer risk factors and breast cancer risk in Utrecht, The Netherlands. For these studies we used data on women who were between 2 and 33 years of age during the famine. Therefore we were not only able to investigate the long-term effects of caloric restriction, but could also relate those effects to specific time-windows in female development. Women were classified to their degree of famine experience on an individual basis, leading to a three-point famine score (‘absent’, ‘moderate’, or ‘severe’ exposure) that enabled dose-response evaluation [14].
In brief, we found that the famine is associated with subsequent reduced reproductive ability in women who were exposed during childhood. This is manifested by decreased chance of childbirth and an earlier mean age at menopause [15, 16]. Strikingly, research on moderate early life diet restriction in Drosophila melanogaster by Tu and Tatar showed also a decrease in adult fecundity [17]. Furthermore, we found that hormone concentrations, measured postmenopausal, seem to be affected by the famine with increases in sex-steroid as well as insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels (resulting in unaffected IGF-I to IGFBP-3 ratios) [18, 19]. All our observations showed a dose-response to degree of famine exposure, with smaller but still observable associations in those moderately exposed.
With regard to breast cancer risk, the associations between the famine and the reproductive system would suggest a protective effect of the famine [20]. However, the associations with hormone concentrations would suggest the contrary [21, 22], with the exception of increased IGFBP-3 that may relate to decreased breast cancer risk [23].
When we actually determined the effect of famine on breast cancer risk in this population, we found that the famine is related to increased risk, again in a dose response manner—a finding that was stronger in women who were children during the 1944–1945 winter [24]. Body mass index at later ages did not confound this relation nor modified it (last data unpublished), suggesting that catch-up growth after the famine did not play an important role. Total cancer risk, exclusive of breast cancer, seemed not to be affected by the famine [25], which does not preclude that famine may have affected risk of specific types of cancer, but the numbers in our study are presently too small for analysis with more detail. Another famine study by Dirx et al. on breast cancer risk could not detect a protection against breast cancer from the famine either, and if anything, showed a moderate increase in risk in women that were exposed at young ages [11]. In addition, Dirx et al. showed that the famine was, non-significantly, associated with increased prostate cancer and decreased colon cancer risk [12, 13]. In these studies, Dirx et al. used place of residence as a measure of famine exposure whereas we used individual exposure data, based on recall.
These findings are not in line with the animal experiments consistently showing caloric restriction to prevent cancer. Several differences between the usually adopted caloric deprivation strategy in animal experiments and the 1944–1945 Dutch famine may explain these differences, such as the amount of restricted calories. The exact degree of caloric restriction during the 1944–1945 Dutch famine is difficult to ascertain, but rations dropped to about 30% of desired norms for adults and to about 50% for young children. The relative amounts of carbohydrates, fats and proteins remained more or less balanced, and supplementations to the rations were sometimes clandestinely available. Young children were relatively protected within families and by charity organisations [9, 10]. Although the amount of caloric restriction during this famine is larger than usually adopted in animal experiments, tumour incidence has been shown to decrease proportionally to degree of caloric restriction in animal experimental settings, amounting to an estimated 62% tumour reduction with 53% caloric restriction [2]. Therefore, it is unlikely that differences in the amount of caloric restriction explain the contradictory results of the famine studies and the animal experiments.
More notably, during the Dutch famine people were transiently exposed for a relatively short duration of time (6 months) [9, 10]. Therefore, this “experiment of history”—as most current famines due to crop disaster or war—is only similar to experiments in rodents that studied short-term caloric restriction followed by ad libitum feeding, whereas the vast majority of these studies investigated dietary interventions that were sustained throughout the animals entire live.
We were able to identify eight animal experiments that investigated transient and mostly short-term caloric restriction, where after animals were allowed to eat at will [26–33]. Two of these experiments studied the effect of caloric restriction for different time periods during and after the chemically induction of breast cancer in female rats [28, 31]. Sustained caloric restriction dramatically decreased tumour incidence: from 50% in the ad libitum group to 20% in the continuously restricted group [31]. It also seemed that caloric restriction during tumour initiation—from 1 week before until 1 week after 7,12-dimethylbenz-[α]anthracene administration—potently reduced mammary tumour development [28]. However, restriction for any period after tumour initiation followed by ad libitum feeding, if anything, showed no substantial effect, and could even lead to increased breast cancer risk [28]. Furthermore, Kritchevsky noticed that when rats were returned from restricted to ad libitum feeding this resulted in hyperphagia, accelerated weight gain, transient mammary hypertrophy, and enhanced tumour growth [31].
Four other experiments investigated the effect of caloric restriction for different periods on, amongst others, spontaneous overall tumour incidence in rats [26, 27, 30], and mice [29]. Again, these studies showed that sustained caloric restriction throughout life lowered cancer risk substantially. However, caloric restriction confined to early life did either not affect cancer risk [30], or actually seemed to increase it [26, 27, 29]. This feeding strategy did not materially increase lifespan, so this cannot explain the observed increase in cancer risk. The study of Cheney et al. in female mice provides some evidence that caloric restriction confined to mid-life may also eventually lead to increased cancer burden [29].
Recently, interest was rekindled with two more studies on prolonged but transient caloric restriction and 1-methyl-1-nitrosaurea induced mammary carcinogenesis in rats [32, 33]. These studies both show that upon refeeding tumour incidence increased.
The disparity between our findings in humans after caloric restriction during a short and severe famine and the abundant literature on sustained caloric restriction and cancer risk in rodents may be ascribed to differences in exposure duration, as is corroborated by the abovementioned animal studies on transient caloric restriction that are in line with the famine observations.
From a biological point of view, it may not be surprising that a short and transient period of caloric restriction in early life may increase human cancer risk. During caloric restriction, a range of responses can be seen, most of which could be directly beneficial to overall cancer risk but are unlikely to be of importance once the restriction is discontinued. Proliferation of cells is reduced with both increased rates of apoptosis together with decreased DNA synthesis and increased DNA repair, limiting the number of preneoplastic lesions. Oxidative stress is reduced, resulting in decreased reactive oxygen species that can damage DNA. Furthermore, of interest to hormone associated tumours, levels of a number of hormones and growth factors are altered during caloric restriction: glucocorticoids are increased whereas concentrations of IGF-I (and to a lesser extent IGFBP-3 resulting in decreased bioavailability of IGF-I), insulin, prolactin, estrogens and leptin are decreased [3–5, 34–36].
Changes in leptin levels can interfere with sexual maturation [37, 38], a period in development during which the Dutch famine showed the largest impact on breast cancer risk in our study. It could be that the hypothalamo-pituitary axis, which is not matured in girls until a few years after menarche when regular menses are established [39], has erroneously adapted to the period of paucity, leading to inappropriate set-levels of hormones that could relate to hormone associated cancers [18, 19]. Such erroneous adaptations, also described as a “thrifty phenotype” [40], are the subject of the “foetal and infant origins of adult disease” hypothesis by Barker and colleagues [41]. Evidence is mounting that such long-lasting effects indeed exist and may contribute considerably to later health [42]. The potential involvement of the hypothalamo-pituitary axis herein has been recognised [43].
In conclusion, the general notion that caloric restriction prevents cancer needs some amendment, even for rodents. Evidence is strong that during caloric restriction, cancer risk is decreased proportionally to the amount of restriction, and such interventions can be effective whether started in early life or later. However, a short and transient period of restriction followed by a “normal” diet does not show such effects and could actually be detrimental.
Thompson et al. made a similar plea. If humans are advised to eat less as a means to prevent cancer, this would probably result in repetitive periods of weight loss followed by periods of weight gain. He warned that such weight cycling may be associated with a modest acceleration of the carcinogenic response [44].
Animal experiments on short-term interventions or weight-cycling diets are scarce and their results yet inconclusive. Such animal experiments are nevertheless highly relevant and need further investigation before any preventive strategy is researched in experimental settings, or actually adopted, in humans, as short-term interventions are the most feasible for the human situation but may bring along considerable hazards. It would be of importance to see if our observations can be replicated in such animal experiments and in human studies making use of other famine episodes, e.g. the 1959–1961 Chinese famine [45]. Other human studies may involve for instance children from countries with poor nutrition that are adopted by families in economically prosperous countries. These children have been exposed to adverse nutritional circumstances at young ages for a clearly demarcated period followed by nutritional abundance (in contrast to immigration studies of for example Japanese women to the United States who gradually adapt, often partly, to a Western lifestyle). Indian girls adopted in Sweden have for example been shown to reach menarche at younger ages compared to Indian standards [46]. It would be intriguing to see whether other physiologic changes occur in these children, e.g. with regard to hormonal levels.
Furthermore, studies on cancer risk in patients with anorexia nervosa are also of interest. Two studies have reported on the topic and found a decreased risk of breast cancer [47, 48]. The generalisability of these observations is however troubled as factors underlying this disease may contribute to the decrease in breast cancer risk, so this may not merely be ascribed to a decreased caloric intake per se.
Currently, the relation between famine exposure in early life and risk of other types of cancer than that of the breast is largely unknown. It would be valuable to further investigate these relations to see whether associations are different between cancer types, e.g. comparing hormone to non-hormone associated cancer types. This would give further insight into whether general mechanisms in human cancer aetiology are involved or whether adaptation of hormonal axes leading to harmful hormone concentrations is the potential culprit.

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caloric restriction
cancer
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famine