Preconception Optimization -

Investing in the Next Generation

Bonnie Nedrow, ND

Preconception Care

Preconception care supports the health of both parents-to-be and begins at least six months prior to a planned conception. The focus on parental health is based on the growing understanding that healthy parents are more likely to have healthy children. The desired outcome of preparing for conception is to optimize biomarkers and reduce medical complications. When an individual has a health challenge that cannot be fully resolved prior to conceiving a baby, focus is on minimally invasive management with medications and supplements shown to be safer for reproduction.

 

Care begins with a complete health history, an environmental health history, a full physical and a biomarker assessment. Biomarkers for all preconception patients include body composition, CBC, lipid panel, glucose, hemoglobin A1C (HgA1C), homocysteine, vitamin D, TSH, C-reactive protein (CRP) and the liver enzymes ALT, AST and GGT. Additional markers may be indicated for specific health concerns or when nutritional deficiencies are suspected. Areas of concern are identified and a course of treatment with a specific time-line is negotiated.

 

Preconception planning can be emotionally challenging and financially daunting for many patients. This is particularly true when working with healthy, presumably fertile young people who do not anticipate any complications with getting pregnant and having a healthy baby. However, parents-to-be are often very motivated to invest in their own health prior to conception when they understand the life-long health benefits for their future child. Educational topics include nutritional counseling, endocrine disruptive and oxidative damaging chemical exposures, and genetic and epigenetic effects on reproduction. For the clinician offering preconception care, there is a delicate balance of honestly outlining the risks while at the same time empowering patients to choose healthful interventions that are both manageable and prudent.

 

The preconception period begins with the maturation of the gametes from both parents and ends with the successful union of the sperm and egg. Gamete restructuring with demethylation and remethylation prior to conception marks this window as one of the most genetically vulnerable. Nutritional deficiencies, nutritional excess, stress and environmental toxicants can all negatively affect the genetic material of the baby-to-be during this time of rapid development. Because of this susceptibility, optimizing preconception health may be viewed as equally important as pregnancy and early childhood healthcare. In light of the expanding research on paternal epigenetic programming of both children and grandchildren, fathers-to-be should be considered equally important participants in preconception optimization.

 

For sperm, the preconception window is the three months prior to conception. Spermatogenesis occurs when a sperm stem cell divides through mitosis to create a haploid spermatocyte with 23 chromosomes and a new diploid stem cell capable of repeating the process. The haploid spermatocytes become mature spermatozoa and are then transported to the epididymis in preparation for ejaculation. Oocytes, on the other hand begin mitosis in the developing female fetus in-utero in the fifth month of her mother’s pregnancy. At this time, a female’s lifetime supply of ovum is produced and stored as primordial follicles, also known as primary oocytes. The primary oocytes remain in this relatively protected dormant state until the young woman reaches puberty. Each month from puberty until the supply of eggs is exhausted at menopause, luteinizing hormone stimulates resumption of meiosis producing a secondary haploid oocyte from the primordial follicle. It takes roughly four months for maturation of the female gamete.

 

Developmental Origins of Health and Disease

Most people are aware that the pregnancy environment can significantly impact the health of the newborn baby and young child. Pregnant women generally strive to eat healthy food, get plenty of rest, avoid stressors and take their prenatal vitamins, all with the goal of having a healthy baby. Parents often give a sigh of relief and believe they have dodged a genetic bullet once the baby is born, takes its first breath, responds to stimuli and appears normal and healthy. However, research has demonstrated that chronic disease processes not overtly observed until later in life can be initiated during early development. This phenomenon is referred to as the developmental origin of health and disease (DOHaD). DOHaD maternal factors include infections, nutritional status, maternal stress, medications and exposure to environmental toxicants during the preconception window, throughout pregnancy and during the lactation period. Poor outcomes include congenital defects noted at birth, neurobehavioral disorders diagnosed in childhood, cancer at any age, and metabolic disease including obesity, cardiovascular disease, and insulin resistance.(1)

 

Male Epigenetics

The majority of studies on the DOHaD have, to date, focused on the mother-child dyad. However, both epidemiological and animal studies indicate that the paternal contribution to birth defects and chronic illnesses in offspring is not insubstantial. Nutritional factors, environmental toxicant exposures, and ionizing radiation have all been shown to epigenetically alter the paternal genome and can have lasting effects on the health of the next generation. There are four critical windows when the paternal germ-line is vulnerable to these gene alterations: the father’s embryonic stage, prior to puberty, preconception spermatogenesis and post-conception embryo development. These insults are not due to changes in DNA sequencing, but to epigenomic alterations of DNA methylation, histone modifications, and transcription of non-coding RNAs.(2)

 

A 2011 study of 242 babies with birth defects as compared to 270 children with no defects examined environmental toxicant exposures of parents in the preconception window. They found a positive correlation with preconception paternal occupational exposure to pesticides, solvents, and welding fumes. (3)

 

In a review of the next generation health impact of paternal preconception smoking, multiple animal and human studies demonstrated both genetic and epigenetic negative effects. Cigarettes contain more than 7,000 chemicals including 69 polycyclic aromatic hydrocarbons that are proven carcinogens and mutagens. Studies link paternal preconception smoking to birth defects including cardiovascular anomalies, congenital heart disease, cleft palate, hydrocephalus and spina bifida. Some of the genetic mechanisms that were discovered include DNA oxidation, sperm DNA strand breaks and chromosomal abnormalities. A mouse study further revealed the epigenetic effect of hypomethylation of testicular DNA when exposed to benzo(a)pyrene, a compound in cigarettes.(4)

 

Information gleaned from the afore mentioned studies indicates that paternal avoidance of chemicals in the three months prior to pregnancy has the potential to positively impact outcomes not only for the newborn but extending to life-long wellbeing. Because avoidance of toxic compounds is not always possible, measures to mitigate toxicant effects on sperm should be employed. Unfortunately, intervention studies to counter the negative effects of unavoidable toxicant exposure for fathers-to-be are extremely limited. Hypothetically, supplementation with folate and additional methylation support may reverse insults leading to hypomethylation. While there are no studies currently on treating sperm, studies on repletion of cellular hypomethylation with folate supplementation in adults is promising.(5)

 

Zinc is frequently found to be effective in treating male infertility where poor sperm quality due to oxidative stress has been identified. Since sperm DNA damage has also been linked to oxidative stress, zinc has a potential role as a nutrient in male preconception care. In sperm studies, zinc is thought to act as an antioxidant via direct scavenging of superoxide radicals and protection of sulfhydryl proteins from oxidation.(6)  Selenium as a co-factor of glutathione peroxidase is another important trace mineral with antioxidant properties. While copper and iron are essential for sperm function, the balance of trace mineral ratios suggests that excess copper and iron with low zinc and selenium lead to increased sperm oxidative stress.(7)

 

Paternal Inheritance of Metabolic Syndrome

Undoubtedly one of the most concerning trends in human health is the exponential rise in all age groups of overweight and obesity with metabolic co-morbidities including diabetes, cardiovascular disease and hepatic steatorrhea. Optimizing body composition in the preconception window is a safe strategy to reduce the risk of metabolic syndrome in the next generation. It is well recognized that the uterine environment of obese and diabetic mothers increases the risk of offspring metabolic disease.  More recent research points to the additive impact of paternal epigenetic programming of offspring metabolism.

 

In a rare analysis of life-style modifications on paternal epigenetics, an animal study found that nutrition and exercise reduce paternally inheritable metabolic syndrome. Overweight male mice were found to program their female offspring for insulin resistance and enlarged adipocytes, leading to an increased risk for obesity and associated metabolic diseases. The study used a short-term eight-week intervention of exercise and balanced macronutrient diet on obese male mice that had been sedentary and eating a high-fat diet. This intervention was shown to improve the male mice’s metabolic health and significantly decrease metabolic disease in their female offspring even when there was no change in paternal weight. This study not only demonstrates that preconception exercise and nutrition can improve reproductive outcomes, it also provides us with measurable biomarkers. Paternal preconception biomarkers that correlated in this study with offspring metabolic disease include fasting glucose, cholesterol, triglycerides, CRP, insulin, and leptin.(8)

 

Endocrine Disruptors and Female Reproduction

An endocrine disruptor is defined as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action.”(9)  These chemicals can bind to the body’s endocrine receptors to activate, block, or alter natural hormone synthesis and degradation. Over 1,000 man-made chemicals have been identified as endocrine disruptors including plasticisers, flame-retardants, metals, dioxins, air pollutants and pesticides. One of the best-studied and most ubiquitous endocrine disrupters is the estrogenic plasticizer bisphenol A (BPA).(10)  BPA alters DNA methylation in the developmental stage where the primary oocyte returns to meiosis to develop into the secondary haploid oocyte in preparation for conception. This has been shown to either block maternal imprinting or affect the imprint stability. Such alterations are associated with both infertility and offspring defects. Disturbances of maternal imprinting have been linked to infertility, cancer and neurodevelopmental diseases such as Angleman, Prader-Willi, and Russell-Silver syndromes.(11)

 

In a mouse study, BPA at physiologically relevant doses poorly impacted placental implantation. Inadequate implantation caused poor oxygen perfusion leading to increase sequelae of preterm birth and intrauterine growth retardation (IUGR).(12)   This is an important finding because IUGR is one of the causative factors of gestational induction of metabolic syndrome.

 

The general public is increasingly knowledgeable about the ill health effects of BPA. Industry has responded by creating a line of BPA-free products using alternate bisphenols including BPS. This is an example of what has been termed a “regrettable substitution” of one toxic chemical for another less understood but equally damaging compound. In a study on pig oocytes, BPS was found to both slow and block maturation of the secondary oocyte by interfering with both estrogen and aromatase metabolism. Pig oocytes are frequently utilized for maturation studies due to their similarity to human oocytes, particularly when compared to the more common mouse and rat studies, animals whose oocytes mature in a relatively rapid time frame.(13)

 

It is often discovered that chemicals negatively impact health by operating on multiple systems. Mancozeb, one of the most commonly used fungicides on golf courses and produce, acts both as an oocyte endocrine disruptor and a contributor to oxidative stress. In a 2017 mouse study, resveratrol was shown to reduce apoptosis and suboptimal formation of mature oocytes. The study authors attributed the positive effects of resveratrol not only to enhance mitochondrial performance through redox pathway, but also protection from mancozeb-induced histone methylation, an epigenetic affect.(14)

 

Maternal Programming of Metabolic Syndrome

As mentioned earlier, metabolic syndrome (MetS) is perhaps the greatest health concern of our times. MetS is a constellation of medical conditions including obesity, dyslipidemia, diabetes, non-alcoholic fatty liver disease and cardiovascular disease. Parents-to-be who have MetS are more likely to pass on the condition to their children. While the paternal line has been shown to epigenetically induce metabolic syndrome in the next generation, maternal developmental programing is much more complex. In addition to the developing oocyte, we need to take into consideration the intrauterine environment and post-natal lactation.

Mothers who exhibit MetS features of obesity, gestational diabetes, and gestational hypertension are at increased risk of programming MetS in their children. Additional risk factors include malnutrition associated with IUGR, maternal smoking exposure, and in-utero exposure to endocrine-disrupting chemicals.(15)  An obvious health goal is to reduce or eliminate features of MetS in the mother prior to conception. However, additional protective measures are warranted when full recovery is not attainable. A 2012 review article cites a number of potential maternal dietary interventions to prevent MetS in offspring. The use of vitamin C, vitamin E, folate, zinc, multivitamins and iron appeared beneficial only when a specific nutrient was found to be deficient in the maternal diet and was repleted. As a word of caution, studies on high doses of nutrients in the conception and gestation windows have been conversely shown to exhibit health risks including IUGR. Therefore, treatment with these nutrients should be conservative and take into account maternal diet. In this literature review the two agents that were found to have the most positive risk-benefit ratio were melatonin and resveratrol.(16)

 

Melatonin plays a significantly protective role in a healthy pregnancy through regulation of the circadian rhythm, antioxidant-free radical scavenging, and immune modulation. Additionally, melatonin impacts both fetal growth and organogenesis. An interesting finding that warrants more research is the ability of melatonin to act epigenetically by inhibiting DNA methyltransferase and histone deacetylase. In this review, multiple studies demonstrated gestation reprogramming by melatonin that prevented adult onset of disease in offspring. While this is an exciting finding, more research is needed to determine the timing and dosage that will produce a positive effect.(17)   In the meantime, preconception optimization can safely include establishment of circadian rhythms with sleep during the hours of darkness to enhance natural production of melatonin.

 

Resveratrol is a powerful antioxidant found to be highly effective for the treatment of MetS. Mechanisms include inhibition of platelet aggregation, improvement of endothelial function, restoration of nitric oxide bioavailability, and increased activity of superoxide dismutase and glutathione peroxidase. In a small human study of 110 obese women, resveratrol combined with inositol positively affected lipid and blood glucose levels; however, effects on the next generation of the intervention were not reported.(18)  Other studies on the long-term impacts of resveratrol are animal models and offer interesting yet limited applications for the prevention of developmental programming of MetS in humans.

 

Neuroinflammation

One of the most challenging pediatric conditions that parents are most interested in reducing the risk for is autism spectrum disorder (ASD), which occurs in roughly 1 in 100 births. The cause is complex and multifactorial and includes both genetic susceptibility and environmental insults, particularly in fetal and early-life development. One hypothesized mechanism for an in-utero initiation of ASD is maternal inflammation secondary to infection including viral, bacterial and parasitic. Maternal immune activation in response to infection could plausibly initiate fetal cytokine upregulation. Cytokines, generally considered immune modulators, are also essential for fetal and neonatal brain remodeling.(19)  When maternal immune cytokines increase, alterations in fetal brain cytokines can become imbalanced causing neuroinflammation. Potential interventions in the preconception window include optimization of maternal microbiota and repletion of omega-3 fatty acids.(20)

 

In addition to infection, inflammatory maternal health conditions including gestational diabetes and obesity are associated with a higher risk of having a child with ASD. It has been hypothesized that CRP, which is elevated in cases of metabolic syndrome, may be the initiator of fetal neuroinflammation and could therefore be an important biomarker for ASD risk. However, research on this association is conflicting. A 2014 cohort of over a million pregnancies in Finland demonstrated a linear association of elevated CRP in pregnant mothers who then had children diagnosed with ASD. In this study the highest measurements of CRP were associated with a 43% increase in incidence in ASD.(21)   Two years later a second case-control study including 500 children with ASD and 580 general population controls demonstrated the exact opposite finding. In the 2016 study the highest mid-pregnancy levels of CRP were associated with the lowest incidence of ASD. The study author’s interpretation was that CRP was not a marker for ASD.(22)   A third 2016 study of over 4,000 mother-baby pairs measured CRP in early pregnancy prior to week 18 and found no association of CRP with pervasive developmental problems.(23)   More studies on biomarkers for ASD are needed to support earlier clinical intervention. Because CRP is a plausible marker, it deserves more scrutiny in future studies with additional data points in preconception and throughout pregnancy. Studies of other plausible biomarkers should also be considered. Potential measurable elements would include BMI, fasting and postprandial blood sugars, insulin and HgA1C. In the meanwhile, weight reduction for obese and overweight preconception patients would theoretically reduce the risk of having a child with ASD.

 

In Summary

It is evident that preconception health of both parents has a life-long impact on the wellbeing of their children, especially when we consider the DOHaD. Chronic illnesses such as MetS and ASD are affecting the quality of life for an increasing number of humans and exponentially inflating health-care cost worldwide. Preconception interventions allow time to optimize nutrition, reduce toxicant exposure and chemical body burden and help parents-to-be achieve ideal body weight: all factors that can program life-long health and disease. Optimizing preconception presents an opportunity to reduce developmental disorders in future child and adult populations.

 

Bonnie Nedrow, ND

Bonnie Nedrow, ND

Bonnie Nedrow, ND, lectures nationally on environmental medicine and reproductive health, preconception optimization, and the ketogenic diet for metabolic flexibility. She is currently located in Santa Rosa, California, at Farmacopia, where she has a private practice and teaches classes on her programs to the public. In addition, she offers coaching for her ketogenic detoxification program to patients in Oregon and California. She has co-published two books, The Seasonal Cleanse Workbook and The Cleanse Companion Cookbook.

Dr. Nedrow is available for case consultations on the ketogenic diet, single nucleotide polymorphisms, and detoxification. For more about her programs and publications, or to contact Dr. Nedrow, go to ketocleanse. com.

 

References

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