Improving the periconceptual environment: the next frontier for improved fertility outcomes?

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Improving the periconceptual environment the
next frontier for improved fertility outcomes?

• Prof. Dr. Nilgün Turhan
• Fatih University Medical School
• IVF Unit

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• Several studies using animal models have shown
  that preimplantation embryos are sensitive to
  environmental conditions that can affect future
  growth and developmental potential both pre- and
  postnatally.

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Epigenetics

• All cells in the body have a phenotype that is a
  culmination of the cells gene structure,
  epigenetic marks and environmental influences.
• Normal embryogenesis can not proceed without the
  machinery of epigenetic regulation.

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Epigenetics

• A mitotically and/or meiotically heritable
  changes in gene expression that occur owing to
  modifications of the helical structure without
  changes in the DNA sequence.

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Epigenetics

• Four main types of epigenetic inheritance
• DNA methylation
• Chromatin remodelling (Histone modification)
• Genomic imprinting
• Long-range control by chromatin structure
• These mechanisms are interdependent and may be
  synergistic.

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Epigenetic modifications in gene silencing

• A series of epigenetic modifications transforms
  transcriptionally active regions of DNA into
  inactive compact chromatin.
• Transcriptionally active chromatin is associated
  with acetylated histones, whereas inactive
  chromatin has methylated DNA and de-acetylated
  histones.

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Epigenetic Reprogramming
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Epigenetic Reprogramming

• DNA methylation patterning and chromatin
  modifications are
• required for normal tissue development during
  early development stages.
• While cell-specific methylation patterns are
  relatively stable in somatic cells, DNA
  methylation is subject to dynamic variations in
  preimplantation embryos.
• Embryo is most vulnerable to environmental
  factors during
• embryogenesis since the DNA synthetic rate is
  high.
• The proper or improper handling of these highly
  sensitive
• periods may have significant short-term and
  long-term effects on the individual and his/her
  progeny.

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Epigenetic Reprogramming

• In normal developmental or disease situations,
  some cells
• undergo major epigenetic reprogramming.
• The epigenome is particularly susceptible to
  dysregulation
• during gestation, neonatal development, puberty
  and old age.

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Epigenetic Reprogramming

• The physiology and later the pathophysiology of
  epigenetic
• reprogramming dynamics may be studied in four
  distinct phases
• -Fertilisation
• -Early embryo development
• -Gametogenesis
• -Lifelong reprogramming

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Dynamic reprogramming of the epigenome during
development
The first phase of methylation reprogramming
occurs between fertilisation and formation of
the blastocyst.
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Methylation levels in imprinted and nonimprinted
genes during early embryogenesis and gametogenesis
Nafee TM. BJOG 2008115158168
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Dynamic reprogramming of the epigenome during
development
Primordial germ cells undergo demethylation as
they migrate along the genital ridge, both
genomewide and within imprinted loci and
following this erasure, CpG methylation of
imprinted genes is reestablished during
gametogenesis through de novo methylation, in
both eggs.
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Abnormal expression of imprinted genes

• Abnormal expression of imprinted genes, through
  genetic or
• epigenetic alterations, can lead to a number of
  diseases.
• These diseases are all characterized by a
  non-mendelian
• inheritance and a parent-of-origin effect.
• Neuron-developmental BWS, PWS and AS
• Metabolic disorders transient neonatal diabetes
  mellitus
• Psychiatric/behavioral disorders autism,
  schizophrenia, and bipolar disorder
• Cancer retinoblastoma

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DEFECTIVE IMPRINTING IN ART

• Various environmental factors, such as gamete in
  vitro manipulation, or exposure to specific
  compounds during pregnancy may lead to changes in
  the imprinting patterns of genes and affect
  gametogenesis and embryonic development.

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DEFECTIVE IMPRINTING IN ART

• New technical steps have been recently added to
  the IVF/ICSI procedures, like testicular/ovarian
  tissue cryopreservation and oocyte in vitro
  maturation as well as preimplantation genetic
  diagnosis.
• It is presently not known whether these may
  expose the gametes or early embryos to risks of
  imprinting defects.
• Recent studies have suggested that a number of
  specific imprinting disorders might be more
  frequent in children conceived by ART than
  naturally.

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Selected human disorders linked to an imprinting
defect reported after ART
ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH
200761, No. 5, Pt 2,
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Embryo environment Glucose, energy
substrates Amino acids Growth factors Steroid
hormones Cytokines Metabolic regulators
In Vitro culture Protein supplements Media
composition
In vivo environment Diet Body composition
Potential short-term responses developmental
plasticity Epigenetic modifications Altered
intracellular signalling Metabolic
stress Apoptosis Cell proliferation disturbed
Tom P. Fleming, BIOLOGY OF REPRODUCTION 71,
10461054 (2004)
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• Evidence now indicates that singletons born after
  ART are at
• increased risk of premature birth, very low
  birth weight, and
• perinatal mortality, compared with singletons
  born to fertile
• women.
• They are also at increased risk for sex
  chromosome abnormalities, attributable in part to
  parental chromosomal abnormalities.
• Presented at the ART Workshop Evaluation of
  Genetic and Epigenetic Risks Associated with
• Reproductive Technologies and Infertility,
  January 1415, 2005, Toronto, Ontario, Canada.

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• Evidence is suggestive but not sufficient to
  conclude that there is an increased risk for rare
  genetic syndromes involving loss of imprinting,
  such as Beckwith-Wiedemann syndrome
• and Angelman syndrome.

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PREGNANCY OUTCOME

• ARTs were linked to an increased risk of
• Intrauterine growth restriction (OR 1.59)
• Premature birth
• lt 33 weeks of gestation OR2.99
• lt 37 weeks of gestation OR, 1.93
• Low birth weight (1,500 g OR3.78)
• In utero death (OR2.40)
• Angelman syndrome and Beckwith-Wiedemann
  syndrome
• Jackson RA, Obstet Gynecol 2004, Halliday J, Am J
  Hum Genet 2004,
• Wennerholm , 2000, Anthony 2002, Hansen 2005,
  Klemetti 2005, Kallen
• 2005, Schieve 200 4 Jackson 2004,
  Helmerhorst 2004

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PREGNANCY OUTCOME
Poikkeus et al 2007
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OBSTETRICS VE NEONATAL OUTCOME
Poikkeus et al 2007
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Lifelong epigenetic reprogramming ageing, diet
and environmental toxins
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Lifelong epigenetic reprogramming ageing, diet
and environmental toxins

• DNA methylation patterns change with age
• Global DNA hypomethylation
• Gene-specific hypermethylation of some CpG
  islands
• 
  Richardson B. Ageing Res Rev 20032245-61.
• 
  Waterland RA, Jirtle RL. Nutrition
  200420638.

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Lifelong epigenetic reprogramming ageing, diet
and environmental toxins

• DNA hypomethylation
• Genomic instability
• Overexpression of proto-oncogenes

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Lifelong epigenetic reprogramming ageing, diet
and environmental toxins
Gene silencing due to hypermethylation ? with
age. Silencing of genes impair control of cell
cycle, apoptosis, detoxification and cholesterol
metabolism.
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Lifelong epigenetic reprogramming ageing, diet
and environmental toxins

• Dietary and other lifestyle exposures
• Epigenetic-mediated changes in gene expression
• Change cell function and
• health throughout the life course

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NUTRITION
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NUTRITION

• Folate, B12, Se, phytochemicals
  (genistein,polyphenolics)
• food contaminants (As)
• DNA methylation

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DIET
Folic acid
DHF
DNA methylation
DNMT
Choline
Diet
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Potential implications of epigenetic modulation
in obstetrics
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Nutrient-gen interactions in early pregnancy

• Periconceptional and early pregnancy
  nutrient-gene interactions
• The quality of gamates and fertilization capacity
• Embryogenesis and fetal growth
• The trophoblast invasion of decidua and spiral
  arteries
• Angiogenesis, vasculogenesis and vascular
  function

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Nutrient-gen interactions in early pregnancy

• Folate, present in follicular fluid and seminal
  plasma, may
• influence the quality of oocytes and sperm.
• This is supported by the significantly increased
  sperm count after folic acid and zincsulphate
  intervention.
• Wong WY. Fertil Steril 2002
• OLeary VB. Am J Med Genet 2002

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Nutrient-gen interactions in early pregnancy

• Folate deficiency and mild hyperhomocysteinemia
  detrimentally
• affect the precise control of embryonic cellular
  processes such as migration, differentiation,
  proliferation, apoptosis and intracellular
  signaling.
• Loscalzo J. Circulation 2001

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Nutrient-gen interactions in early pregnancy

• A diminished embryonic folate status, due to
  MTHFR and MTHFR polymorphisms and interactions
  with exogenous and
• endogenous determinants are risk factors for
  neural tube and
• congenital heart defects.
• Folate deficiency and hyperhomocysteinemia are
  related to
• carotid artery wall thickness and cardiovascular
  diseases in later life.

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Nutrient-gen interactions in early pregnancy

• The disbalanced folate, homocysteine and
  NO-status may disturb embryonic vasculogenesis.
• Nutrient shortages will affect trophoblast
  function and invasion
• and may contribute to spontaneous abortion,
  preeclampsia and fetal growth restriction.
• Steegers-Theunissen RPM. Br J Obstet Gynaecol,
  2000, Leung DH. Am J Obstet Gynecol
• 2001, Makedos G. Arch Gynecol Obstet 2007,
  Cotter AM.Am J Obstet Gynecol 2001

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Nutrient-gen interactions in early pregnancy

• Apoptosis increases in trophoblastic cells
  cultured in folate-free
• medium.
• Increased apoptosis demonstrated in the placentas
  from the pregnancies complicated by preeclampsia.
  
• Women who develop severe preeclampsia have higher
  plasma
• homocysteine levels in early pregnancy than
  women who remain normotensive throughout
  pregnancy.

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DEFECTIVE IMPRINTING
Nutrient-gen interactions in early pregnancy

• Imprinted genes acting on fetoplacental growth
• Paternally expressed
• IGF2, MEST/PEG1, PEG3, INS1, INS2, and MEST
• Maternally expressed
• IGF2R, H19, and GRB10
• These genes are thought to play a role in
  matching the
• placental nutrient supply to fetal nutrient
  demands.

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Nutrient-gen interactions in early pregnancy
DEFECTIVE IMPRINTING

• Fetal growth
• Maternally imprinted genes enhance
• Paternally imprinted genes diminish or suppress
• Placental growth
• Paternally expressed genes enhance
• Maternally expressed genes reduce
• Imprinting depends on differential methylation.
• Early malnutrition may alter the methylation
  pattern, with
• consequences for placental function and embryo
  development.

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ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH
200761, No. 5, Pt 2,
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Nutrient-gen interactions in early pregnancy

• High-protein diets in sheep during the
  periconceptional period have been associated with
  reduced developmental viability and increased
  fetal and birth weights.
• McEvoy TG. Anim Reprod Sci 1997
• McEvoy TG. Theriogenology 2001

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Nutrient-gen interactions in early pregnancy

• A low-protein diet fed to rats during the
  preimplantation period before return to control
  diet for the remainder of gestation is associated
  with several changes in postnatal phenotype even
  though offspring were fed a normal diet
• low birth weight
• subsequent overcompensatory adolescent growth
• onset of adult hypertension
• alterations in relative organ sizing in a
  gender-specific manner
• Kwong WY. Development 2000

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Nutrient-gen interactions in early pregnancy

• Humans ingest approximately 50 mmol of methyl
  groups per
• day of which 60 are derived from choline.
• Excess or deficiency of endogenous or exogenous
  choline,
• methionine, folic acid, vitamin B12, vitamin B6,
  and zinc may
• alter the methyl supply.
• Such a change is expected to affect DNA
  methylation.
• Genomic DNA methylation status was found to
  correlate
• directly with folate status and inversely with
  homocysteine levels.

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Low concentrations of dietary and circulating
folate

• Neural tube defect
• Preterm delivery
• Low infant birthweight
• Fetal growth retardation
• Premature rupture of membranes
• Defective maternal erythropoiesis

Scholl TO. Am J Clin Nutr 200071(5
Suppl)1295S1303S. Tamura T. Am J Clin Nutr
2006839931016. Heil SG. Mol Genet Metab
20017316472. Shaw GM. Public Health Rep
20041191703. Knudtson EJ.Am J Obstet Gynecol
200419153741.
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Low concentrations of dietary and circulating
folate

• Defective growth of the uterus and mammary gland
  and growth of the placenta, placental infarctions
• The subsequently elevated maternal homocysteine
  concentrations, a metabolic consequence of folate
  deficiency, has been associated both with
  increased recurrent miscarriage, placental
  abruption, and pre-eclampsia.

Scholl TO. Am J Clin Nutr 200071(5
Suppl)1295S1303S. Tamura T. Am J Clin Nutr
2006839931016. Heil SG. Mol Genet Metab
20017316472. Shaw GM. Public Health Rep
20041191703. Knudtson EJ.Am J Obstet Gynecol
200419153741.
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Folate supplementation during pregnancy

• Supplementing a mothers nutritionally adequate
  diet with extra folic acid, vitamin B12, choline,
  and betaine can permanently affect the
  offsprings DNA methylation at epigenetically
  susceptible loci.
• Population-based supplementation with folic acid,
  intended to
• reduce the incidence of neural tube defects, may
  have unintended influences on the establishment
  of epigenetic gene regulatory mechanisms during
  human embryonic development.
• Waterland RA, Jirtle RL Mol Cell Biol
  2003235293300.
• Finnell RH et al. J Nutr 2002132(8 Suppl)
  2457S2461S.
• Friso S, Choi SW. Curr Drug Metab 200563746.

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Conclusion
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Conclusion

• Epigenetic modifications may persist
  transgenerationally despite the lack of continued
  exposure to environmental influences in future
  generations.
• Aberrant epigenetic gene regulation has been
  proposed as a
• mechanism for several diseases, including
  carcinogenesis,
• imprinting disorders, Alzheimers disease,
  schizophrenia,
• asthma, and autism.

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Conclusion

• Obstetricians are undoubtedly responsible for
  providing care to women and their fetuses during
  some of the most dynamic windows for epigenetic
  reprogramming.
• Reproductive life planning and periconception
  advice
• Women
• Men
• Approaches to life style in fertility clinics
• Preconception interview
• Planning
• Advice
• Information
• Resources

53
Conclusion

• Fertility fitness
• Lessons on diet
• Periconception medicine
• Life style factors before conception for natural
  and induced pregnancies.

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Conclusion
55
Conclusion

• The impact of environmental and nutritional
  factors on the dynamic state of the epigenome and
  their potential roles in epigenetic dysregulation
  in determining maternal, fetal and long-term
  outcomes should be taken into consideration.
• Obstetricians are undoubtedly responsible for
  providing care to women and their fetuses during
  some of the most dynamic windows for epigenetic
  reprogramming.

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IVF TEK GEBELIKLERI

• Helsinki University Central Hospital
• 7 yillik kohort çalisma (19972003)
• Tek dogumla sonuçlanan Taze TET, ÇET ve spontan
  tek gebeliklerin obstetrik ve neonatal sonuçlari
  karsilastirilmis
• Poikkeus P. Hum Reprod 2007

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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR
Poikkeus et al 2007
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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR

• TET gebeliklerinde yas, parite ve sosyoekonomik
  duruma
• göre sonuçlar düzenlendiginde kontrol grubuna
  göre
• C/S riski OR1.54
• Preterm dogum OR2.85
• Düsük dogum agirligi OR2.01
• Poikkeus et al 2007

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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR
Tekil IVF gebeliklerinde transfer edilen embryo
sayisindan çok kisiye ait faktörler ve
infertilite ile ilgili mekanizmalar neonatal
sonuçlari etkiler.
Poikkeus et al 2007
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IVF TEK GEBELIKLERI

• Acaba tranfer edilen embryo sayisinin etkisi var
  mi?
• Ikiz veya daha fazla çogul gebelikle baslayan
  IVF/ICSI tekil gebeliklerinde prematür dogum
  orani yüksek
• Dickey et al 2004
• Erken USG de birden fazla FKA olan IVF/ICSI tekil
  gebeliklerinde düsük dogum agirligi orani yüksek
• Schieve et al 2002

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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR

• 1998 -2003 TET gebelikleri prospektif olarak
  toplanmis
• 251 TET sonrasi tekil gebelik sonuçlari 59 535
  spontan
• tekil gebelik sonuçlari ile karsilastirilmis
• D. De. Neubourg et al. Hum Reprod 2006

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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR
De Neubourge 2006
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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR
De Neubourge 2006
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TET SONRASI OBSTETRIK VE NEONATAL SONUÇLAR

TET yapilan iyi prognozlu hastalarda gebelik
sansi daha düsük olsa da gebelik sonuçlari
spontan tekil gebeliklerden farkli degildir.
De Neubourge 2006
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Genomic imprinting

• Genomic imprinting in mammals describes the
• situation where there is nonequivalence in
  expression
• of alleles at certain gene loci, dependent on the
  parent
• of origin.
• 
  Reik
  W, Walter J.Genet Dev 1998815464.
• 
  
  Tilghman SM. Cell 19999618593.

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Genomic imprinting

• The expression of either the paternally or
  maternally
• inherited allele is consistently repressed,
  resulting in
• monoallelic expression of a particular gene.
• The same pattern of monoallelic expression is
  faithfully
• transmitted to daughter cells following cell
  division.

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Genomic imprinting

• PWS and AS are both due to
• deletion of 15q11-13, but manifest
• differently depending on whether the
• allele was inherited from the mother
• or the father. Failure to inherit the paternal
• region gives PWS.
• Failure to inherit the maternal region gives AS.
  

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Fetal origins hypothesis of adult disease
70
Fetal origins hypothesis of adult disease

• Barker hypothesis
• The observation that individual subjects who were
  small or
• disproportionately large at birth had higher
  occurrence of adult
• obesity
• coronary artery disease
• hypertension
• type II diabetes at middle age
• Ravelli GP. N Engl J Med 197629534953,
  Muskiet FA. Reprod Toxicol 200520403
• 10, Curhan GC. Circulation 199694324650,
  Barker DJ. Br J Obstet Gynaecol
• 1992992756, Barker DJ. J Am Coll Nutr
  200423(6 Suppl)588S595S.

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Fetal origins hypothesis of adult disease

• Experimental data in animals and recent human
  observations have suggested that early-life
  exposures can result in alterations to a range of
  systems, including the hypothalamicpituitaryadre
  nal axis, blood pressure and insulin sensitivity.
• Michael J.Davies and Robert J. Norman TRENDS in
  Endocrinology Metabolism Vol.13 No.9 2002

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Fetal origins hypothesis of adult diseases

• The presence of PCO is associated positively with
  birth weight
• and insulin sensitivity, whereas an underlying
  insulin resistance
• appears to be associated with indicators of
  impaired fetal growth.
• Studies have consistently related low birth
  weight with insulin
• resistance.
• Cresswell, J.L. Lancet 199735011311135
• Michelmore, K. Clin. Endocrinol. (Oxf.)
  200155439446
• Phillips, D.I. Clin. Exp. Pharmacol. Physiol
  200128967970

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Fetal origins hypothesis of adult diseases
Of babies weighing gt3.9 kg born to mothers
weighing gt58.1 kg in pregnancy, 44 had PCO. The
heavy babies were also larger as adults, with an
average BMI gt25 kg m2. Cresswell JL. Lancet.
1997 Oct 18350(9085)1131-5.
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Fetal origins hypothesis of adult diseases
Obese, hirsute women with PCO with higher ovarian
androgens have higher birthweight and maternal
obesity. Thin women with PCO have altered
hypothalamic control of LH release resulting from
prolonged gestation. Cresswell JL.
Lancet. 1997 Oct 18350(9085)1131-5.
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Fetal origins hypothesis of adult diseases
Experimental administration of testosterone to
pregnant rhesus monkeys results in virilization
of external genitalia, masculinization of
behavior, delayed menarche, increased insulin
secretion and enlarged and polyfollicular
ovaries. Abbott, D.H. In Polycystic Ovary
Syndrome (Chang, R.J. et al., eds), pp. 119133,
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Periconceptional Environment

• Fetal growth is most vulnerable to maternal
  dietary deficiencies
• of nutrients (e.g. protein and micronutrients)
  during the peri-
• implantation period and the period of rapid
  placental development.
• Maloney CA, Rees WD.Reproduction 20051304011,
  Waterland RA, Jirtle RL Nutrition
• 200420638, Gluckman PD, Hanson MA. Horm Res
  200665(Suppl 3)514.

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Smoking Female Infertility

• Current tobacco smoking by women decreases
  ovarian function and is manifested by increased
  basal levels of follicle stimulating hormone.
• Such women produce fewer oocytes during ART and
  have lower pregnancy rates.
• Neal MS. Hum Reprod 20052025315.

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Smoking Male Infertility

• Current smoking by the male partner also
  decreases pregnancy rates through direct effects
  on sperm and by exposing the woman partner to
  side-stream smoke.

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Maternal Smoking during pregnancy

• Inverse association between maternal smoking
  during pregnancy
• and total sperm count (p 0.002). Men exposed to
  more than 19
• cigarettes daily during pregnancy had
• 9 lower semen volume (p 0.04)
• 38 lower total sperm count (p 0.11)
• 17 lower sperm concentration (p 0.47) compared
  with unexposed men.
• The odds ratio for oligospermia was 2.16 among
  exposed men compared with the unexposed.
• No associations were found for sperm motility or
  morphology.

Ramlau-Hansen CH. Am J Epidemiol. 2007
165(12)1372-9.
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Parental periconceptional smoking and male
female ratio of newborn infants

• The offspring sex ratio (male to female) was
  lower when either one or both of the parents
  smoked more than 20 cigarettes per day compared
  with couples in which neither of the parents
  smoked.
• The lowest sex ratio among children whose mothers
  and fathers both smoked more than 20 cigarettes
  per day (plt0.0001).
• Parental periconceptional smoking might be a
  contributing factor to a lower male to female sex
  ratio of offspring.
• Fukuda M, Fukuda K, Shimizu T, Andersen CY,
  Byskov AG.

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Oxidative Stress and Male Infertility
Tremellen K. Hum Reprod Update 2008, pp. 1-16
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Oxidative Stress and Male infertility
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Mens age and infertility

• As mens age increases, the time required for a
  couple to conceive lengthens, even after
  controlling for the womans age and other risk
  factors for reduced fertility.
• Hassan MAM. Fertil Steril 2003

88
the odds ratio for infertility was 1.20 for
overweight men BMI 2529.9) and 1.36 for obese
men (BMI 3034.9) relative to men with low-normal
BMI (20.022.4). When BMI was divided into eight
categories, there was a trend of increased
infertility with increased male BMI.
89
Linear regression revealed a significant (P ,
.05) and negative relationship between BMI and
the total number of normal-motile sperm
cells. The number of normal-motile sperm cells
per BMI group was as follows normal, 18.66106
overweight, 3.66106 and obese, 0.7 6 106.
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• a steadily increasing rate of infertility for
  BMIs above 24
• Even among women who subsequently became
  pregnant, increasing BMI was correlated with
  longer times to conception and pregnancy (3).
  Once pregnancy is achieved in a woman with a high
  BMI, there is a substantially increased risk of
  miscarriage and of pregnancy complications.
• The chances of congenital abnormalities,
  pregnancy induced hypertension, diabetes
  mellitus, preterm labor, surgically assisted
  delivery, shoulder dystocia, stillbirth and
  neonatal death, and postpartum complications are
  all substantially increased (4).

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data from Wang et al. on several thousand women
undergoing IVF indicated a very substantial
increase in failed IVF once the BMI reached 30.
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Obesity early and recurrent miscarriage

• There is a high incidence of early and recurrent
• miscarriages in overweight women compared
• with controls.
• Wang JX. Obes Res 2002105514.
• Lashen H. Hum Reprod 20041916446.

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Factors associated with premature delivery
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Effects of obesity on assisted reproductive
technology outcomes

• The first cycles of ovum donation and stratified
  the recipients by BMI
• The eggs obtained from healthy donors with a BMI
  range of 22.3 3.5 kg/m2.
• A significantly decreased implantation rate as
  the BMI increased and an ongoing pregnancy rate
  that was significantly decreased with the raised
  BMI.
• Bellver J. Fertil Steril. 200788446-51.

98
Effects of obesity on assisted reproductive
technology outcomes

• The other studies on the use of the donor egg
  model did not support the observation that
  increased BMI has a negative impact on
  implantation rates.
• Wattanakumtornkul S. Fertil Steril
  20038033640.
• Styne-Gross A. Fertil Steril 200583162934.

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Nonobese users had a reduction (OR ¼ 0.54) in
risk of SGA (lt5th percentile) there was no
effect among obese women. There was no effect of
multivitamin use on risk of preterm births
(34lt37 weeks) or SGA(5thlt10th percentiles).
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Conclusion

• Reproductive life planning and periconception
  advice
• Women
• Men
• Approaches to life style in fertility clinics
• Preconception interview
• Planning
• Advice
• Information
• Resources

110
Conclusion

• Fertility fitness
• Lessons on diet
• Periconception medicine
• Life style factors before conception for natural
  and induced pregnancies.

111
Histone modification
Methylation Acetylation
112
Histone modification

• Change the chromatin structure
  
• Influence DNA accessibility to factors
  regulating
• replication, repair and
  transcription
• Genes repressed or active

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Fetal programming

• Both increased and decreased expression of IGF2
  alter
• placental size and efficiency.
• Imprinting, in this case, depends on differential
  methylation.
• Early malnutrition may alter the methylation
  pattern, with
• consequences for placental function and embryo
  development.

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Fetal origins hypothesis of adult diseases

• The severity and duration of nausea and vomiting
  
• Negatively correlated with birth weight
• Reduced risk of miscarriage in women identified
  to be at risk
• Reduced risk of miscarriage in teenage pregnancy.
• Zhou, Q. et al. () Birth 199926 108114
• Furneaux, E.C. Obstet. Gynecol. Surv.
  200156775782

115
Fetal origins hypothesis of adult diseases
Elevated mean serum insulin ( SD) after oral
glucose tolerance test by age in low-birthweight
children (triangles) compared to normal
birthweight children (circles). Ibanez L.
1998 J. Clin. Endocrinol. Metab.
116
Nutrient-gen interactions in early pregnancy

• Maternal diet may have a lifelong effect on gene
• expression with the potential to cause
  susceptibility for
• chronic diseases in adulthood.

117
Nutrient-gen interactions in early pregnancy

• Folate, present in follicular fluid and seminal
  plasma, may
• influence the quality of oocytes and sperm.
• This is supported by the significantly increased
  sperm count after folic acid and zincsulphate
  intervention.
• The associations between polymorphisms in MTHFR
  and MTHFR
• genes and the increasing likelihood of meiotic
  nondisjunctions,
• such as in Down syndrome, support this
  hypothesis.
• Wong WY. Fertil Steril 2002
• OLeary VB. Am J Med Genet 2002

118
Fetal origins hypothesis of adult diseases

• Birth weights gt4 kg were associated with
  relative risks of 1.51.7 for breast cancer
  compared with normal birth weights of 2.52.9 kg.
• Trichopoulos, D. Lancet 1990335939940

119
Nutrient-gen interactions in early pregnancy

• Angiogenesis, vasculogenesis and vascular
  function are
• dependent on the genetic constition of the
  embryo, derived
• from both parents, and the maternal genetically
  controlled
• nutritional environment.
• The disbalanced folate, homocysteine and
  NO-status may disturb embryonic vasculogenesis,
  through which the delivery and clearence of these
  and other nutrients is compromised.
• Nutrient shortages will affect trophoblast
  function and invasion
• and may contribute to spontaneous abortion,
  preeclampsia and fetal growth restriction.
• Steegers-Theunissen RPM. Br J Obstet Gynaecol,
  2000, Leung DH. Am J Obstet Gynecol
• 2001, Makedos G. Arch Gynecol Obstet 2007,
  Cotter AM.Am J Obstet Gynecol 2001

120
Fetal programming

• Intrauterine epigenetic reprogramming of the
  GH/IGF axis may
• influence postnatal growth and insulin
  resistance, serving as the
• link between fetal growth and adult onset
  disease.
• IUGR is likely to involve GH/IGF axis with
  distinct changes in the
• growth factors and their interaction with
  corresponding receptors.

121
Periconceptional Environment

• The chance of having a live birth from ART
  therapy is influenced
• by the health habits and the infertility
  diagnoses of the couple.

122
IVF TEK GEBELIKLERI

• Helsinki University Central Hospital
• 7 yillik kohort çalisma (19972003)
• Tek dogumla sonuçlanan Taze TET, ÇET ve spontan
  tek gebeliklerin obstetrik ve neonatal sonuçlari
  karsilastirilmis
• Poikkeus P. Hum Reprod 2007

123
Low concentrations of dietary and circulating
folate

• Neural tube defect
• Preterm delivery
• Low infant birthweight
• Fetal growth retardation
• Defective maternal erythropoiesis
• Defective growth of the uterus and mammary gland
  and growth of the placenta, placental infarctions
• Premature rupture of membranes
• The subsequently elevated maternal homocysteine
  concentrations, a metabolic consequence of folate
  deficiency, has been associated both with
  increased recurrent miscarriage, placental
  abruption, and pre-eclampsia.
• Scholl TO. Am J Clin Nutr 200071(5
  Suppl)1295S1303S. Tamura T. Am J Clin Nutr
  2006839931016. Heil SG. Mol Genet Metab
  20017316472. Shaw GM. Public Health Rep
  20041191703. Knudtson EJ.Am J Obstet Gynecol
  200419153741.