improving the periconceptual environment: the next frontier for improved fertility outcomes? prof....

• 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.

Epigenetics• All cells in the body have a phenotype that is a culmination of

the cell’s gene structure, epigenetic marks and environmental influences.

• Normal embryogenesis can not proceed without the machinery of epigenetic regulation.

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.

4

EpigeneticsFour 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.

• 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.

Epigenetic modifications in gene silencing

EPİGENETİC REPROGRAMMİNG

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.

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.

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

Dynamic reprogramming of the epigenome during development

The first phase of methylation reprogramming occurs between

fertilisation and formation of the blastocyst.

Methylation levels in imprinted and nonimprinted genes during early embryogenesis and gametogenesis

Nafee TM. BJOG 2008;115:158–168

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.

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

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.

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.

Selected human disorders linked to an imprinting defect reported after ART

ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH 2007;61, No. 5, Pt 2,

In Vitro cultureProtein supplementsMedia composition

Embryo environmentGlucose, energy substratesAmino acidsGrowth factors Steroid hormonesCytokines Metabolic regulators

In vivo environmentDietBody composition

Potential short-term responses “developmental plasticity”Epigenetic modificationsAltered intracellular signalling Metabolic stressApoptosisCell proliferation disturbed

Tom P. Fleming, BIOLOGY OF REPRODUCTION 71, 1046–1054 (2004)

• Evidence now indicates that singletons born after ART are atincreased risk of premature birth, very low birth weight, andperinatal mortality, compared with singletons born to fertilewomen.

• 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 14–15, 2005, Toronto, Ontario, Canada.

• 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 syndromeand Angelman syndrome.

PREGNANCY OUTCOMEARTs were linked to an increased risk of;• Intrauterine growth restriction (OR: 1.59) • Premature birth

• < 33 weeks of gestation: OR:2.99 • < 37 weeks of gestation: OR, 1.93

• Low birth weight (1,500 g: OR:3.78)• In utero death (OR:2.40)• 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, Ka¨lle´n 2005, Schieve 200 4; Jackson 2004, Helmerhorst 2004

PREGNANCY OUTCOME

N.Turhan

Poikkeus et al 2007

N.Turhan

OBSTETRİCS VE NEONATAL OUTCOME

Poikkeus et al 2007

LİFELONG EPİGENETİC REPROGRAMMİNG: AGEİNG, DİET AND ENVİRONMENTAL

TOXİNS

Lifelong epigenetic reprogramming: ageing, diet and environmental toxins

DNA methylation patterns change with age;

1. Global DNA hypomethylation

2. Gene-specific hypermethylation of some CpG islands

Richardson B. Ageing Res Rev 2003;2:245-61.

Waterland RA, Jirtle RL. Nutrition 2004;20:63–8.

DNA hypomethylation

Genomic instability

Overexpression of proto-oncogenes 27


28

Gene silencing due to hypermethylation with age.

Silencing of genes impair control of cell cycle, apoptosis,

detoxification and cholesterol metabolism.


Dietary and other lifestyle exposures

Epigenetic-mediated changes in gene expression

Change cell function and

health throughout the life course

29


NUTRITION

NUTRITION

Folate, B12, Se, phytochemicals (genistein,polyphenolics)

food contaminants (As)

DNA methylation

31

32

DIETFolic acid

DHF

Diet

Choline

DNA methylationDNMT

POTENTİAL İMPLİCATİONS OF EPİGENETİC MODULATİON İN OBSTETRİCS

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


• 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 2002O’Leary VB. Am J Med Genet 2002


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


• A diminished embryonic folate status, due to MTHFR and

MTHFR polymorphism’s 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.


• 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


• 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.

DEFECTIVE IMPRINTING

• 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.


• 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.


DEFECTIVE IMPRINTING

ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH 2007;61, No. 5, Pt 2,

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 1997McEvoy TG. Theriogenology 2001


• 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


• 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.


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 2000;71(5 Suppl):1295S–1303S. Tamura T. Am J Clin Nutr 2006;83:993–1016. Heil SG. Mol Genet Metab 2001;73:164–72. Shaw GM. Public Health Rep 2004;119:170–3. Knudtson EJ.Am J Obstet Gynecol 2004;191:537–41.

• 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.



Folate supplementation during pregnancy

• Supplementing a mother’s nutritionally adequate diet with extra folic acid, vitamin B12, choline, and betaine can permanently affect the offspring’s 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 2003;23:5293–300.Finnell RH et al. J Nutr 2002;132(8 Suppl): 2457S–2461S.Friso S, Choi SW. Curr Drug Metab 2005;6:37–46.

CONCLUSİON

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, Alzheimer’s disease, schizophrenia,

asthma, and autism.

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

Conclusion

Fertility fitness;• Lessons on diet• Periconception medicine;

– Life style factors before conception for natural and induced pregnancies.

Conclusion

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.

• Helsinki University Central Hospital • 7 yıllık kohort çalışma (1997–2003) • Tek doğumla sonuçlanan Taze TET, ÇET ve spontan tek

gebeliklerin obstetrik ve neonatal sonuçları karşılaştırılmış

Poikkeus P. Hum Reprod 2007N.Turhan

IVF TEK GEBELİKLERİ

TET SONRASI OBSTETRİK VE NEONATAL SONUÇLAR

N.Turhan

Poikkeus et al 2007

TET gebeliklerinde yaş, parite ve sosyoekonomik duruma göre sonuçlar düzenlendiğinde kontrol grubuna göre;

– C/S riski OR=1.54– Preterm doğum OR=2.85– Düşük doğum ağırlığı OR=2.01

Poikkeus et al 2007

N.Turhan


N.Turhan


Poikkeus et al 2007

Tekil IVF gebeliklerinde transfer edilen embryo sayısından çok kişiye ait faktörler ve infertilite ile ilgili mekanizmalar neonatal sonuçları etkiler.

İVF TEK GEBELİKLERİ

Acaba tranfer edilen embryo sayısının etkisi var mı? • İkiz veya daha fazla çoğul gebelikle başlayan IVF/ICSI

tekil gebeliklerinde prematür doğum oranı yüksekDickey et al 2004

• Erken USG de birden fazla FKA olan IVF/ICSI tekil gebeliklerinde düşük doğum ağırlığı oranı yüksek

Schieve et al 2002

N.Turhan


1998 -2003 TET gebelikleri prospektif olarak toplanmış251 TET sonrası tekil gebelik sonuçları 59 535 spontan tekil gebelik sonuçları ile karşılaştırılmış

D. De. Neubourg et al. Hum Reprod 2006

N.Turhan

N.Turhan

De Neubourge 2006



N.Turhan

De Neubourge 2006

TET yapılan iyi prognozlu hastalarda gebelik şansı daha düşük olsa da gebelik sonuçları spontan tekil gebeliklerden farklı değildir.

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 1998;8:154–64. Tilghman SM. Cell 1999;96:185–93.

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.

Genomic imprintingPWS 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.

FETAL ORİGİNS HYPOTHESİS OF ADULT DİSEASE

Fetal origins hypothesis of adult diseaseBarker 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 1976;295:349–53, Muskiet FA. Reprod Toxicol 2005;20:403–10, Curhan GC. Circulation 1996;94:3246–50, Barker DJ. Br J Obstet Gynaecol 1992;99:275–6, Barker DJ. J Am Coll Nutr 2004;23(6 Suppl):588S–595S.

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 hypothalamic–pituitary–adrenal axis, blood pressure and insulin sensitivity.

Michael J.Davies and Robert J. Norman TRENDS in Endocrinology & Metabolism Vol.13 No.9 2002

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 1997;350:1131–1135Michelmore, K. Clin. Endocrinol. (Oxf.) 2001;55:439–446 Phillips, D.I. Clin. Exp. Pharmacol. Physiol 2001:28;967–970


Of babies weighing >3.9 kg born to mothers weighing >58.1 kg in pregnancy, 44% had PCO. The heavy babies were also larger as adults, with an average BMI >25 kg m2.

Cresswell JL. Lancet. 1997 Oct 18;350(9085):1131-5.


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 18;350(9085):1131-5.


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. 119–133,

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 2005;130:401–1, Waterland RA, Jirtle RL Nutrition 2004;20:63–8, Gluckman PD, Hanson MA. Horm Res 2006;65(Suppl 3):5–14.

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 2005;20:2531–5.

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.

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.

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 (p<0.0001).

• 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.

Oxidative Stress and Male Infertility

Tremellen K. Hum Reprod Update 2008, pp. 1-16

Oxidative Stress and Male infertility

Men’s age and infertility

As men’s age increases, the time required for a couple to conceive lengthens, even after controlling for the woman’s age and other risk factors for reduced fertility.

Hassan MAM. Fertil Steril 2003

the odds ratio for infertility was 1.20 for overweight men [BMI 25–29.9) and 1.36 for obese men (BMI 30–34.9) relative to men with low-normal BMI (20.0–22.4). When BMI was divided into eight categories, there was a trend of increased infertility with increased male BMI.

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.

• 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).

data from Wang et al. on several thousand women undergoing IVF indicateda very substantial increase in failed IVF once the BMI reached 30.

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 2002;10:551–4.Lashen H. Hum Reprod 2004;19:1644–6.

Factors associated with premature delivery

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. 2007;88:446-51.

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 2003;80:336–40.

Styne-Gross A. Fertil Steril 2005;83:1629–34.

Nonobese users had a reduction (OR ¼ 0.54) in risk of SGA (<5th percentile); there was no effect among obese women. There was no effect of multivitamin use on risk of preterm births (34–<37 weeks) or SGA(5th–<10th percentiles).

Conclusion

• Reproductive life planning and periconception advice• Women • Men

• Approaches to life style in fertility clinics• Preconception interview• Planning• Advice • Information• Resources

Conclusion

Fertility fitness;• Lessons on diet• Periconception medicine;

– Life style factors before conception for natural and induced pregnancies.

111

MethylationAcetylation

Histone modification

Histone modification Change the chromatin structure

Influence DNA accessibility to factors regulating replication, repair and transcription

Genes repressed or active

112

Fetal programmingBoth 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.


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 1999:26; 108–114Furneaux, E.C. Obstet. Gynecol. Surv. 2001:56;775–782


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.


Maternal diet may have a lifelong effect on gene

expression with the potential to cause susceptibility for

chronic diseases in adulthood.


• 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 polymorphism’s in MTHFR and MTHFR

genes and the increasing likelihood of meiotic nondisjunctions,

such as in Down syndrome, support this hypothesis.

Wong WY. Fertil Steril 2002O’Leary VB. Am J Med Genet 2002


Birth weights >4 kg were associated with relative risks of 1.5–

1.7 for breast cancer compared with normal birth weights of

2.5–2.9 kg.

Trichopoulos, D. Lancet 1990:335;939–940


• 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

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.

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.

• Helsinki University Central Hospital • 7 yıllık kohort çalışma (1997–2003) • Tek doğumla sonuçlanan Taze TET, ÇET ve spontan tek

gebeliklerin obstetrik ve neonatal sonuçları karşılaştırılmış

Poikkeus P. Hum Reprod 2007N.Turhan

IVF TEK GEBELİKLERİ


• 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.


improving the periconceptual environment: the next frontier for improved fertility outcomes? prof....

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epigenetic reprogramming

lifelong reprogramming

major epigenetic reprogramming

dynamic reprogramming

gene silencing slide

epigenetic marks

chromatin modifications

chromatin structure