Omocisteina e
riproduzione femminile
Prof. Irene Cetin
Clinica Ostetrica e Ginecologica
Università degli Studi di Milano
Ospedale Luigi Sacco
Omocisteina e Riproduzione
Omocisteina: sulfidril-aminoacido essenziale, derivato
dalla metionina
Alterazioni genetiche
Deficit nutrizionali
Iperomocistinemia/omocistinuria
Alterazione
embriogenesi
Fattore trombofilico
malformazioni
aborto
distacco di placenta
Preeclampsia IUGR
Etiology of Neural Tube Defects
diabetes mellitus
fever
hyperhomocysteinemia
increased risk
of recurrence
nutrition
folic acid / vit. B12
low socioeconomic
status
anticonvulsive drugs
folic acid antagonists
environment
preferably girls
NTD
preferably white race
more common in
certain families
genetic factors
FOLATE DEFICIENCY may impede adequate cell turnover during a critical point in the
closure of the neural tube
Relationship of red cell folate levels to
neural tube defect risk
JAMA, December 6, 1995 – Vol 274., No.21
Risk of neural tube defects as a function of red cell folate
(based upon Daly 1995 and Ernährungssurvey
(nutritional survey) 1988 (Thamm 2001))
Red cell folate level
nmol/L
% of population
Risk increase
< 340
3%
8 times
340-453
14%
4 times
453-680
48%
3 times
680-906
22%
twice
>906
13%
----
RBC folate (nmol/L)
Red Cell
Blood
Folate
(nmol/L)
Data presented as geometric mean (95% CI)
400µg/d
folic acid
800µg/d
folic acid
906 nmol/L
Placebo
0
4
8
12
16
20
24
BERTI C, BIESALSKI HK, GARTNER R, LAPILLONNE A, PIETRZIK K, POSTON L, REDMAN C, KOLETZKO B, CETIN I.
Micronutrients in pregnancy: Current knowledge and unresolved questions.
Clin Nutr 2011; 30:689-701
Neural tube defects (NTD)
• 1991 MRC Vitamin Study Research Group showed the
RECOMMENDATION
protective effect of folic acid against the recurrence of
NTD Folic acid 400 µg/day for primary prevention
(4 mg/day
for recurrence)
• Hyperhomocysteinemia
embryonal toxicity by acting
at DNAVitamin
level, producing
hypomethylation
or insufficient
B12 fosters
cell intake
of folic acid,
synthesis, structural alterations in the genes implicated in
and so even though concentrations of folic acid
DNA synthesis.
are
normal,
a
deficiency
of
Vitamin
B12
could
•
levels of homocysteine have been detected in the
also increase
the who
riskare
of carriers
NTD of MTHFR
amniotic
fluid of patients
mutation and concomitant NTD
MRC Vitamin Study Research Group 1991;Pitkin 2007
M. De la Calle, Eur J Obst Gynecol and Rep Biol 107 2003; 125–134
Czeizel AE, New Engl J Med 1992;327:1832–5.
Brouwer IA. Eur J Obstet Gynecol 2000;92:183–4.
Am J Clin Nutr 2000
Other Congenital Defects
• Statistically higher levels of homocysteine in the
mothers of children with OFC malformations vs
controls (Wong, Teratology, 2001)
• Mothers of children with heart defects found that
46% had hyperhomocysteinemia vs 14.3% in
controls (Wong, Teratology, 2000)
• Folate supplementation significantly reduces the
incidence of OFC, as well as defects of the heart,
pylorus or urinary tract (Hall et al. 1998; van Rooij, 2004)
REPRODUCTIVE
HEALTH OUTCOMES
Pregnant women do not always meet their
increased micronutrient requirements
Diet = important determinant of pregnancy outcomes and infant
health both in short and long-terms:
• significant association between inadequate or poor nutrition and
high “reproductive” risks
• different impacts of the timing of nutritional insults during
gestation on both the overall outcome of pregnancy and the
nature of adult diseases (i.e. programming the postnatal
pathophysiology [Buckley et al. (2005) Cell Tissue Res 322: 73–79]) potential
to affect cell numbers or differentiation in the developing
embryo
Cetin et al, Hum Reprod Update 2010
Iperomocisteinemia e Outcomes riproduttivi
Forges Hum Rep 2007
Iperomocisteinemia e Outcomes riproduttivi
Boxmeer Hum Rep 2009
High concentrations of folate in monofollicular fluid are
associated with an increased chance of achieving biochemical
pregnancy.
Nutritional phenotype of pregnancy
• Dynamic state: adjustments in nutrient metabolism
evolve continuously as the mother switches from an
anabolic condition during early pregnancy to a
catabolic state during late pregnancy
• Three compartments model, i.e,
mother/placenta/fetus, each of them has different
metabolism - fetal growth regulated by the balance
between fetal nutrient demand and maternal-placental
nutrient supply
Cetin et al, Hum Reprod Update 2010
Homocysteine and pregnancy
• Normal homocysteine concentration in non-pregnant
women: 5.8-12.8 mmol/l
• Homocysteine levels decrease during pregnancy.
Most studies conclude that values above 10.9 mmol/l
are suggestive of hyperhomocysteinemia during
pregnancy
• Folate requirements: 5- to 10-fold higher than in the
non-pregnant condition (Antony 2007) because of rapid
fetal growth, placenta development, uterine
enlargement and expansion of blood volume
(Tamura & Picciano 2006; Kim et al. 2009).
Fekete, Maternal and Child Nutrition 2010
Iperomocisteinemia e trombofilia
GRAVIDANZA: stato di ipercoagulabilità
FATTORI PRO COAGULANTI
FATTORI ANTI COAGULANTI
TROMBOFILIA
tendenza a sviluppare trombosi conseguenti ad alterazioni del sistema coagulativo o
fibrinolitico su base ereditaria o acquisita
Implantation and placentation
- direct contact of fetal with
maternal tissues
- culminating in the erosion of
maternal tissues by fetal cells
Deficient remodelling of
the spiral arteries
↓
Placental insufficiency
Fetal side
↓
Mismatch in the
uterine -umbilical
exchange surface
↓
IUGR or abortion
Maternal side
↓
Increased oxygen levels
↓
dismission of
inflammatory molecules,
endothelial damage
↓
PREECLAMPSIA
Tot 14 492
pregnancies in 5883
women
Am J Clin Nutr 2000
The odds ratios (ORs) are presented with adjustment for parity, year of birth, age of mother at birth,
and smoking habit
Am J Clin Nutr 2000
Repeated spontaneous miscarriages
Direct relationship between high levels of
homocysteine and alterations in the
vascularisation of chorionic villosities, which
presented reduced vascular areas, perimeters
and diameters (Hum Reprod 2000)
IPEROMOCISTEINEMIA
MUTAZIONE MTHFR
PREECLAMPSIA
IPEROMOCISTEINEMIA
MUTAZIONE MTHFR
Both hyperhomocysteinaemia and homozygosity for the
677C→T mutation in the MTHFR gene seems to lead to an
increased risk of pre-eclampsia.
Nelen, ClinChemLabMed 2001;39(8):758–763
Mello et al. Hypertension 2005;46:1270-1274
Preeclampsia and Folate
Supplementation
• A prospective cohort study on 2951 pregnancies
aimed at evaluating the relationship between
folic acid supplementation and MTHFR genotype
with the risk of pre-eclampsia, showed that
supplementation of folic acid in a dose of 1.0 mg
in the second trimester is associated with
reduced risk of pre-eclampsia
(Wen et al. 2008)
ANAMNESI
PRECONCEZIONALE
• età adolescenziale, diete particolari, obesità
• condizioni di malassorbimento: obesità,
celiachia, altre malattie intestinali, chirurgia
bariatrica…..
• precedenti episodi trombotici
• precedenti eventi riproduttivi sfavorevoli (aborti,
preeclampsia, distacco di placenta, IUGR)
• terapie mediche come antiepilettici
Conclusioni
• La supplementazione periconcezionale di acido folico e
vitamine del gruppo B riduce significativamente il rischio di
NTD e malformazioni fetali
• Indicato il dosaggio di tHcy nelle donne con mutazione
MTHFR. La mutazione non associata ad iperomocisteinemia
non sembra influenzare gli outcomes della gravidanza
• Nelle donne con iperomocisteinemia è indicata la
supplementazione con vitamine del gruppo B (folato, B6, B12)
allo scopo di normalizzare i livelli sierici di omocisteina e
ridurre i rischi ad essa associati.