Preconception counselling directed on nutrition and lifestyle

Research and practise

Régine P.M. Steegers-Theunissen, MD, PhDProfessor in Periconception Epidemiology

Erasmus MC: Departments of Obstetrics and Gynecology, Pediatrics, Epidemiology, and Clinical Genetics

P r ec o n c ep ti o n h ea l th a n d c a r e ex p er i en c es i n Th e Neth er l a n d s a n d I ta l y

R o m e, J a n u a r y 2 7, 2 0 11

Conception Birth 1 5 10 20 40 80

Complex diseases:CardiovascularDiabetes type 2Metabolic syndrome…

Periconception period

Fertility disorderMiscarriageCongenital malformations Growith restrictionLow birth weight

Gene - environment: nutrition and lifestyle

05

1015202530354045

2001 2003 2005 2007 0102030405060708090

100

2001 2002 2003 2004 2005 2006 2007vrouw 15-45 jr man 15-45 jr

>45%80%31%

Unhealthy nutrition and lifestylesMan and woman: 15 - 45 years

vrouw 15-45 jr man 15-45 jr vrouw 15-45 jr man 15-45 jr

Centraal Bureau voor de Statistiek 2009

Woman OR (BI) Fertility disorder 1.6 (1.3 - 1.9) Congenital malformation: Heart 2.7 (1.7 - 4.5) Cleft lip- palate 2.4 (1.1 - 5.3) Miscarriage 2.3 (1.5 - 3.5) Birthweight < 300 - 500 gr

Man OR (BI) Semen < 12 - 15% Congenital malformation: Spina bifida 1.6 (1.0 - 2.5) Cleft lip- palate 1.4 (0.9 - 2.1) Miscarriage 1.8 (1.0 - 3.3)

Smoking and risks before and during pregnancy

Augood et al. 1998; Venners et al. 2004; Karatza et al. 2009; Shaw et al. 2009; Zhang et al. 2010

Woman: Fecundity: >3 months 37%, >6 months 17%

Subfertility: 1.3 x increased (BMI 24-31), 2.7 increased (BMI >32)

Pregnancy: PIH, pre-eclampsia, Diabetes Gravidarum and

artificial delivery(Zaadstra et al., 1993; Norman et al., 1998; Bolumar et al., 2000; Rich-Edwards et al., 2002)

Man: BMI >25: 22% reduction semenconcentration and

more DNA damage (DFI)(Bolumar et al., 2000; Jensen et al., 2004)

Overweight and obesity and risksbefore and during pregnancy

Quantitative undernutrition Reproductive and pregnancy failures

and diseases in later life

Prof. R.W. Smithells 1924-2003

Periconceptional folate intake

Periconceptional folic acid use

reduces the risk of spina bifida, heart defects

and cleft lip- and or palate between 50% to 70%.

Folate sources

Qualitative undernutritionReproductive failures and disease in later life

Mediterranean

Traditional Dutch

Pregnancy chance OR 1.4 (1.0 - 1.9)

Growth restriction OR 2.8 (1.6 - 4.8)

Semen, number 37.106 - 62.106

Periconceptional Dietary patterns

Vujkovic et al. 2009; 2010; Timmermans et al. 2010

Western

Spina Bifida OR 0.3 (0.1 - 0.9)

Congenital heart disease OR 0.4 (0.2 - 0.7)

Cleft lip- and/or palate OR 1.9 (1.2 - 2.9)

Vujkovic et al. 2007, 2008, 2009; Oberman-Borst et al. 2010

One carbon metabolism

Periconceptional dietary patterns and congenital anomalies

Mediterranean

Mediterranean

Cardiovascular disease HR 0.41 (0.18-0.95)Metabolic syndrome << 22% Epithelial cancer <<

Cardiovascular disease OR 0.30 (0.12-0.71)

Dietary patterns in adulthood and disease in later life

Martinez-Gonzales et al, 2010; Runawas et al, 2009; Babio et al, 2009; La Vecchi, 2009; Weikert et al, 2005

One carbon metabolism

5,10-methylene-THF

5-methyl-THF

MS

SAM

SAH

CBS

[vitamin B12]

[vitamin B6]

cystathionine

cysteine

DMG

Betaine

BHMT

dTMP

dUMP

MTHFR

homocysteine

methionineDHF

THFTS

Methyl acceptor

Methylated acceptor

[vitamin B6]

NO //

Derangements in one carbon pathwayHyperhomocysteinemia, DNA hypomethylation

and free radicals (oxydative stress)

FOLATE

HOMOCYSTEINE

NADPH

NADP++H+

Glutamate

Glutathione

GSSG

ROH

ROOH+

Free radicals

ROS

Proteins, LipidsCHROMATIN - DNA METHYLATIONNNMT

MTRRTC2

nicotinamide

Periconceptional hyperhomocysteïnemiaReproductive and pregnancy failures

Homocysteïne

Folate

Oxidative stress

OR (CI) Congenital heart disease 4.4 (2.6 - 7.3) Cleft lip- and/or palate 2.3 (0.4 - 11.9) Spina bifida 2.1 (1.4 - 3.3) Miscarriage 2.7 (1.4 - 5.2) Growth restriction 0.4 (0.2 - 0.7)

Oocytes Semen Embryo quality Pregnancy chance 0.6 (0.3 - 1.0)

van der Put et al. 1997;Neelen et al. 2000;Verkleij-Hagoort et al. 2007;Timmermans et al. 2009;Boxmeer et al. 2008

12-03-2010

3D ultrasound

Enables volume measurements

10+2 10+0

Rousian et al, BJOG 2008Verwoerd-Dikkeboom et al, Ultrasound Obstet Gynecol 2008

7+4

ProgrammingEmbryo

8wk

Genetic programming in the periconception period

ProgrammingGametes

-10 wk

Conception Birth

Low and high folic acid: Les and more markers

Waterland et al. Mol Cell Biol 2003

Dutch famine:Less markers

Heijmans et al. PNAS 2008

Folic acid use 0.4 mg\day: More markers

Steegers-Theunissen et al. PLoS One 2009

Epigenetics in animals and human: folic acid - IGF2

Main conclusions

Periconception parental nutrition and lifestyles

seem to be environmental conditions that can cause

(epigenetic) changes in humans that persist throughout

life and may explain reproductive and pregnancy

outcome, and long term health and disease risks.

Objective: to improve the use of healthy

nutrition, folic acid supplements and lifestyles in the preconception period.

Target population:couples planning pregnancy.

Tailored preconceptional dietary and lifestyle counselling in a tertiary centre

Preconceptional tailored nutrition and lifestyle counselling in routine reproductive/obstetrical care

1e consultation Gynaecologist Letter+flyer

www.zwangerwijzer.nl

Questionnaires

Informed consent

Obstetrics

Prenatal Medicine

Reproductive Medicine

Preconceptional Nutrition and

Lifestyle Counselling

One stop shop

Referral to Gynaecologist

Blood test: Vitamin B12, Folate, Homocysteïne

Physical examination length, weight (BMI), RR, waist-to-hip ratio; Nutrition and Lifestyle advice; results of the web application

PatientLetter

Preconceptional tailored Nutrition and Lifestyle counselling (PC): 419 couples planning pregnancy PC1 and PC2 (3 months)

Time Period: 10/2007 until 04/2009

Methods: general questionnaire 6-item food questionnaire (Dutch Dietary Guidelines, 2009)

Preconception Dietary Risk score (PDR), maximum PDR score= 6 (highly inadequate nutritional intake)

Evaluation

Questionnaires

Rotterdam Reproduction Risk Score (R3-score): No folic acid supplement use

Medication, smoking, alcohol, caffeine (≥6 cups a day)Lack of physical activity, infection riskBMI (<20 of ≥30), waist circumference (woman:≥88 cm and man: ≥102 cm) waist to hip-ratio (≥0.8)blood pressure (systolic ≥160 en diastolic ≥90) Derangement homocysteine pathway (biomarkers)

R3-score maximum for woman: 13 and for man: 10

ASE model (Attitude, Social influence, Self-Efficacy ) (De Vries et al., 2000)

Lifestyle

  PC 1 (N=309)

PC 1 and PC 2(N=110)

Age (years) 31 (19 - 44) 32 (19 - 42)

BMI (kg/m2) 24.6 (17.0 - 43.2) 25.1(18.7 - 42.2)

Ethnicity:

Dutch 167 (54.0%) 56 (50.9%)European-others 29 (9.4%) 11 (10.0%)Non- European 109 (35.3%) 42 (38.2%)

Indication of referral

Subfertility 289 (93.5%) 104 (94.5%)High obstetrical risk 10 (3.2%) 1 (0.9%)Recurrent miscarriages 10 (3.2%) 5 (4.5%)

Educational Level:    Low 41 (13.3%) 23 (20.9%)Intermediate 157 (50.8%) 42 (38.2%)High 111 (35.9%) 34 (30.9%)

Medication use 122 (29.1%) 39 (35.5%)

GZW vrouwen: AlgemeenWomen: Baseline Characteristics

  PC 1(N=306)

PC 1 and 2(N=103)

Age (years) 34.1 (22-63) 34.5 (22-60)

Ethnicity:    Dutch-native 190 (58.5%) 55 (53.4%)European others 43 (7.2%) 10 (9.7%)Non-European 73 (30.8%) 38 (36.9%)

Educational Level:  

Low 68 (21.5%) 22 (21.4%)Intermediate 118 (38.6%) 35 (34.0%)High 120 (39.5%) 37 (35.9%)

Medication use 94 (22.4%) 28 (27.2%)

Man: Baseline Characteristics

% compliance to Dutch Dietary Guideline

0102030405060708090

100

Women PC1 36 86 26 65 85 39 67Women PC2 41 84 27 80 81 64 85

Bread Butter/Oils Vegetables Fruit ** Meat Fish ** Folic acid use **

Women: Dietary intake and Folic Acid use

Man: Dietary Intake

% compliance according to Dutch Dietary Guideline

0102030405060708090

100

Men PC 1 65 87 19 49 86 45Men PC 2 66 84 22 68 87 54

Bread Butter/Oils Vegetables Fruit ** Meat Fish

PDR-PC 1 median

(min-max)

PDR-PC 1 median

(min-max)

PDR-PC 2 median

(min-max)

p

Women 3.0 (0-6) 3.0 (0-6) 2.0 (0-6) ≤0.05

Ethnicity:

Dutch 3.0 (0-5) 3.0 (1-4) 2.0 (0-6) ≤0.05European others 2.5 (0-5) 2.5 (1-4) 2.8 (0-6) n.sNon-European 3.0 (0-6) 2.6 (0-6) 2.3 (0-6) n.s

Educational Level:

Low 2.8 (0-5) 3.0 (1-5) 2.3 (0-5) ≤0.05Intermediate 2.6 (0-6) 2.8 (1-5) 2.6 (0-6) n.sHigh 2.3 (0-6) 2.3 (1-4) 2.3 (0-6) n.s

BMI:

20-25 2.5 (0-6) 2.7 (0-6) 2.3 (0-6) n.s 25-30 2.4 (0-5) 2.3 (1-4) 2.3 (0-4) n.s >30 2.8 (0-6) 2.8 (0-5) 2.6 (0-6) n.s

Woman: Preconception Dietary Risk Score (PDR)

PC1 median

(min-max)

PC1median

(min-max)

PC1median

(min-max)

p

Men 2.5 (0-6) 2.5 (0-6) 2.2 (0-6) ≤0.05

Ethnicity:

Dutch-native 2.3 (0-5) 2.3 (0-5) 1.9 (0-6) ≤0.01European Others 2.0 (0-4) 2.6 (1-4) 2.9 (0-4) n.sNon-European 2.7 (0-6) 2.6 (1-5) 2.4 (0-6) n.s

Educational level:

Low 2.5 (0-5) 2.5 (1-5) 2.3 (0-6) n.sIntermediate 2.3 (0-6) 2.3 (0-4) 2.0 (0-5) n.sHigh 2.3 (0-6) 2.5 (1-5) 2.4 (0-6) n.s

BMI:

20-25 2.3 (0-6) 3.0 (1-5) 2.2 (0-4) ≤0.05 25-30 2.3 (0-5) 2.3 (0-5) 2.0 (0-6) n.s >30 2.6 (0-5) 2.5 (0-5) 2.6 (0-6) n.s

Man: Preconception Dietary Risk Score

1) Ineadequate dietary intake in women (99.1%) and men(97.3%).

2) Tailored PC is effective in women to improve fruit (+16%), fish (+25%) and folic acid

use (+17%) and in men to improve fruit (+20%) intake.

3) Also in low educated women.

Conclusions

Woman: Lifestyle risk factors

  PC 1(N=309)

PC 1(N=110)

p PC 2 (N=110)

p

BMI 26 (17.0-43.2) 25.1 (18.4-42.4) n.s 25.3 (18.8-40.3) n.s

25-30 50 (16.2%) 21 (19.1%) n.s 25 (22.7%) n.s

>30 89 (28.8%) 34 (34.0%) ≤0.05 31 (28.2%) ≤0.05

Folic acid use 192 (62.1%) 74 (67.3%) n.s 93 (84.5%) ≤0.01

Smoking 69 (23.3%) 18 (16.4%) n.s 17 (15.4%) n.s

Alcohol 136 (44.0%) 39 (35.5%) n.s 23 (20.9%) ≤0.01

Drugs 5 (1.6%) 4 (3.6%) n.s 4 (3.6%) n.s

Man: Lifestyle risk factors

PC 1(N=306)

PC 1(N=103)

p PC 2(N=103)

p

BMI 26.9 (17.4- 46.8) 26.4 (18.5- 42.5) n.s 26.6 (19.1- 41.9) n.s

25-30 116 (37.9%) 40 (38.8%) n.s 50 (45.5%) n.s

>30 67 (21.9%) 20 (19.4%) n.s 18 (16.4%) n.s

Smoking 103 (33.7%) 21 (20.4%) ≤0.05 21 (20.4%) n.s

Alcohol 204 (66.7%) 61 (59.2%) n.s 48 (46.6%) ≤0.05

Drugs 25 (8.2%) 5 (4.9%) n.s 4 (3.9%) n.s

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6 7 8 9 10 11

%

R-3

vrouwen, bezoek 1

vrouwen, bezoek 2

mannen, bezoek 1

mannen, bezoek 2

Rotterdam Reproduction Risk score (R-3 score)Modifiable risk factors

Women visit 1

Women visit 2

Men visit 1

Men visit 2

R-3 score Women: 3.9 vs.2.8; p<0.01* R-3 score Men: 2.3 vs. 1.6; p<0.01*

At PC1 women (100%) and men (98,5%) had =>1 lifestyle risk factor .

At PC2 R3-score 30% (women) and 45% (men) reduction.

Reduction also in high risk women (non-Western, low SES, living in

deprived neigbourhood).

Future studies should corroborate on the predictive value of the PDR and

R3-Score on reproductive performance and pregnancy outcome.

Cave selection: tertiaire medical hospital centre, RCT

Conclusions

(E-)Healthcare programs

Development of tailored personalized tools to improve (pre)pregnancyHealth, nutrition and lifestyle of parents-to-be:1. inventarisation of risk factors2. risk profile3. advise4. support5. maintenance

Central Database (ErasmusMC - RijnmondZorgPortaal):1. Personal data, profiles, questionnaires, advises, compliance2. Safe, privacy3. Patients(users), Patientcare, Research and Healthcare providers

E - Healthcare Tool 1: www.zwangerwijzer.nl

Screeningsinstrument

E - Healthcare Tool 2: www.preconceptiewijzer.nl

Zorginstrument

E - Healthcare Tool 3: Personal dietary measurement tool

Screening-, Care-, Intervention-, and Researchinstrument

E - Healthcare Tool 3:Personal dietary measurement tool

Women with overweight (BMI 28.5) following a diet to loose weight.

<many deficiencies, i.e., folate (B11): 52% RDA.

E - Healthcare Tool 3: Personal dietary measurement tool

Tailored and personal interventionCombination of internet AND mobile phone

E - Healthcare Tool 3: Personal dietary measurement tool

sms

E - Healthcare Tool 4: Personal Mobile Pregnancy Program

E - Healthcare Tool 4: Questions on nutritional intake

E - Healthcare Tool 4: Personal feedback

Periconceptional intakereduces the risk of birth defects

Voeding

Supplement Voeding

Supplement

E - Healthcare Tool 4: Folic acid intake

Periconceptional intakereduces the risk of birth defects

E - Healthcare Tool 4: Personal feed back

Automatic reminder to consult Personal Mobile Pregnancy Programme

!sms

New life in a changing environment

Healthy periconceptional nutrition and lifestyles

improve health of parents, children and next generations!