Role of Maternal Obesity and

Metabolic Dysfunction on
Prenatal Stress and Stress Biology
(Related to Fetal Programming)
Detty S Nurdiati
Div of Maternal Fetal Medicine, Dept of Obstetric & Gynecology
Fac of Medicine, Universitas Gadjah Mada, Yogyakarta
Obesity Overview
Epidemiology
Health Impact
 Epidemiology
• Worldwide obesity >2x since 1980.
• In 2014, adults, 18 years and older,
– 39% (> 1.9 million) were overweight.
– Of these 13% (> 600 million) were obese.
• children under the age of 5
– 41 million were overweight or obese.
• Most of the world's population live in countries
where overweight and obesity kills more people
than underweight.
• Obesity is preventable.
 Nurdiati et al, Concurrent prevalence of chronic energy deficiency and obesity among
women in Purworejo, Central Java, Indonesia, Food & Nutr Bull, 1998, Vol 19(4):321-33.

Classification BMI Indo-

(WHO, 1995) nesia
Underweight <18.5 17%
CED I <16.0
CED II 16.0-16.9
CED III 17.0-18.4
Normal weight 18.5-24.9 71,7%
Overweight 25.0-29.9 11,4%
Obese >29.9
Class I 30.0-34.9
Class II 35.0-39.9
Class III >40
Obesity trends and determinants in
Indonesia

Roemling C & Qaim M, Obesity trends and determinants in Indonesia . Appetite 58 (2012) 1005–1013
 Obesity trends and determinants in
Indonesia

Roemling C & Qaim M, Obesity trends and determinants in Indonesia . Appetite 58 (2012) 1005–1013
 Indonesian Obesity Information

Adult women
8,2% obese
24,2% overweight
(Riskesdas 2013)
 Obesity and -Type 2 Diabetes Mellitus
-Cardiovascular Disease
Being obese increase the risk of CVD
- Coronary artery disease by 2.7 times
- Hypertension by 5.4 times

Metabolic syndrome ↑
Degree of insulin • Risk factor for diabetes
resistance ↑ • Risk factor for CVD

Overweight/Obese ↑
• Central or visceral
distribution of body fat Being obese increase the risk of
developing DM by 12.41 times
Guh et al, 2009; Kulie et al, 2011, Patterson, 2004
Obesity and Infertility
Abdominal Obesity
Hyperandrogenism
↑insulin  ↓SHBG synthesis & ↑ovarian
androgen production  ↑functional androgen
levels
Menstrual disorders
Peripheral adipose Tissue

↑aromatization  ↑circulating estrogen Anovulatory cycles

Circulating Leptin ↑
Infertility/Subfertility
↓ovarian follicular development and
↓steroidogenesis
Kulie et al, 2011; Shah, 2009, ASRM 2008
 Obesity and Pregnancy

Higher health care

↑ delivery expenditures
complications Maternal morbidity
• CS and mortality
↑ pregnancy • Operative delivery Perinatal/Neonatal
complications • LOS morbidity and
• Antepartum complications mortality
Obesity ↑ • Hypertension
• 20-29 yo • Preeclampsia/Eclampsia
• ≥3 children • Gestational diabetes
• Pregnancy loss ASRM 2008; Kulie et al, 2011
Risk of pregnancy-related complications (BMI ≥40 kg/m2)

OR 95% cI
Preeclampsia 4.8 4.0-5.7
Gestational Diabates 4.0 3.1-5.2
LGA infant 3.8 3.5-4.2
Early neonatal death 3.4 2.0-5.6
Hypertension 3.2 2.6-4.0
Shoulder dystocia 3.1 1.9-5.3
Meconeum aspiration 2.9 1.6-5.0
Antenatal stillbirth 2.8 1.9-4.0
Cesarean section 2.7 2.5-2.9
Fetal distress 2.5 2.1-3.0
ASRM 2008
 Birth defects associated with maternal obesity
(BMI ≥30 kg/m2
OR 95% CI
Ventral wall defects 3.3 1.0-10.3
Neural tube defects 2.7 1.2-6.1
Cardiac defects 2.0 1.2-3.4
Multiple congenital anomalies 2.0 1.0-3.8

ASRM 2008
 Obesity and Depression

Inconsistent Association
Higher past-month ↑ Depression risk
Higher rates of depression in women No effect of sex
depression in women
compared in men (OR 1.82; 1.01-3.3 vs (OR 2.16; 1.47-3.19 vs
1.73: 0.56-5.37) 2.11; 1.29-3.47)

Kulie et al, 2011; pic from www.palitra-pitania.ru

Concept of Fetal Programming of Health and Disease

• Maternal Obesity Fetal

• Metabolic Dysfunction Programming
Gaillard 2015; Victoria et al, 2014
Concept of Fetal Programming of Health and Disease

• Maternal Obesity Prenatal Stress Fetal

• Metabolic Dysfunction Stress Biology Programming
 Proposed Hypothesis

• Mechanisms or pathway by which nutritional

programming can exert life long effects on the
developing organism?
– Effect of nutritional insults on maternal-placental-
fetal glucose/insulin physiology
– Downstream effects on the developing fetal brain
and peripheral system
 Potential Role of
Prenatal Stress and Stress Biology?

Entringer & Wadhwa 2013

 Role of Stress in Fetal Programming

• The developing fetus acquires and incorporates information

about the nature of its environment in part via the same
biological systems that in an already-developed individual
mediate adaptation and central and peripheral responses
to endogenous and exogenous stress (i.e. the
neuroendocrine and immune systems)
– Many of the effects of nutritional insults (both undernutrition
and overnutrition) may be mediated by common stress-related
pathways involving the hypothalamic-pituitary-adrenal axis and
inflammation

Entringer & Wadhwa 2013

 Role of Stress in Fetal Programming

• Environmental conditions (i.e. nutrition) have the

potential to impact the structural or functional
integrity and survival of the organism (i.e. stress)
• Prenatal stress represents an important aspect of
the intra-uterine environment that would be
expected to influence developmental outcomes
 Stress ↔ Nutrition
Prenatal stress and stress
biology alter nutrition at
multiple levels
• caloric intake
• selection of food types
• metabolic fate of energy
Entringer & Wadhwa 2013
Nutritional status alter
stress at multiple levels in
the brain and periphery
• appraisals of potentially stressful
circumstances
• psychological and physiological
stress responses
• feedback regulation
 Stress

Fetal Programming
 Stress Biology in Pregnancy

• Biological adaptation in response to challenges or demand that

threaten or are perceived to have the potential to threaten the
stability of the internal millieu of the organism
• Major role stress adaptation
– Nervous
– Endocrine
– Immune
– Vascular system
• Maternal fetal communication mediated via placenta
Entringer & Wadhwa 2013
 Stress Biology in Pregnancy

Erhuma 2012
 Stress Biology in Pregnancy

Erhuma 2012
 Prenatal Stress

• Adverse circumstances during pregnancy

(physiological as well as psychological stressors)
• Potential to induce changes in maternal-
placental-fetal stress biology
– maternal and fetal cortisol
– placental corticotrophin-releasing-hormone (CRH)
– inflammatory mediators
Entringer 2012

Prenatal Stress

sensitive or critical developmental windows

adipose tissue pancreas liver brain

related to body composition, energy balance homeostasis, and metabolic function

 Prenatal Stress
• Prenatal stress can affect lifelong physical growth, including increased
obesity risk.
• Natural disasters provide models of independent stressors unrelated to
confounding maternal characteristics.
– Research using the Iowa floods as a stressor (n=106) showed that exposure in
early pregnancy and both objective and subjective stress are associated with
greater adiposity in early childhood and a greater increase with age.
– Dannish study (n=65,212) showed that prenatal stress, like maternal
bereavement during pregnancy, is expected to affect the fetus and increase
the frequency of adverse birth outcomes. Severe pre-pregnancy stress may
increase the susceptibility to overweight in childhood. Overweight and obesity
in childhood are associated with adult obesity and many other negative health
consequences.
Dancause et al, 2015; Li et al, 2010
Rivera et al, 2015; Sullivan et al, 2014
 Summary
• Prenatal stress exposure may interact with the nutritional
milieu and stress biology may represent an underlying
mechanism mediating the effects of diverse intrauterine
perturbations, including but not limited to maternal
nutritional insults, on brain and peripheral targets of
programming of body composition, energy balance
homeostasis, and metabolic function.
• Maternal-placental-fetal endocrine and
immune/inflammatory mechanisms may underlie the long-
term effects of intrauterine stress.
 Exposure of the fetus/offspring to different insults during critical periods of development may lead to adaptations
that prove to be detrimental and associated with adult defects in several organ systems. IUGR, intrauterine growth restriction.
Published in: Vasantha Padmanabhan; Rodolfo C. Cardoso; Muraly Puttabyatappa; Endocrinology 2016, 157, 1328-1340. DOI: 10.1210/en.2016-1003.
THANK YOU
 References
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 Curriculum Vitae
Name: Dr. Detty Siti Nurdiati, MPH, PhD, SpOG(K)
Address: Department of Obstetrics & Gynecology,
Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital
Jl.Kesehatan, Yogyakarta 55281, Indonesia
BoD: Tasikmalaya, October 6, 1966
Education:
1990 MD Universitas Gadjah Mada, Yogyakarta, Indonesia
1997 MPH Umeå University, Umeå, Sweden
2001 PhD Umeå University, Umeå, Sweden
2006 SpOG Universitas Gadjah Mada, Yogyakarta, Indonesia
2011 MFM Universitas Gadjah Mada, Yogyakarta, Indonesia
Present position:
Head of Obstetric and Gynecology Department, FM UGM/Dr. Sardjito Hospital.
Director of Clinical Epidemiology and Biostatistic Unit, FM UGM/Dr. Sardjito Hospital.
Contact Person of Indonesian Cochrane Network.