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. 2018 Apr 25;15(5):857. doi: 10.3390/ijerph15050857

Table A1.

Description of the included studies, the variables and parameters collected and the main findings (p-value = probability value, SD = standard deviation, CI = confidence interval, n = number of subjects).

First Author, Year Cohort Description Aim of Study Collected Variables and Parameters Outcomes and Effect Size
The Dutch Famine Birth Cohort
Stein, 1975 [63] Seven cohorts of unequal size, based on the criterion of stage of gestation in relation to famine exposure:
August–October 1944 (conceived and born before famine);
November–January 1944–1945 (exposed at the third semester);
Februar–April 1945 (exposed at the second and third trimester);
May–June 1945 (exposed to famine during the middle 6 months of gestation);
July–September 1945 (exposed during first and second trimester of gestation);
October–January 1945–1946 (exposed during the first semester);
Februar–March 1946 (conceived and born after the famine).		 To study the effects of famine during pregnancy on six indices at birth of the newborns. Independent variables:
  • -

    Maternal characteristics: age, primipara, manual class;

  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

Outcome parameters:
  • -

    Birth weight;

  • -

    Placental weight;

  • -

    Infant length;

  • -

    Head circumference;

  • -

    Duration of gestation;

  • -

    Maternal weight.
  • -

    Birth weight (g): Amsterdam (mean = 3211, SD = 665, n = 1148), Leiden (mean = 3331, SD = 607, n = 457), Rotterdam (mean = 3245, SD = 654, n = 806), Groningen (mean = 3311, SD = 659, n = 1290), Heerlen (mean = 3345, SD = 551, n = 1149);

  • -

    Placental weight (g): Rotterdam (mean = 573, SD = 130, n = 775), Groningen (mean = 641, SD = 147, n = 1236), Heerlen (mean = 575, SD = 160, n = 1097);

  • -

    Infant length (cm): Amsterdam (mean = 49.0, SD = 4.1, n = 973), Leiden (mean = 50.0, SD = 3.9, n = 457), Rotterdam (mean = 49.6, SD = 3.6, n = 794), Groningen (mean = 49.3, SD = 3.5, n = 1272), Heerlen (mean = 49.6, SD = 2.8, n = 1129);

  • -

    Head circumference (cm): Rotterdam (mean = 34.9, SD = 2.1, n = 644), Groningen (mean = 33.7, SD = 1.5, n = 1197), Heerlen (mean = 35.1, SD = 1.7, n = 760);

  • -

    Duration of gestation (weeks): Amsterdam (mean = 39.4, SD = 2.3, n = 1144), Rotterdam (mean = 39.4, SD = 2.9, n = 791), Groningen (mean = 39.5, SD = 2.4, n = 1021), Heerlen (mean = 39.5, SD = 2.5, n = 1085);

  • -

    Maternal weight (kg): raw data available only for births in Rotterdam, difficult to estimate the reliability of the results.
Lopuhaa, 2000 [30] Five cohorts of unequal size, based on the criterion of stage of gestation in relation to famine exposure:
264 born before famine 1 November 1943 to 6 January 1945);
140 exposed to famine in late gestation 29 April 1945 to 18 August 1945);
137 exposed to famine in mid gestation (29 April 1945 to 18 August 1945);
87 exposed to famine in early gestation (19 August 1945 to 8 December 1945);
284 conceived after famine (9 December 1945 to 28 February 1947 ).		 To study the effects of famine during pregnancy on the prevalence of the obstructive airways disease and atopy in the first generation. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight at the end of pregnancy, manual class;

  • -

    Characteristics at age 50: current smoker, socioeconomic status.

Outcome parameters:
  • -

    Birth characteristics: weight, body length, head circumference, ponderal index, gestational age.

  • -

    Characteristics at age 50: weight, height;

  • -

    Total immunoglobulins E (IgE);

  • -

    Lung function: forced expiratory volume(FEV), forced vital capacity (FVC), FEV/FVC;

  • -

    Respiratory symptoms and disease: wheeze, productive cough, obstructive airway disease (OAD).
  • -

    Total IgE (IU/mL): mean = 30.4, SD = 4.6, n = 726;

  • -

    Lung function (L: n = 733, FEV (L): mean = 3.1, SD = 0.6, FVC (L): mean = 4.3, SD = 0.7, FEV/FVC: mean = 0.72, SD = 0.1;

  • -

    Respiratory symptoms and disease: n = 912, wheeze 11.7%, productive cough 4.5%, OAD 18.1%.
Roseboom, 2000 [64] Five cohorts of unequal size, based on the criterion of stage of gestation in relation to famine exposure:
264 born before famine (1 November 1943 to 6 January 1945);
140 exposed to famine in late gestation (7 January 1945 to 28 April 1945);
137 exposed to famine in mid gestation (29 April 1945 to 18 August 1945);
87 exposed to famine in early gestation (19 August 1945 to 8 december 1945);
284 conceived after famine (9 December 1945 to 28 February 1947).		 To study the effects of famine during pregnancy on the prevalence of coronary heart disease in first generation. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    Alcohol habits;

  • -

    Socioeconomic status (SES).

Outcome parameters:
  • -

    Birth characteristics: weight, body length, head circumference, ponderal index, gestational age.

  • -

    Adult characteristics: body mass index (BMI), systolic blood pressure (SBP), glucose 20 min, low density lipoproteins (LDL), high density lipoprotein (HDL);

  • -

    Prevalence of coronary heart disease (CHD).
  • -

    Prevalence of CHD: 3.3%, SD = 24, n = 736;

  • -

    BMI (kg/m3): mean = 27.0, SD = 1.2, n = 736;

  • -

    SBP (mmHg): mean = 126, SD = 16, n = 734;

  • -

    Glucose 120 min (mmol/L): mean = 6.0, SD = 1.4, n = 697;

  • -

    LDL: HDL cholesterol (mmol/L): mean = 2.9, SD = 1.5, n = 697;

  • -

    SES: mean = 48, SD = 13, n = 736;

  • -

    Smoking: 34%, n = 736;

  • -

    Alcohol (units/day): mean = 9, SD = 11, n = 736.
Fransen, 2016 [65] The Prospect-EPIC cohort [66], categorized as [67]:
Unexposed (3450);
Moderately exposed (2838);
Severely exposed (1237).
Total: 7527 women.		 To investigate the association between exposure to famine in childhood and adolescence and unhealthy lifestyle later in life for the first generation. Independent variables:
  • -

    Age at start of famine;

  • -

    Period of exposure to famine;

  • -

    Age at recruitment.

Outcome parameters:
  • -

    BMI;

  • -

    Waist;

  • -

    Level of education;

  • -

    Smoking status;

  • -

    Alcohol consumption;

  • -

    Energy intake;

  • -

    Modified Mediterranean diet score (mMDS);

  • -

    Unhealthy diet;

  • -

    Physical inactivity.
  • -

    Prevalence of smoking: 1.10 (95% CI, 1.05; 1.14) for moderately exposed and 1.18 (95% CI, 1.12; 1.25) for severely exposed women (p-value < 0.0001);

  • -

    Pack years of smoking: moderately exposed women reported smoking 0.98 (95% CI, 0.10; 1.87) more pack years than unexposed women, while severely exposed women reported 2.53 (95% CI, 1.39; 3.66) more pack years ( p-value < 0.0001);

  • -

    Prevalence of heavy drinking: moderately: 0.94 (95% CI, 0.85; 1.03) and severely exposed women: 0.95 (95% CI, 0.84; 1.07), compared to unexposed women (p = 0.04);

  • -

    Unhealthy diet: prevalence ratio 0.92 (95% CI, 0.86; 0.98) for moderately exposed to unexposed, no differences between severely exposed and unexposed (p = 0.51);

  • -

    mMDS: moderately exposed women had a 0.08 point (95% CI: 0.00; 0.16) higher mMDS than unexposed women, no differences between severely exposed and unexposed (p = 0.77);

  • -

    Physical inactivity: prevalence ratio for moderately exposed: 1.18 (95% CI, 0.99; 1.42) and severely exposed: 1.32 (95% CI, 1.06; 1.64) (p for trend = 0.08).
Elias, 2003 [68] The Prospect-EPIC cohort [66], categorized as [67]:
Unexposed (45);
Moderately exposed (28);
Severely exposed (14).
Total: 87 women.		 To investigate the consequences of childhood exposure to famine on the insulin-like growth factor axis in first generation. Independent variables:
  • -

    Age during famine;

  • -

    Age at recruitment;

  • -

    Smoking status;

  • -

    Alcohol habits.

Outcome parameters:
  • -

    BMI;

  • -

    Waist;

  • -

    Insulin-like growing factor I (IGF-I);

  • -

    Insulin-like growing factor binding protein (IGFBP)-1,2,3;

  • -

    Connecting peptide (C-peptide).
  • -

    IGF-I (ng/mL) (mean (95% CI)): unexposed: 132.9 (121.4–145.6), moderately exposed: 142.0 (1126.6–159.3), severely exposed: 162.3 (138.0–191.0), p-value = 0.038;

  • -

    IGFBP-1 (ng/mL) (mean (95% CI)): unexposed: 12.6 (10.0–16.0), moderately exposed: 10.2 (7.5–13.8), severely exposed: 9.6 (6.2–14.7), p value = 0.179;

  • -

    IGFBP-2 (ng/mL) (mean (95% CI)): unexposed: 388.2 (341.2–441.7), moderately exposed: 335.4 (284.7–395.2), severely exposed: 344.6 (270.8–438.7), p-value = 0.219;

  • -

    IGFBP-3 (ng/mL) (mean (95% CI)): unexposed: 3170.7 (3029.0–3319.1), moderately exposed: 3236.9 (3053.1–3431.7), severely exposed: 3511.8 (3235.6–3811.7), p-value = 0.045;

  • -

    C-peptide (ng/mL) (mean (95% CI)): unexposed: 3.3 (2.8–3.8), moderately exposed: 3.3 (2.7–4.1), severely exposed: 3.2 (2.4–4.3), p-value = 0.946.
Painter, 2005 [44] Five cohorts of unequal size, based on the criterion of stage of gestation in relation to famine exposure:
264 born before famine (1 November 1943 to 6 January 1945);
140 exposed to famine in late gestation (7 January 1945 to 28 April 1945);
137 exposed to famine in mid gestation (29 April 1945 to 18 August 1945);
87 exposed to famine in early gestation (19 August 1945 to 8 December 1945);
284 conceived after famine (9 December 1945 to 28 February 1947).		 To study the effects of famine during pregnancy on the prevalence of microalbuminuria in first generation. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period;

  • -

    Smoking status;

  • -

    Alcohol habits;

  • -

    SES.

Outcome parameters:
  • -

    Birth outcomes (weight, length, placental area);

  • -

    Maternal characteristics (weight at last prenatal visit);

  • -

    Adult characteristics (BMI, SBP, diastolic blood pressure (DBP), total cholesterol, impared glucose tolerance (IGT), electrocardiogram (ECG), creatinine clearance, hemoglobin alpha 1 (HbA1).

 Odds ratio (OR) for albumin-creatinine ratio (ACR) ≥ 2.5 compared with non-exposed group, adjusted for gender, age, adult BMI, smoking, SES (ISEI-92), SBP, IGT or non-insulin dependent diabetes mellitus (NIDDM) (2-h glucose > 7.8 or known diabetic), cholesterol, and ECG abnormalities:
  • -

    Late exposure: 1.27 (0.49–3.26);

  • -

    Mid exposure: 3.22 (1.34–7.65);

  • -

    Early exposure: 1.89 (0.59–6.11).
Van Noord, 2004 [14] Doorlopend Onderzoek Morbiditeit en Mortaliteit (DOM) cohort [69], categorized as [67] unexposed, moderately and severely exposed. To explain the opposing effects of caloric deprivation during pregnancy and childhood on breast cancer and its risk factors in the first generation. Independent variables:
  • -

    Stage of gestation or age in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period;

Outcome parameters:
  • -

    Age at menarche;

  • -

    Adult height, weight, BMI, waist: hip ratio;

  • -

    Age at menopause;

  • -

    Mammographic density patterns and dysplasia;

  • -

    Urinary postmenopausal hormones: estrone, estradiol, testosterone;

  • -

    Plasma IGF-1 and IGFBP-3 levels.

 Crude hazard ratio for breast cancer risk:
  • -

    Unexposed: 1, number of cases = 265;

  • -

    Moderately exposed: 1.17 (0.96–1.42), number of cases = 234;

  • -

    Severely exposed: 1.54 (1.16–2.05), number of cases = 79.
Painter, 2006 [26] Subjects exposed to the 1944–1945 Dutch famine during late (n = 160), mid- (n = 138), or early (n = 87) gestation and 590 unexposed subjects at age 50 or 58 year. To investigate the early onset of coronary disease in first generation after prenatal exposure to famine. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    Alcohol habits;

  • -

    SES.

Outcome parameters:
  • -

    Birth characteristics: weight, body length, head circumference, ponderal index, gestational age.

  • -

    Adult characteristics: BMI, SBP, glucose 120 min, LDL, HDL cholesterol;

  • -

    Cumulative incidence of CAD.

 Persons conceived during the famine were 3 years younger than the unexposed persons at the time of CAD diagnosis (47 years compared with 50 years) and had a higher cumulative incidence of CAD [13%; hazard ratio (HR) adjusted for sex: 1.9; 95% CI: 1.0, 3.8] than did the unexposed persons.
Stein, 2007 [70]
  • -

    exposed persons born in western Netherlands between January 1945 and March 1946 whose mothers experienced famine during or immediately preceding pregnancy (by ordinal weeks 1–10, 11–20, 21–30, and 31 through delivery) (356);

  • -

    unexposed persons born in the same 3 institutions during 1943 or 1947 whose mothers did not experience famine during this pregnancy (296);

  • -

    unexposed same-sex siblings of persons in series 1 or 2 (310).

 To assess the relation between gestational exposure to famine and offspring length, weight, indexes of adiposity in middle age (for the first generation). Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Maternal characteristics: age, primipara, weight at the end of pregnancy, manual class.

Outcome parameters (in adults):
  • -

    Height;

  • -

    Trunk length;

  • -

    Leg length;

  • -

    Arm length;

  • -

    Weight;

  • -

    Waist circumference;

  • -

    Hip circumference;

  • -

    Supine sagittal abdominal diameter (SAD);

  • -

    Midthigh circumference;

  • -

    Subscapular skinfold thickness;

  • -

    Triceps skinfold thickness;

  • -

    Anterior midthigh skinfold thickness.

 Exposure to starvation during gestation is strongly associated with a wide range of distribution of BMI among middle-age women (p-value < 0.05 for all, except the waist-to-hip ratio, for which p-value < 0.10). No other measures of length or body proportions in either men or women were associated with this condition.
De Rooij, 2007 [15] Seven hundred and eighty-three subjects born before the famine (n = 238), exposed to famine in late gestation (n = 141), in mid gestation (n = 116), in early gestation (n = 74) and conceived after the famine (n= 214). To determine the association between prenatal famine exposure and the prevalence of metabolic syndrome in first generation. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight in 3rd trimester and at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    Sport practice;

  • -

    Alcohol habits;

  • -

    SES;

  • -

    Current age.

Outcome parameters (in adults):
  • -

    Adult characteristics: BMI, SBP, glucose 120 min, LDL, HDL cholesterol, waist circumference, blood pressure.

 Exposure to famine during gestation was not significantly associated with the metabolic syndrome (OR: 1.2; 95% CI: 0.9, 1.7). Birth weight also was not significantly associated with the metabolic syndrome (OR: 1.3/1-kg decrease in birth weight; 95% CI: 0.9, 1.8/1-kg decrease in birth weight). Exposure to famine during gestation was associated with significantly higher triacylglycerol concentrations (0.1 g/L; 0.0, 0.2 g/L). Men exposed to famine in early gestation had significantly lower HDL-cholesterol concentrations (−0.08 mmol/L; −0.14, 0.00 mmol/L) than did unexposed men
Painter, 2008 [71] Eight hundred and fifty-five subjects: 264 unexposed and born before famine, 350 prenatally exposed to famine, 242 unexposed and conceived after famine;
1496 subjects of the second generation (F2), accordingly to the exposure status of the first generation (F1).		 To assess the effects of prenatal exposure to famine on neonatal adiposity and health in later life. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Maternal characteristics: age, primipara, weight in 3rd trimester and at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    SES;

  • -

    Current age.

Outcome parameters (in adults):
  • -

    Birth characteristics: weight, body length, head circumference, ponderal index, gestational age.

  • -

    Adult characteristics: age, BMI, waist circumference, SBP, glucose 120 min, LDL, HDL cholesterol;

  • -

    Number of offspring.

 F2 birth length was decreased (−0.6 cm, p adjusted for F2 gender and birth order = 0.01) and F2 ponderal index was increased (+1.2 (kg/m3), p adjusted for F2 gender and birth order = 0.001).
F1 women exposed to famine in utero also responded that had poor health 1.8 (95% CI, 1.1–2.7) times more frequently in later life than that of F1 unexposed women.
Van Hoek, 2009 [72] Seven hundred and seventy-two subjects born before the famine (n = 233), exposed to famine in late gestation (n = 140), in mid gestation (n = 117), in early gestation (n = 71) and conceived after the famine (n = 211). To investigate the effects of fetal malnutrition on type 2 diabetes risk and related phenotypes in first generation of offspring. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Maternal characteristics: age, primipara, weight in 3rd trimester and at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    SES;

  • -

    Current age.

Outcome parameters (in adults):
  • -

    Birth characteristics: weight, body length, head circumference, ponderal index, gestational age.

  • -

    Adult characteristics: age, BMI, waist circumference;

  • -

    Fasting blood samples for genomic analyses of rs7754840 (CDKAL1), rs10811661 (CDKN2AB), rs1111875 (HHEX), rs4402960 (IGF2BP2), rs5219 (KCNJ11), rs13266634 (SLC30A8), and rs7903146 (TCF7L2) polymorphisms.

 The TCF7L2 and IGF2BP2 variants were associated with increased type 2 diabetes mellitus (T2DM)/IGT risk (TCF7L2: OR 1.39 [95% CI 1.08–1.79], IGF2BP2: 1.43 [1.11–1.85]) and increased area under curve (AUC) for glucose (TCF7L2: β = 4.5 [1.0–8.1], IGF2BP2: β = 3.6 [0.1–7.1]). The CDKAL1 variant associated with a decreased AUC for insulin (β = −8.2 [−16.1 −0.41]), which became less strong after adjustment for BMI.
The IGF2BP2 showed a significant interaction on AUC glucose (β interaction −9.2 [−16.2 −2.1], p-value = 0.009).
None of the polymorphisms was associated with birth weight.
Haars, 2010 [73] One thousand and thirty-five women from DOM project [69]: 452 unexposed to the famine, 358 moderately exposed and 225 severely exposed. To examine how breast density is affected by short caloric restriction in childhood and adulthood, and whether the effect is dependent on the exposure age. Independent variables:
  • -

    Age at exposure to famine;

  • -

    Age at mammography;

  • -

    Height, weight, BMI;

  • -

    Menopausal status;

  • -

    Parity.

Outcome parameters (in adults):
  • -

    Breast size;

  • -

    Breast density (mammography).

 In unexposed compared to severely exposed women, means varied from 124 cm2 to 121 cm2 (p-value = 0.50) for breast size, from 23.4 to 21.8 cm2 (p-value = 0.48) for amount of dense tissue, from 87.7 to 85.4 cm2 (p-value = 0.55) for non-dense tissue and from 22.8 to 22.3% (p-value = 0.78) for relative density. Only among women who were younger than 10 years during the famine was the amount of non-dense tissue significantly lower with higher exposure, with 53.1 cm2 for severely exposed compared to 77.8 cm2 (p-value = 0.03) for unexposed.
Botden, 2012 [74] Seven hundred ninety-three individuals born as term singletons in Amsterdam around the famine in the Netherlands during World War II, as described in detail earlier [75]. To investigate whether Sirutin 1 (SIRT1) influences fetal programming during malnutrition. Independent variables:
  • -

    Period of exposure to famine.

Outcome parameters (in adults):
  • -

    Fasting glucose level;

  • -

    Oral glucose tolerance test (OGTT);

  • -

    AUC for glucose and insulin;

  • -

    BMI;

  • -

    Blood samples for SIRT1 genetic investigation.

 A significant interaction was found between two SIRT1 single nucleotide polymorphisms (SNPs) and exposure to famine in utero on T2DM risk (p-value = 0.03 for rs7895833; p-value = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of T2DM only in individuals who had been exposed to famine prenatally (OR for rs7895833 0.50 [95% CI 0.24–1.03], p-value = 0.06; for rs1467568 0.48 [0.25–0.91], p-value = 0.02).
Van Abeelen, 2012 [76] Seven thousand five hundred and fifty-seven women from Prospect-EPIC cohort [66], with the exposure age classified into three categories: childhood (age 0–9 years), adolescence (age 10–17 years), and young adulthood (age ≥18 years) [67]. To investigate the association between childhood and adulthood undernutrition and T2DM in adulthood. Independent variables:
  • -

    Period of exposure to famine.

Outcome parameters (in adults):
  • -

    Weight, height, BMI;

  • -

    Waist: hip ratio;

  • -

    Urinary samples for glucose strip test.

 For moderate famine exposure, the age-adjusted T2DM HR was 1.36 (95% CI [1.09–1.70]); for severe famine exposure, the age-adjusted HR was 1.64 (1.26–2.14) relative to unexposed women.
Tobi, 2012 [77] One hundred and twenty individuals:
60 (28 males and 32 females, age at examination 58.1 year [SD, 0.35 year]) exposed to famine around the moment of conception and first 10 weeks of gestation;
24 same-sex siblings (11 male, 13 female) conceived and born before the famine;
36 same-sex siblings (17 male, 19 female) conceived and born after the famine.
Age at examination 57.0 year [SD, 5.9 year].		 To test if the associations between famine exposure and genetic variation are independent and to contrast the effect sizes of these associations. Independent variables:
  • -

    Period of exposure to famine.

Outcome parameters (in adults):
  • -

    Blood samples for analysis of IGF2/H19 methylation.

 The average deoxyribonucleic acid (DNA) methylation difference between exposed and unexposed was 0.5 SD for significantly associated differentially methylated regions (DMRs).
Only the interactions between prenatal famine exposure and INSIGF SNPs rs3842756 (p = 0.048) and rs689 (p = 0.016) in relation to IGF2 DMR1 methylation were significant.
Tobi, 2015 [78] Three hundred and forty-eight exposed to famine in utero:
73 in weeks 1–10 of gestation;
123 in weeks 11–20 of gestation;
143 in weeks 21–30 of gestation;
128 in weeks 31-delivery.
(Some individuals meet the definition for exposure in two adjacent gestation periods.)
160 time-controls (1943–1947).
303 same-sex siblings.		 To study the epigenome-wide association for famine exposure during specific gestation periods and for exposure to famine in any period during gestation. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Smoking habits;

  • -

    Dietary intake of micro- and macronutrients;

  • -

    SES.

Outcome parameters (in adults):
  • -

    Blood samples to study the DNA methylation.

 Famine exposure during gestation weeks 1–10, but not weeks 11–20, 21–30 or 31-delivery, was associated with an increase in DNA methylation of cytosine phosphate guanine (CpG) dinucleotides cg20823026 (FAM150B), cg10354880 (SLC38A2) and cg27370573 (PPAP2C) and a decrease of cg11496778 (OSBPL5/MRGPRG) (p < 5.9 × 10−7, positive false discovery rate (PFDR) <0.031). There was an increase in methylation of TACC1 and ZNF385A after exposure during any time in gestation (p < 2.0 × 10−7, PFDR = 0.034) and a decrease of cg23989336 (TMEM105) after exposure around conception. SD: 0.3–0.6.
De Rooij, 2016 [34] One hundred and eighteen subjects:
41 exposed to famine in early gestation;
77 unexposed to famine in gestation.
Mean age: 67.5 year. 		To assess the effects of undernutrition during early gestation on brain size, structure, and white matter integrity at 68 year. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight in 3rd trimester and at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    Sport practice;

  • -

    Alcohol habits;

  • -

    SES;

  • -

    Current age.

Outcome parameters (in adults):
  • -

    Adult characteristics: BMI, SBP, glucose 120 min, LDL, HDL cholesterol, waist circumference, blood pressure.

  • -

    Magnetic Resonance Imaging (MRI) scan:

T1 structural scan;
Diffusion Tensor Imaging (DTI) scan;
Fluid-attenuated inversion recovery (FLAIR) scan.		 Intracranial volume (ICV) and total brain volume (TBV) were larger in males than in females [119 mL (95% CI: 88–150) and 116 mL (86–146)]. Birth weight, head circumference at birth and at age 68 were all significantly positively associated with ICV and TBV (all p < 0.05).
Males exposed to famine during early gestation had smaller ICV than unexposed males with a mean difference of 58 mL (98% CI: 11–106), corresponding to a difference of ∼5%.
Roseboom, 2000 [42] Seven hundred and twenty-five subjects:
209 born before famine;
117 exposed to famine in late gestation;
41 exposed to famine in mid-gestation;
65 exposed to famine in early gestation;
226 conceived after famine.		 To assess the effect of maternal malnutrition on plasma fibrinogen and factor VII concentrations in first generation adults. Independent variables:
  • -

    Stage of gestation, in relation to famine exposure;

  • -

    Rations of calories, fats, proteins, carbohydrates on averages for the exposure period.

  • -

    Maternal characteristics: age, primipara, weight in 3rd trimester and at the end of pregnancy, manual class;

  • -

    Smoking status;

  • -

    Sport practice;

  • -

    Alcohol habits;

  • -

    SES;

  • -

    Current age.

Outcome parameters (in adults):
  • -

    Adult characteristics: BMI, SBP, glucose 120 min, LDL, HDL cholesterol, waist circumference, blood pressure.

  • -

    Plasma fibrinogen;

  • -

    Factor VII.

 Plasma fibrinogen concentrations differed by −0.01 g/L (95% CI, −0.14–0.11) in those exposed in late gestation, by −0.03 g/L (95% CI, −0.16–0.11) in those exposed in mid gestation, and by 0.13 g/L (95% CI, −0.03–0.30) in those exposed in early gestation, compared with non-exposed people.
Plasma factor VII concentrations differed by 0.4% (95% CI, −5.4%–6.6%) in those exposed to famine in late gestation, by 1.5% (95% CI, −4.6%–8.1%) in those exposed in mid gestation. and by −11.8% (95% CI, −18.4–−4.8%) in those exposed in early gestation, compared with non-exposed people.
The Chinese Famine Cohort
Li Y, 2011 [17] Seven thousand eight hundred and seventy-four individuals
From severely affected famine area: 834 non-exposed, 334 fetal exposed, 641 early childhood exposed, 630 mid-childhood exposed, 613 late childhood exposed;
From less severely affected famine area: 1120 non-exposed, 671 fetal exposed, 1013 early childhood exposed, 958 mid-childhood exposed, 1060 late childhood exposed.		 To examine if there is any association between fetal exposure to famine and the risk of metabolic syndrome in later life. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area.

Outcome parameters (in adults):
  • -

    Weight;

  • -

    Height;

  • -

    Waist circumference;

  • -

    Blood pressure;

  • -

    Fasting plasma glucose (FPG);

  • -

    Blood samples for OGTT;

  • -

    Blood samples for LDL, HDL, triglyceride (TG) plasma concentrations.

 Severely affected famine area (prevalence, OR, 95% CI, p of metabolic syndrome):
  • -

    Non-exposed: 3.1%, 1.0;

  • -

    Fetal exposed: 7.8%, 3.13, [1.24–7.89], p = 0.016;

  • -

    Early childhood exposed: 7.1%, 2.85, [1.19–6.83], p = 0.019;

  • -

    Mid-childhood exposed: 5.7%, 2.07, [0.77–5.53], p = 0.15;

  • -

    Late childhood exposed: 6.4%, 2.21, [0.91–5.40], p = 0.08.

Less severely affected famine area (prevalence, OR, 95% CI, p of metabolic syndrome):
  • -

    Non-exposed: 9.4%, 1.0;

  • -

    Fetal exposed: 7.4%, 0.80, [0.46–1.41], p = 0.44;

  • -

    Early childhood exposed: 9.7%, 0.91, [0.55–1.51], p = 0.72;

  • -

    Mid-childhood exposed: 10.1%, 0.97, [0.57–1.64], p = 0.91;

  • -

    Late childhood exposed: 11.6%, 1.29, [0.76–2.19], p = 0.34.
Li QD, 2012 [79] Birth cohorts who were exposed to the 1959–1961 Chinese famine and birth cohorts who were not exposed. To describe the stomach cancer mortality trends in different cohorts that had been exposed to long-term malnutrition during early life. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area.

Outcome parameters (in adults):
  • -

    Data of stomach cancer mortality.

 For males: relative risk (RR) 2.39, 95% CI 1.51–3.77.
For females: RR 1.64, 95% CI 1.02–2.62.
Wang PX, 2012 [28] Twelve thousand and sixty-five subjects born in Nanhai and Zhongshan areas in 1957–1964. To assess the impact of exposure to the 1959–1961 Chinese Great Famine during fetal development and first 2 years of postnatal life on the risk of hypertension, short stature and obesity in adulthood. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area;

  • -

    Questionnaire to assess: sex, age, occupation, smoking, alcohol use, regular physical activity, preference for salty foods, municipality, place of residence.

Outcome parameters (in adults):
  • -

    Weight;

  • -

    Height;

  • -

    Blood pressure.

 Subjects exposed during the 1st trimester only had significantly higher SBP, DBP and risk of hypertension [adjusted OR = 1.36 (1.03, 1.79)].
The risk of hypertension was about 1.8-fold higher in subjects exposed to famine during infancy only (p < 0.001), and 1.3-fold higher in subjects exposed during both fetal development and infancy (p < 0.001), but was not significantly elevated in those exposed during fetal development only overall (p =  0.15).
Shi, 2013 [80] Two thousand and seven subjects born between 1952 and 1964, from Jiangsu province, China. To investigate if early life exposure to famine is related to higher risk of anemia in adulthood. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area;

  • -

    Questionnaire to assess: sex, age, occupation, smoking, alcohol use, regular physical activity, preference for salty foods, municipality, place of residence;

  • -

    Nutrients intake using a 3-day weighted food diary.

Outcome parameters (in adults):
  • -

    Weight;

  • -

    Height;

  • -

    Blood pressure;

  • -

    Overnight fasting blood samples for hemoglobin (cyanmethemoglobin method).

 Prevalence of anemia in adulthood:
  • -

    non-exposed: 26.0%,

  • -

    fetal-exposed: 33.8%,

  • -

    early-childhood: 28.1%,

  • -

    mid-childhood: 28.2%,

  • -

    late-childhood: 29.7%.

RR for fetal-exposed to famine (95% CI) (RR (95% CI)) was 1.37 (1.09, 1.71).
Huang, 2014 [43] Seventy thousand five hundred and forty-three women born between 1957–1965, in Zhejiang Province, China. To investigate the associations between early life exposure to the 1959–1961 Chinese Great Famine and the levels of protein in urine in adulthood. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area;

  • -

    Questionnaire to assess: sex, age, occupation, smoking, alcohol use, regular physical activity, preference for salty foods, municipality, place of residence.

Outcome parameters (in adults):
  • -

    Weight;

  • -

    Height;

  • -

    Blood pressure;

  • -

    Urine samples for protein concentration.

 Famine exposure and levels of proteinuria in the rural sample (mg/day), (n= 51,978, OR (95% CI), p-value):
Pre-famine cohort: 1.28 (0.73, 2.25), 0.366;
Famine cohort: 1.53 (1.04, 2.16), 0.031;
Post-famine cohort: 1.26 (0.99, 1.59), 0.052.
Famine exposure and levels of proteinuria in the urban sample (mg/day), (n = 4563, OR (95% CI), p-value):
Pre-famine cohort: 0.63 (0.18, 2.21), 0.471;
Famine cohort: 0.90 (0.36, 2.28), 0.824;
Post-famine cohort: 1.17 (0.65, 2.10), 0.610.
Wang, 2015 [18] Six thousand eight hundred and ninety-seven adults from East China, Shanghai and 7 provinces:
1245 non-exposed (born after 1975);
1808 non-exposed born between 1963–1974);
745 fetal-exposed (1959–1962);
1911 childhood-exposed (1949–1958);
1188 adolescence/adult-exposed (1921–1948).		 To explore whether early life exposure to famine and high economic status in adulthood is associated with diabetes in later life. Independent variables:
  • -

    Age period for famine exposure;

  • -

    Severity of famine in the area;

  • -

    Questionnaire to assess: sex, age, occupation, smoking, alcohol use, regular physical activity, preference for salty foods, municipality, place of residence.

Outcome parameters (in adults):
  • -

    Weight;

  • -

    Height;

  • -

    Blood pressure;

  • -

    Venous blood samples for plasma glucose test, HbA1C, fasting plasma glucose (FPG), lipid profile (cholesterol, TG, HDL, LDL, insulin secretion, insulin resistance).

 Exposure to starvation in utero, associated with a high economic status in adult life increases the prevalence of diabetes in middle ages and old ages.
Famine exposure during the fetal period (OR 1.53, 95% CI 1.09–2.14) and childhood (OR 1.82, 95% CI, 1.21–2.73) was associated with diabetes.
Subjects living in areas with high economic status had a greater diabetes risk in adulthood (OR 1.46, 95% CI 1.20–1.78).
In gender-specific analyses, fetal-exposed men (OR 1.64, 95% CI, 1.04–2.59) and childhood-exposed women (OR 2.81, 95% CI, 1.59–4.97) had significantly greater risk of diabetes.
The Siege of Leningrad Survivors (prospective cohort study, St. Petersburg, Russia)
Sparen, 2004 [24] Three thousand nine hundred and seven men born in 1916–35 in Petrogradsky district, Russia To determine whether starvation during increased growth periods have long term health consequences. Independent variables:
  • -

    Age at siege;

  • -

    Food shortage;

  • -

    Questionnaire to assess: marital status, education, occupational class, smoking and alcohol consumption.

Outcome parameters (in adults):
  • -

    BMI;

  • -

    Height;

  • -

    Skinfold thickness;

  • -

    LDL/HDL cholesterol;

  • -

    Blood pressure;

  • -

    CHD (according to Rose questionnaire);

  • -

    Data on mortality.

 Men exposed to famine in puberty had an increased mortality from ischemic heart disease (RR 1.39, 95% CI 1.07–1.79) and stroke (1.67, 1.15–2.43), including hemorrhagic stroke (1.71, 0.90–3.22).
Koupil, 2007 [25] Five thousand six hundred and thirty-four subjects, resident in St. Petersburg between 1975–1982:
3905 men born between 1916–1935;
1729 women born between 1910–1940.		 To investigate the long-term consequences of the food deprivation on cardiovascular risk factors and mortality in surviving adults. Independent variables:
  • -

    Age at siege;

  • -

    Food shortage;

  • -

    Questionnaire to assess: marital status, education, occupational class, smoking and alcohol consumption.

Outcome parameters (in adults):
  • -

    BMI;

  • -

    Height;

  • -

    Skinfold thickness;

  • -

    LDL/HDL cholesterol;

  • -

    Blood pressure;

  • -

    CHD (according to Rose questionnaire);

  • -

    Data on mortality.

 Higher mean SBP among women who experienced the severest starvation at age 6–8 years and in men who were exposed to the starvation at age 9–15 years: age adjusted differences in SBP were 7.4 (95% CI: −1.4, 16.2) mm Hg in women and 3.3 (95% CI: 1.1, 5.5) mm Hg in men.
Exposure to siege was associated with a statistically significant excess among men only, with a fully adjusted overall OR for men exposed at age 6–25 of 1.20 (95% CI: 1.03, 1.39) for mean blood pressure.
Rotar, 2015 [81] Three hundred and six subjects of 64–81 years, who experienced famine during the Siege;
51 age and sex-matched subjects, aged 67–82, non-exposed.		 To assess cardiovascular health, markers of cardiovascular aging and telomere length in survivors of the Siege of Leningrad. Independent variables:
  • -

    Age at siege;

  • -

    Food shortage;

  • -

    Questionnaire to assess: marital status, education, occupational class, smoking and alcohol consumption.

Outcome parameters (in adults):
  • -

    BMI;

  • -

    Height;

  • -

    Weight;

  • -

    Skinfold thickness;

  • -

    LDL/HDL cholesterol;

  • -

    Glucose level;

  • -

    Blood pressure;

  • -

    CHD (according to Rose questionnaire);

  • -

    Data on mortality;

  • -

    Echocardiography;

  • -

    ECG;

  • -

    Blood samples for relative telomere length measurement by quantitative Polymerase Chain Reaction (PCR).

 Both men and women exposed had shorter telomere length: T/S ratio 0.44 (0.25; 0.64) vs. controls 0.91 (0.47; 1.13) (p-value  <  0.0001).
The Biafran Study Cohort (cohort study, Enugu, Nigeria)
Hult, 2010 [27] One thousand three hundred and thirty-nine adults, from the Human group igbo, born between 1965–1973, Nigeria:
388 exposed to famine in early childhood (born 1965–1967);
292 exposed to fetal-infant famine (born 1968–January 1970);
486 unexposed (born 1971–1973);
173 in transitional period (Februar–December 1970).		 To study the risks for hypertension, diabetes and overweight in adults, after fetal and infant exposure to famine. Independent variables:
  • -

    Birth date in relation to Biafran Famine;

  • -

    Sex, age, smoking status, education.

Outcome parameters (in adults):
  • -

    BMI;

  • -

    Height;

  • -

    Weight;

  • -

    Waist circumference;

  • -

    Glucose level;

  • -

    Blood pressure.

 OR and CI for 40 years-old subjects exposed to famine:
  • -

    SBP ≥ 140: childhood (1.78 [1.19–2.68]), fetal-infant (3.02 [2.01–4.52]), unexposed (1);

  • -

    DBP ≥ 90: childhood (1.35 [0.93–1.97]), fetal-infant (2.49 [1.72–3.62]), unexposed (1);

  • -

    Severe HT: childhood (1.36 [0.63–2.93]), fetal-infant (2.68 [1.31–5.46]), unexposed (1);

  • -

    IGT: childhood (1.15 [0.70–1.86]), fetal-infant (1.76 [1.09–2.85]), unexposed (1);

  • -

    Diabetes: childhood (1.88 [0.66–5.33]), fetal-infant (3.11 [1.14–8.51]), unexposed (1);

  • -

    Overweight: childhood (1.02 [0.77–1.34]), fetal-infant (1.41 [1.03–1.93]), unexposed (1);

  • -

    Obesity: childhood (1.20 [0.87–1.67]), fetal-infant (1.30 [0.92–1.85]), unexposed (1).