The fetal origins of adult disease, the evidence and mechanisms
Veenendaal, M.V.E.
Publication date
2012
Link to publication
Citation for published version (APA):
Veenendaal, M. V. E. (2012). The fetal origins of adult disease, the evidence and
mechanisms.
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The fetal origins of hypertension:
a systematic review and meta-analysis of
the evidence from animal experiments of
maternal undernutrition
Annet FM van Abeelen*
Marjolein VE Veenendaal*
Rebecca C Painter
Susanne R de Rooij
Shakila Thangaratinam
Joris AM van der Post
Patrick MM Bossuyt
Sjoerd G Elias
Cuno SPM Uiterwaal
Diederick E Grobbee
George R Saade
Ben Willem J Mol
Khalid S Khan
Tessa J Roseboom
*both authors contributed equally to this work
Journal of Hypertension, accepted for publicationabsTracT
Objective: Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on systolic, diastolic, and mean arterial blood pressure in offspring. Methods: A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on systolic, diastolic, and mean arterial blood pressure were obtained through meta-analysis.results: Of the 6,151 articles identified, 194 were considered eligible after screening titles
and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased systolic blood pressure (general undernutrition: 14.5 mmHg, 95% CI 10.8 to 18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1 to 21.8) and mean arterial pressure (general undernutrition: 5.0 mmHg, 95% CI 1.4 to 8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7 to 14.2). There was substantial heterogeneity in the results. Diastolic blood pressure was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6 to 16.3), while general undernutrition had no significant effect. conclusion: The results of this meta-analysis generally support the view that in animals maternal undernutrition ‒ both general and protein - results in increased systolic and mean arterial blood pressure. Diastolic blood pressure was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.
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inTroDucTion
The fetal origins hypothesis proposes that hypertension originates in utero. It postulates that undernutrition during important periods of growth and development during fetal life can result in adaptations in structure and function of the body. In the short term these adaptations may be beneficial for fetal survival, but in the long term they can lead to cardiovascular, metabolic, and endocrine disease in adult life.Hypertension is one of these long-term effects of maternal undernutrition1. Numerous
studies, in different populations, have reported associations between small size at birth, as a proxy for undernutrition during fetal development, and high blood pressure or hypertension in later life2. Most studies found an inverse association between birth weight and blood
pressure, showing that small size at birth is associated with raised blood pressure in later life. A systematic review of eighty studies on the association between birth weight and blood pressure demonstrated that a kilogram increase in birth weight is associated with a 2 mmHg decrease in systolic blood pressure3. Birth weight, however, is only a proxy for maternal undernutrition during gestation and the epidemiological studies in humans are non-experimental, lacking the ability to derive definite causal conclusions. Animal studies can be used to experimentally investigate the effects of maternal undernutrition on blood pressure in the offspring in later life. A variety of animal species, including the mouse, rat, and sheep, have been used to study this effect. The models employed differ, using various protein:lipid:carbohydrate ratios of the maternal diet during gestation, and varying timing and duration of dietary manipulation. Some of these animal experiments observed significantly raised blood pressure in the offspring of undernourished mothers, while others did not. These inconsistencies may be due to differences in dietary regimens or strains or species of animals used but also to limited sample size and chance. We therefore systematically reviewed animal studies on maternal undernutrition during gestation and blood pressure in the offspring and performed a meta-analysis to obtain precise summary estimates of the effects of maternal undernutrition.
METhoDs
search strategy
We performed a search in the electronic databases Medline (1951 – August 2011) and Embase (1980 – August 2011) to identify articles that reported on maternal undernutrition and hypertension in offspring in experimental animal studies. The search terms ‘undernutrition’, ‘malnutrition’, ‘famine’, ‘starvation’, ‘nutrition disorder’, ‘caloric restriction’, ‘protein restriction’, ‘low protein diet’, ‘low calorie diet’, ‘blood pressure’ and ‘hypertension’ were used. There were no language restrictions.Study selection
We included papers describing outcomes in experimental animal models of maternal undernutrition that reported on systolic and/or diastolic blood pressure and/or mean arterial pressure in the offspring. Maternal undernutrition included low protein malnutrition and general caloric malnutrition. Studies had to report outcomes in comparison to control animals that were born to a mother that was normally fed throughout pregnancy. After screening of titles and abstracts, two reviewers (AFMvA and MVEV) independently examined full text articles from potentially eligible papers. Disagreements were resolved in consensus discussions. Reference lists of reviews and included papers were hand searched to identify additional studies.
Data extraction
From all included papers, two reviewers (AFMvA and MVEV) independently extracted information on study design, exposure period, animal species and type of undernutrition, and sample size. To assess risk of bias, data on allocation concealment, randomization, blinding were extracted. When more than two experimental groups were formed, we focused on the experimental group with malnutrition as early in pregnancy as possible and preferably limited to pregnancy alone. When outcome in offspring was measured at multiple time points, we chose the oldest age at which measurements were taken. Studies that reported on fetal blood pressure were excluded. If results were only displayed graphically, outcome was read as precise as possible. Studies that reported results as mean and standard deviation or standard error, and number of animals per group were used for meta-analysis.Data analysis
Summary estimates of the effects of maternal undernutrition were obtained using a random effects model for meta-analysis, which accounts for both within- and between- study variability. Separate estimates were obtained for sex, model type (protein or general undernutrition), and outcome measures (systolic, diastolic blood pressure and mean arterial pressure). The summary effects were expressed as mean differences with 95% confidence intervals (CI). We evaluated heterogeneity in results across studies by calculating the I² statistic, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling variability. When significant statistical heterogeneity was detected, further stratification was applied to investigate whether heterogeneity could be explained by different animal species or method to measure blood pressure (tail cuff and intra-arterial). To evaluate the robustness of our results against influential studies, a leaving-one-out sensitivity analysis was performed. To examine potential publication bias we constructed funnel plots. Data were analyzed using Review Manager Version 5.1.
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rEsulTs
The search resulted in 6,151 articles, of which 194 were considered potentially eligible. In total, 101 primary studies met the inclusion criteria and were used for data extraction after reading full text articles (AFMvA and MVEV) (Figure 1). Thirty-four studies reported on general (caloric) undernutrition; 18 using a Wistar rat model4-21 and 4 using a Sprague-Dawley rat model22-25, 8using a sheep model26-33, 2 using a guinea pig model34,35, and 2 using a mouse model36,37
. Sixty-seven studies reported on protein undernutrition; 47 using a Wistar rat model38-84, 15 using a
Sprague-Dawley rat model85-99, 1 using a spontaneously hypertensive rat model100, and 4 using a
mouse model101-104. The age of the studied animals ranged from four weeks in rats to three years
in sheep.
figure 1 Literature search results for studies reporting on maternal undernutrition with regard to
hypertension.
6,151 potenally eligible studies idenfied (database searches and references lists)
5,957 studies were excluded based on the inclusion criteria and tle and abstract review 194 full text arcles were reviewed
93 studies were excluded for not having the required exposure / not reporng the outcome of interest / not reporng data in a form fit for meta-analysis / non-animal
or fetal studies 101 studies were included in the meta-analysis
risk of bias
Forty-five studies reported randomization, either randomization to the dietary regimen5,8-11,13,18,20,21,25,27-30,32,33,40,42,48,70,72,79,81,83,92,93,103,104, or randomization in selecting the pups from
the litters that were studied12,22,24,45,55,57,60,68,74,82,99,102, or both6,7,14,41,67. Eighteen studies reported
performed a sample size calculation67. Funnel plots of all six outcomes showed symmetrical
scattering of the study results around the summary estimate. There was no evidence of a small study effect or publication bias.
Systolic blood pressure after maternal general undernutrition
Thirty studies provided data on systolic blood pressure in offspring after maternal general undernutrition. Twenty-two studies had been performed in rats4-25, two in mice36,37, one in guinea
pigs35, and five in sheep27,28,30-32. In total, 384 undernourished animals and 420 control animals
were described. Mean systolic blood pressure was 14.5 mmHg (95% CI 10.8 to 18.3) higher in undernourished animals compared to controls (Figure 2). There was considerable heterogeneity, with an I2 of 92%, which persisted after stratifying for sex or measurement method. Stratifying for species did not reduce heterogeneity in the different rodent models. Meta-analysis in sheep only (37 undernourished animals and 43 controls) showed no difference in systolic blood pressure between undernourished and control animals, with a mean difference systolic blood pressure of -1.1 mmHg (95% CI -6.4 to 4.3, I2 57%). Stratifying for measurement method showed a mean difference in systolic blood pressure of 19.7 mmHg (95% CI 15.3 to 24.2, I2 92%) in studies using the tail cuff method and a 4.2 mmHg (95% CI -1.2 to 9.6, I2 81%) mean difference in studies using intra-arterial catheters. Three studies reported both blinding of the investigator and randomization 27,28,30. Separately analysing these studies reduced heterogeneity (I2 32%) and showed no significant difference in systolic blood pressure (2.1 mmHg, 95% CI -3.0 to 7.2) after maternal general undernutrition.
Systolic blood pressure after maternal protein undernutrition
Fifty-four animal studies provided data on systolic blood pressure in offspring after maternal protein undernutrition. Fifty studies were performed using rats40-42,44-71,74,76-78,80-88,90,91,93-95,100 and
four using a mouse model101-104. We found a significantly higher mean systolic blood pressure
in animals prenatally exposed to a low protein diet (n = 1,421) compared to control animals (n = 1,427), with a mean difference in systolic blood pressure of 18.9 mmHg (95% CI 16.1 to 21.8) (Figure 3). The results showed considerable heterogeneity (I2 91%). Heterogeneity persisted after stratifying the analysis for sex or species. Stratifying for measurement method showed a mean difference in systolic blood pressure of 19.8 mmHg (95% CI 16.8 to 22.8, I2 91%) in studies using the tail cuff method and a 5.2 mmHg (95% CI -2.1 to 12.6, I2 0%) mean difference in studies using intra-arterial catheters. Separately analysing studies that used radiotelemetry showed a non significant difference in systolic blood pressure (mean difference systolic blood pressure 8.8 mmHg, 95% CI -9.8 to 27.3, I2 81%).
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figure 2 Systolic blood pressure after maternal general undernutrition according to sex of the animal
and measurement method
figure 3 Systolic blood pressure after maternal protein undernutrition according to sex of the animal
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Figure 3 ContinuedM: Males, F: Females, TC: Tail cuff, IC: Intra-arterial, RT: Radiotelemetry.
Six studies reported both blinding of the investigator and randomization55,57,67,81,103,104. Separately
analysing these studies reduced heterogeneity (I2 60%) and showed a significant but smaller
difference in systolic blood pressure (9.1 mmHg, 95% CI 5.6 to 12.6) after maternal protein undernutrition.
Diastolic blood pressure after maternal general undernutrition
Ten animal studies provided data on diastolic blood pressure in offspring after maternal general undernutrition. Five studies had been performed in rats12,14,16,22,24, four in sheep27,30-32, and one in
guinea pigs35. There was no significant difference in diastolic blood pressure (1.6 mmHg, 95% CI
-2.1 to 5.3 higher in prenatally undernourished animals (n = 95) compared to control animals (n = 108) (I2 65%) (Figure 4). Meta-analysis of the effects on sheep only (29 undernourished
animals and 31 controls) demonstrated a non-significant difference in diastolic blood pressure (-3.5 mmHg, 95% CI -7.8 to 0.9, I2 20%). Heterogeneity was not further reduced by stratification for other species, sex, or measurement method. Stratifying for measurement method showed a mean difference in diastolic blood pressure of 0.7 mmHg (95% CI -9.7 to 11.1, I2 66%) in studies using the tail cuff method and a 1.8 mmHg (95% CI -2.5 to 6.1, I2 68%) mean difference in studies using intra-arterial catheters.
Two studies reported both blinding of the investigator and randomization27,30. Separately
difference in diastolic blood pressure (-1.8 mmHg, 95% CI -10.6 to 6.9) after maternal general undernutrition.
figure 4 Diastolic blood pressure after maternal general undernutrition according to sex of the animal
and measurement method
M: Males, F: Females, TC: Tail cuff, IC: Intra-arterial, RT: Radiotelemetry.
Diastolic blood pressure after maternal protein undernutrition
Data for meta-analysis were available from four animal studies. Three studies were performed in a rat model45,48,54 and one in a mouse mode101. In total, 48 animals had been prenatally
exposed to a low protein diet and 40 animals were control fed. Mean diastolic blood pressure was significantly higher in animals prenatally exposed to a low protein diet compared to control animals (mean difference diastolic blood pressure 9.5 mmHg, 95% CI 2.6 to 16.3) (Figure 5). There was no heterogeneity (I2 0%). Stratifying for measurement method showed a mean
difference in diastolic blood pressure of 11.0 mmHg (95% CI -12.6 to 34.6) in the study using the tail cuff method and an 11.0 mmHg (95% CI 1.2 to 20.8) mean difference in the study using an
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non significant differences in diastolic blood pressure (mean difference diastolic blood pressure 7.0 mmHg, 95% CI -7.7 to 21.6, I2 48%). There were no studies that reported both blinding and randomization. figure 5 Diastolic blood pressure after maternal protein undernutrition according to sex of the animal and measurement method M: Males, F: Females, TC: Tail cuff, IC: Intra-arterial, RT: Radiotelemetry.Mean arterial pressure after maternal general undernutrition
Eleven animal studies provided data on mean arterial pressure in offspring after maternal general undernutrition. Two studies were performed using rats14,18, seven studies using sheep26,27,29-33,
and two studies using guinea pigs34,35. Mean arterial pressure was significantly higher in
undernourished (n = 105) compared to control animals (n = 114) (5.0 mmHg, 95% CI 1.4 to 8.6, I2 71%) (Figure 6).
Meta-analysis of the effects on sheep only (71 undernourished and 69 control animals) showed less heterogeneity but demonstrated no significant difference in mean arterial pressure (mean difference mean arterial pressure 1.4 mmHg, 95% CI -3.1 to 5.9, I2 50%). Heterogeneity was not lower after stratification for sex or measurement method. Stratifying for measurement method showed a mean difference in mean arterial pressure of 13.0 mmHg (95% CI 7.4 to 18.6) in the study using the tail cuff method and a 4.2 mmHg (95% CI 0.6 to 7.8, I2 67%) mean difference in studies using intra-arterial catheters. Three studies reported both blinding of the investigator and randomization27,30,34. Separately
analysing these studies did not change heterogeneity (I2 66%) and there was no significant
difference in mean arterial pressure (2.9 mmHg, 95% CI -4.3 to 10.2) after maternal general undernutrition.
figure 6 Mean arterial pressure after maternal general undernutrition according to sex of the animal
and measurement method
M: Males, F: Females, TC: Tail cuff, IC: Intra-arterial, RT: Radiotelemetry.
Mean arterial pressure after maternal protein undernutrition
Seventeen rat studies reported mean arterial pressure in offspring after prenatal exposure to a low protein diet38,39,43,45,48,72-75,79,87,89,92,96-99. Mean arterial pressure was significantly higher in
undernourished (n = 208) compared to control rats (n = 201) (mean difference mean arterial pressure 10.5 mmHg, 95% CI 6.7 to 14.2, I2 85%) (Figure 7). Heterogeneity could not be explained
by stratifying for the different rat species or sex. Stratifying for measurement method showed a mean difference in mean arterial pressure of 17.5 mmHg (95% CI 11.3 to 23.8, I2 0%) in studies
using the tail cuff method and a 10.7 mmHg (95% CI 6.6 to 14.7, I2 85%) mean difference in
studies using intra-arterial catheters. Separately analysing studies that used radiotelemetry showed smaller, non significant differences in mean arterial pressure (mean difference mean arterial pressure -0.9 mmHg, 95% CI -5.9 to 4.2, I2 0%).
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figure 7 Mean arterial pressure after maternal protein undernutrition according to sex of the animal and measurement method M: Males, F: Females, TC: Tail cuff, IC: Intra-arterial, RT: Radiotelemetry.Sensitivity analysis
In a series of sensitivity analyses, we evaluated the robustness of our findings by repeating the analyses a number of times, each time leaving one study out of the meta-analysis. If a study appears to be an outlier, with results very different from the rest of the studies, then its influence will become apparent, as the result without the study would be very different from the result of the meta-analysis of the remaining studies. The observed heterogeneity in the meta-analysis for diastolic blood pressure after maternal general undernutrition was largely due to the study of Ozaki et al14. On removal of this study,the I2 decreased from 62% to 27%. The overall summary estimate, however, did not change
design or characteristics in the study of Ozaki et al14 compared to the other studies which could explain the influence on the heterogeneity. All other sensitivity analyses, for each of the other five outcome measures evaluated, confirmed the stability of our analyses. No influential individual study could be identified.
Discussion
The results generally support the fetal origins hypothesis. We demonstrated that both general and protein undernutrition during gestation resulted in significantly increased systolic and mean arterial blood pressure in the offspring, while diastolic blood pressure was only significantly increased after maternal protein undernutrition. The largest effect of maternal undernutrition – both general and protein – was found on systolic blood pressure, which was significantly increased in prenatally undernourished offspring. This effect was stronger in the protein undernourished animals. This systematic review confirms the substantial variability in results from animal studies which, in most cases, cannot be attributed to chance variability only: heterogeneity was considerable in all meta-analyses. Some of the studies included in this meta-analysis used only male or female animals, while others used both or did not specify sex. Only two studies explained their choice to use male animals alone80,86. The authors of one of these papers suggested that using male animals only reduces the variability86. Furthermore, the authors of the other paper referred to the finding that male animals have been shown to be more vulnerable to developmental programming effects80,97, since male fetuses grow faster than female fetuses from an early stage of gestation and this makes them more vulnerable if their nutrition is compromised105,106. Maternal protein restriction in rats has been associated with fewer nephrons and an increased blood pressure among male but not female offspring97. Female gender seems to be relatively protective against the hypertensiveeffects of maternal protein restriction. However, this protection is lost with more severe protein restriction97. The mechanism of this relative protection is unknown. This meta-analysis
shows, however, that there is also in females a significant effect of maternal undernutrition – both general and protein – on systolic blood pressure and of protein undernutrition on mean arterial pressure. In addition, the effects on blood pressure are of similar size in male and female offspring.
When looking at species separately, we found that sheep prenatally exposed to general undernutrition did not have significantly higher blood pressure. This in contrast to prenatally undernourished rodent offspring, where an increase in systolic and mean arterial pressure was seen. The programming of any outcome measure, including blood pressure, may be amplified in the rat. The sum weight of the products of conception relative to maternal weight is 25-35% in rats versus 6-10% in sheep and 3-5% in humans30. This could very well explain the fact that we
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In humans, the relation between maternal undernutrition during pregnancy and blood pressure in the offspring is less well studied and the results are conflicting. The Hungerwinter Families Study, which studied subjects from three institutions in famine-exposed cities at an age of 59 years, found that people who had been exposed to famine in utero had higher blood pressures as adults107. The Dutch famine birth cohort study did not find significant effects of prenatal
famine exposure on blood pressure but observed that those exposed to famine prenatally had a higher blood pressure response to stress108. In contrast, in utero exposure to the Leningrad siege
between 1941 and 1944 or to the Chinese famine of 1959-1961 was not associated with raised blood pressure in later life109,110. Other meta-analyses of animal data showed marked heterogeneity111,112. The results of the present systematic review are in line with this. Stratifying for sex or species did not consistently explain the heterogeneity. Therefore we chose to primarily report the pooled results of all studies, since consistency of the results would indicate that the effects of maternal undernutrition are based on the same mechanisms and apply to different species. However, the size of the effect might differ between species.
We explored the potential sources of heterogeneity by conducting subgroup analyses for animal model, animal species and animal sex, but this accounted only for a small part of the heterogeneity. Another possible source of heterogeneity could be the fact that a portion of the included articles did not have blood pressure as the primary outcome. This could account for the variety in sample sizes we found between the studies. Furthermore, the fact that different laboratories use differently composed diets in their experiments could be another explanation for the heterogeneity, reflecting the inconsistencies in the results. In a study comparing two low protein diets, only one affected postnatal systolic blood pressure65. The main difference between
the two diets was the source and content of fat. That study demonstrated that exposure to low protein in utero does not in itself determine the development of hypertension in later life. The balance of other nutrients within the maternal diets appears to play a critical role65. The
studies included in our meta-analysis used different diets for the low protein experiments, which could explain part of the heterogeneity. Also, in the general malnutrition experiments, different regimens were applied. Restricted diets varied from 30 to 70% of normal intake. These wide ranges of dietary restriction have undoubtedly affected the outcome and attributed to the reported heterogeneity. Standardization of animal experiments will improve comparability of these studies.
Methodological heterogeneity must also be discussed as a major reason of the observed heterogeneity. The methodological quality of the included studies was poor, with only 18 studies reporting on blinding of the investigators, and 46 reporting on randomization, either when allocating the diet or selecting the pups for the measurements. In contrast to human studies, randomization, blinding, and sample size calculations are not standard practice in animal experiments. It has been shown that animal studies that do not report randomization and blinding are more likely to report a difference in the study groups than studies that do report
on these methods113. We can support this in our study. Separately analysing the methodologically
sound studies resulted in a reduction or disappearance of the effect. Improvements can be made on the quality of animal studies by applying standards for reporting such as those that are routine in human studies.
In rodent models, measurements of blood pressure are done by the tail cuff method or by direct intra-arterial measurements which encompass both direct indwelling catheters and 24 hour radiotelemetry. Radiotelemetry is considered to be a direct, minimally stressful, continuous blood pressure measurement114. There is evidence suggesting that prenatal malnutrition does
not primarily result in increased blood pressure, but in a heightened stress response leading to higher blood pressure levels108,114. This may be reflected in our findings of a greater difference
in systolic blood pressure and mean arterial pressure when measurements were performed with the tail cuff method, which is considered to be a source of stress, compared to direct intra-arterial measurements. Radiotelemetry has only been used in three studies investigating the effects of a low protein diet. Separately analysing studies using radiotelemetry showed smaller and non significant pooled effect estimates compared with the other methods. Of the two studies that reported on systolic and diastolic blood pressure, one showed an increase in both systolic and diastolic blood pressure101, while the other reported no effect45. Two studies
reported on mean arterial pressure after low protein undernutrition, with one study reporting a very small increase45, while the other reported no effect39. Swali et al. reported an increase
in systolic blood pressure when measurements were performed by the tail cuff method while radiotelemetry demonstrated lower mean arterial pressure in the same animals after low protein undernutrition80. These results may indicate that part of the increased blood pressure levels
found after prenatal undernutrition may be due to an increased stress response. In our data on systolic and diastolic blood pressure, although no longer significant, blood pressure levels were still higher after prenatal undernutrition when measured by radiotelemetry. This loss of significance may be caused by the small number of animals.
conclusion
In summary, the results of this meta-analysis generally support the view that maternal undernutrition – both general and protein – leads to an increased systolic and mean arterial blood pressure in the offspring of most animals. Yet, studies show substantial heterogeneity in the results which could not be sufficiently explained by known characteristics of the research. Also, the results depended strongly on the applied measurement technique and animal model. Future animal studies should improve their methodological quality by applying randomization, blinding, and sample size calculation techniques, to prevent selection, performance, and detection bias.
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rEfErEncE lisT
1. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311:171-174.
2. Adair L, Dahly D. Developmental determinants of blood pressure in adults. Annu Rev Nutr. 2005;25:407-434.
3. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000;18:815-831.
4. Almeida JR, Mandarim-de-Lacerda CA. Overweight is gender-dependent in prenatal protein-calorie restricted adult rats acting on the blood pressure and the adverse cardiac remodeling. Life Sciences. 2005;77:1307-1318.
5. Almeida JR, Mandarim-de-Lacerda CA. Maternal gestational protein-calorie restriction decreases the number of glomeruli and causes glomerular hypertrophy in adult hypertensive rats. American Journal of Obstetrics and Gynecology. 2005;192:945-951.
6. Ceravolo GS, Franco MCP, Carneiro-Ramos MS, Barreto-Chaves MLM, Tostes RCA, Nigro D, et al. Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats. Life Sciences. 2007;80:782-787.
7. Franco MCP, Akamine EH, Reboucas N, Carvalho MHC, Tostes RCA, Nigro D, et al. Long-term effects of intrauterine malnutrition on vascular function in female offspring: Implications of oxidative stress. Life Sciences. 2007;80:709-715.
8. Franco MDCP, Arruda RMMP, Dantas APV, Kawamoto EM, Fortes ZB, Scavone C, et al. Intrauterine undernutrition: Expression and activity of the endothelial nitric oxide synthase in male and female adult offspring. Cardiovascular Research. 2002;56:145-153.
9. Franco MDCP, Dantas APV, Akamine EH, Kawamoto EM, Fortes ZB, Scavone C, et al. Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. Journal of Cardiovascular Pharmacology. 2002;40:501-509.
10. Franco MDCP, Arruda RMMP, Fortes ZB, Ferreira de OS, Carvalho MHC, Tostes RCA, et al. Severe nutritional restriction in pregnant rats aggravates hypertension, altered vascular reactivity, and renal development in spontaneously hypertensive rats offspring. Journal of Cardiovascular Pharmacology. 2002;39:369-377.
11. Franco MDCP, Akamine EH, Aparecida de OM, Fortes ZB, Tostes RCA, Carvalho MHC, et al. Vitamins C and E improve endothelial dysfunction in intrauterine-undernourished rats by decreasing vascular superoxide anion concentration. Journal of Cardiovascular Pharmacology. 2003;42:211-217. 12. Holemans K, Gerber R, Meurrens K, De CF, Poston L, Van Assche FA. Maternal food restriction in the
second half of pregnancy affects vascular function but not blood pressure of rat female offspring. British Journal of Nutrition. 1999;81:73-79.
13. Landgraf MAV, Martinez LL, Rastelli VMF, Franco MDCP, Soto-Suazo M, Tostes RDCA, et al. Intrauterine undernutrition in rats interferes with leukocyte migration, decreasing adhesion molecule expression in leukocytes and endothelial cells. Journal of Nutrition. 2005;135:1480-1485. 14. Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. Journal of Physiology. 2001;530:141-152. 15. Perez H, Ruiz S, Nunez H, White A, Gotteland M, Hernandez A. Paraventricular-coerulear interactions:
Role in hypertension induced by prenatal undernutrition in the rat. European Journal of Neuroscience. 2006;24:1209-1219.
16. Perez H, Ruiz S, Nunez H, White A, Gotteland M. Coerulear activation by CRH and its role in hypertension induced by prenatal malnutrition in the rat. International Journal of Neuroscience. 2007;117:627-642. 17. Perez H, Soto-Moyano R, Ruiz S, Hernandez A, Sierralta W, Olivares R, et al. A putative role for
hypothalamic glucocorticoid receptors in hypertension induced by prenatal undernutrition in the rat. Neuroscience Letters. 2010;483:41-46.
18. Riviere G, Michaud A, Breton C, VanCamp G, Laborie C, Enache M, et al. Angiotensin-converting enzyme 2 (ACE2) and ACE activities display tissue-specific sensitivity to undernutrition-programmed hypertension in the adult rat. Hypertension. 2005;46:1169-1174. 19. Vickers MH, Ikenasio BA, Breier BH. IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. Endocrinology. 2001;142:3964-3973. 20. Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatric Research. 1996;40:438-443.
21. Woodall SM, Breier BH, Johnston BM, Bassett NS, Barnard R, Gluckman PD. Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring. J Endocrinol. 1999;163:69-77.
22. Chou HC, Wang LF, Lu KS, Chen CM. Effects of maternal undernutrition on renal angiotensin II and chymase in hypertensive offspring. Acta Histochemica. 2008;110:497-504.
23. Khorram O, Momeni M, Desai M, Ross MG. Nutrient restriction in utero induces remodeling of the vascular extracellular matrix in rat offspring. Reprod Sci. 2007;14:73-80.
24. Olausson H, Uvnas-Moberg K, Sohlstrom A. Postnatal oxytocin alleviates adverse effects in adult rat offspring caused by maternal malnutrition. American Journal of Physiology - Endocrinology and Metabolism. 2003;284:E475-E480.
25. Xu Y, Williams SJ, O’Brien D, Davidge ST. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2006;20:1251-1253.
26. Cleal JK, Poore KR, Boullin JP, Khan O, Chau R, Hambidge O, et al. Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood. Proc Natl Acad Sci U S A. 2007;104:9529-9533.
27. Gardner DS, Pearce S, Dandrea J, Walker R, Ramsay MM, Stephenson T, et al. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension. 2004;43:1290-1296.
28. Gardner DS, Van Bon BWM, Dandrea J, Goddard PJ, May SF, Wilson V, et al. Effect of periconceptional undernutrition and gender on hypothalamic-pituitary-adrenal axis function in young adult sheep. Journal of Endocrinology. 2006;190:203-212.
29. Gilbert JS, Lang AL, Grant AR, Nijland MJ. Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age. J Physiol. 2005;565:137-147.
30. Gopalakrishnan GS, Gardner DS, Rhind SM, Rae MT, Kyle CE, Brooks AN, et al. Programming of adult cardiovascular function after early maternal undernutrition in sheep. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 2004;287:R12-R20.
31. Gopalakrishnan GS, Gardner DS, Dandrea J, Langley-Evans SC, Pearce S, Kurlak LO, et al. Influence of maternal pre-pregnancy body composition and diet during early-mid pregnancy on cardiovascular function and nephron number in juvenile sheep. Br J Nutr. 2005;94:938-947.
32. Hawkins P, Steyn C, McGarrigle HHG, Calder NA, Saito T, Stratford LL, et al. Cardiovascular and hypothalamic-pituitary-adrenal axis development in late gestation fetal sheep and young lambs following modest maternal nutrient restriction in early gestation. Reproduction, Fertility and Development. 2000;12:443-456.
33. Oliver MH, Breier BH, Gluckman PD, Harding JE. Birth weight rather than maternal nutrition influences glucose tolerance, blood pressure, and IGF-I levels in sheep. Pediatric Research. 2002;52:516-524. 34. Bertram C, Khan O, Ohri S, Phillips DI, Matthews SG, Hanson MA. Transgenerational effects of prenatal
nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function. Journal of Physiology. 2008;586:2217-2229.
3
36. Kawamura M, Itoh H, Yura S, Mogami H, Suga S, Makino H, et al. Undernutrition in utero augmentssystolic blood pressure and cardiac remodeling in adult mouse offspring: Possible involvement of local cardiac angiotensin system in developmental origins of cardiovascular disease. Endocrinology. 2007;148:1218-1225.
37. Kawamura M, Itoh H, Yura S, Mogami H, Fujii T, Makino H, et al. Isocaloric high-protein diet ameliorates systolic blood pressure increase and cardiac remodeling caused by maternal caloric restriction in adult mouse offspring. Endocrine Journal. 2009;56:679-689.
38. Alwasel SH, Ashton N. Prenatal programming of renal sodium handling in the rat. Clinical Science. 2009;117:75-84.
39. Augustyniak RA, Singh K, Zeldes D, Singh M, Rossi NF. Maternal protein restriction leads to hyperresponsiveness to stress and salt-sensitive hypertension in male offspring. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2010;298:R1375-R1382.
40. Bertram C, Trowern AR, Copin N, Jackson AA, Whorwood CB. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: Potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology. 2001;142:2841-2853.
41. Bezerra DG, Lacerda Andrade LM, Pinto da Cruz FO, Mandarim-de-Lacerda CA. Atorvastatin Attenuates Cardiomyocyte Loss in Adult Rats From Protein-Restricted Dams. Journal of Cardiac Failure. 2008;14:151-160.
42. Brawley L, Itoh S, Torrens C, Barker A, Bertram C, Poston L, et al. Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatric Research. 2003;54:83-90. 43. Cambonie G, Comte B, Yzydorczyk C, Ntimbane T, Germain N, Le NLO, et al. Antenatal antioxidant
prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2007;292:R1236-R1245.
44. Elmes MJ, Gardner DS, Langley-Evans SC. Fetal exposure to a maternal low-protein diet is associated with altered left ventricular pressure response to ischaemia-reperfusion injury. British Journal of Nutrition. 2007;98:93-100.
45. Fernandez-Twinn DS, Ekizoglou S, Wayman A, Petry CJ, Ozanne SE. Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2006;291:R429-R436.
46. Gardner DS, Jackson AA, Langley-Evans SC. Maintenance of maternal diet-induced hypertension in the rat is dependent on glucocorticoids. Hypertension. 1997;30:1525-1530.
47. Harrison M, Langley-Evans SC. Intergenerational programming of impaired nephrogenesis and hypertension in rats following maternal protein restriction during pregnancy. British Journal of Nutrition. 2009;101:1020-1030.
48. Hu XW, Levy A, Hart EJ, Nolan LA, Dalton GR, Levi AJ. Intra-uterine growth retardation results in increased cardiac arrhythmias and raised diastolic blood pressure in adult rats. Cardiovascular Research. 2000;48:233-243.
49. Jackson AA, Dunn RL, Marchand MC, Langley-Evans SC. Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clinical Science. 2002;103:633-639.
50. Jones SE, Bilous RW, Flyvbjerg A, Marshall SM. Intra-uterine environment influences glomerular number and the acute renal adaptation to experimental diabetes. Diabetologia. 2001;44:721-728. 51. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the
preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127:4195-4202.
52. Lamireau D, Nuyt AM, Hou X, Bernier S, Beauchamp M, Gobeil J, et al. Altered vascular function in fetal programming of hypertension. Stroke. 2002;33:2992-2998.
53. Langley-Evans SC, Phillips GJ, Jackson AA. In utero exposure to maternal low protein diets induces hypertension in weanling rats, independently of maternal blood pressure changes. Clinical Nutrition. 1994;13:319-324.
54. Langley-Evans SC, Jackson AA. Captopril normalises systolic blood pressure in rats with hypertension induced by fetal exposure to maternal low protein diets. Comparative Biochemistry and Physiology - A Physiology. 1995;110:223-228.
55. Langley-Evans SC, Welham SJM, Sherman RC, Jackson AA. Weanling rats exposed to maternal low-protein diets during discrete periods of gestation exhibit differing severity of hypertension. Clinical Science. 1996;91:607-615.
56. Langley-Evans SC, Gardner DS, Jackson AA. Maternal protein restriction influences the programming of the rat hypothalamic-pituitary-adrenal axis. Journal of Nutrition. 1996;126:1578-1585.
57. Langley-Evans SC, Phillips GJ, Gardner DS, Jackson AA. Role of glucocorticoids in programming of maternal diet-induced hypertension in the rat. Journal of Nutritional Biochemistry. 1996;7:173-178. 58. Langley-Evans SC, Phillips GJ, Benediktsson R, Gardner DS, Edwards CRW, Jackson AA, et al. Protein
intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta. 1996;17:169-172.
59. Langley-Evans SC, Gardner DS, Jackson AA. Association of disproportionate growth of fetal rats in late gestation with raised systolic blood pressure in later life. Journal of Reproduction and Fertility. 1996;106:307-312.
60. Langley-Evans SC, Jackson AA. Rats with hypertension induced by in utero exposure to maternal low-protein diets fail to increase blood pressure in response to a high salt intake. Annals of Nutrition and Metabolism. 1996;40:1-9. 61. Langley-Evans SC. Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a protein-replete diet. Clinical Science. 1997;93:423-429. 62. Langley-Evans SC. Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. Journal of Hypertension. 1997;15:537-544.
63. Langley-Evans SC, Nwagwu M. Impaired growth and increased glucocorticoid-sensitive enzyme activities in tissues of rat fetuses exposed to maternal low protein diets. Life Sciences. 1998;63:605-615.
64. Langley-Evans SC, Welham SJM, Jackson AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sciences. 1999;64:965-974.
65. Langley-Evans SC. Critical differences between two low protein diet protocols in the programming of hypertension in the rat. International Journal of Food Sciences and Nutrition. 2000;51:11-17. 66. Langley SC, Jackson AA. Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clinical Science. 1994;86:217-222. 67. Martin DA, McCutcheon D, Wainwright PE. Prenatal dietary docosahexaenoic acid supplementation in combination with protein restriction does not affect blood pressure in adult Wistar rats. Nutritional Neuroscience. 2004;7:141-150. 68. McMullen S, Gardner DS, Langley-Evans SC. Prenatal programming of angiotensin II type 2 receptor expression in the rat. British Journal of Nutrition. 2004;91:133-140.
69. McMullen S, Langley-Evans SC. Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2005;288:R85-R90.
70. Musha Y, Itoh S, Hanson MA, Kinoshita K. Does estrogen affect the development of abnormal vascular function in offspring of rats fed a low-protein diet in pregnancy? Pediatric Research. 2006;59:784-789. 71. Nwagwu MO, Cook A, Langley-Evans SC. Evidence of progressive deterioration of renal function in rats
exposed to a maternal low-protein diet in utero. British Journal of Nutrition. 2000;83:79-85.
3
73. Pladys P, Sennlaub F, Brault S, Checchin D, Lahaie I, Le NLO, et al. Microvascular rarefaction anddecreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2005;289:R1580-R1588.
74. Plank C, Grillhosl C, Ostreicher I, Meissner U, Struwe F, Rauh M, et al. Transient growth hormone therapy to rats with low protein-inflicted intrauterine growth restriction does not prevent elevated blood pressure in later life. Growth Factors. 2008;26:355-364.
75. Sahajpal V, Ashton N. Renal function and angiotensin AT<sub>1</sub> receptor expression young rats following intrauterine exposure to a maternal low-protein diet. Clinical Science. 2003;104:607-614. 76. Sayer AA, Dunn R, Langley-Evans S, Cooper C. Prenatal exposure to a maternal low protein diet
shortens life span in rats. Gerontology. 2001;47:9-14.
77. Sherman RC, Langley-Evans SC. Early administration of angiotensin-converting enzyme inhibitor captopril, prevents the development of hypertension programmed by intrauterine exposure to a maternal low-protein diet in the rat. Clinical Science. 1998;94:373-381.
78. Sherman RC, Langley-Evans SC. Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. Clinical Science. 2000;98:269-275.
79. Silva LA, Veira-Filho LD, Barreto IS, Cabral EV, Vieyra A, Paixao AD. Prenatal Undernutrition Changes Renovascular Responses of Nimesulide in Rat Kidneys. Basic and Clinical Pharmacology and Toxicology. 2011;108:115-121. 80. Swali A, McMullen S, Langley-Evans SC. Prenatal protein restriction leads to a disparity between aortic and peripheral blood pressure in Wistar male offspring. Journal of Physiology. 2010;588:3809-3818. 81. Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, Jackson AA, et al. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension. 2006;47:982-987. 82. Torres TDS, Aguila MB, Mandarim-de-Lacerda CA. Rosiglitazone reverses cardiac adverse remodeling (fibrosis and vascularization) in perinatal low protein rat offspring. Pathology Research and Practice. 2010;206:642-646.
83. Villar-Martini VC, Carvalho JJ, Neves MF, Aguila MB, Mandarim-de-Lacerda CA. Hypertension and kidney alterations in rat offspring from low protein pregnancies. Journal of Hypertension. 2009;27:S47-S51. 84. Langley-Evans SC. Intrauterine programming of hypertension in the rat: Nutrient interactions.
Comparative Biochemistry and Physiology - A Physiology. 1996;114:327-333.
85. Chen J, Xu H, Shen Q, Guo W, Sun L. Effect of postnatal high-protein diet on kidney function of rats exposed to intrauterine protein restriction. Pediatric Research. 2010;68:100-104.
86. Dagan A, Habib S, Gattineni J, Dwarakanath V, Baum M. Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2009;297:R93-R99.
87. Gangula PRR, Reed L, Yallampalli C. Antihypertensive effects of flutamide in rats that are exposed to a low-protein diet in utero. American Journal of Obstetrics and Gynecology. 2005;192:952-960. 88. Habib S, Gattineni J, Twombley K, Baum M. Evidence that prenatal programming of hypertension
by dietary protein deprivation is mediated by fetal glucocorticoid exposure. American Journal of Hypertension. 2011;24:96-101.
89. Hoppe CC, Evans RG, Moritz KM, Cullen-McEwen LA, Fitzgerald SM, Dowling J, et al. Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 2007;292:R462-R469.
90. Manning J, Vehaskari VM. Low birth weight-associated adult hypertension in the rat. Pediatric Nephrology. 2001;16:417-422.
91. Petry CJ, Ozanne SE, Wang CL, Hales CN. Early protein restriction and obesity independently induce hypertension in 1 year-old rats. Clinical Science. 1997;93:147-152.
92. Sathishkumar K, Elkins R, Yallampalli U, Yallampalli C. Protein restriction during pregnancy induces hypertension and impairs endothelium-dependent vascular function in adult female offspring. Journal of Vascular Research. 2009;46:229-239. 93. Shen Q, Xu H, Wei L-M, Chen J, Liu H-M. Intrauterine growth restriction and postnatal high-protein diet affect the kidneys in adult rats. Nutrition. 2011;27:364-371. 94. Stewart T, Ascani J, Craver RD, Vehaskari VM. Role of postnatal dietary sodium in prenatally programmed hypertension. Pediatric Nephrology. 2009;24:1727-1733. 95. Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat. Kidney International. 2001;59:238-245. 96. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatric Research. 2001;49:460-467. 97. Woods LL, Weeks DA, Rasch R. Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis. Kidney International. 2004;65:1339-1348.
98. Woods LL, Ingelfinger JR, Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2005;289:R1131-R1136.
99. Woods LL, Morgan TK, Resko JA. Castration fails to prevent prenatally programmed hypertension in male rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2010;298:R1111-R1116.
100. Otani L, Shirasaka N, Yoshizumi H, Murakami T. The effects of maternal mild protein restriction on stroke incidence and blood pressure in stroke-prone spontaneously hypertensive rats (SHRSP). Bioscience, Biotechnology and Biochemistry. 2004;68:488-494.
101. Bol V, Desjardins F, Reusens B, Balligand J-L, Remacle C. Does early mismatched nutrition predispose to hypertension and atherosclerosis, in male mice? PLoS ONE. 2010;5:1-11.
102. Rexhepaj R, Boini KM, Huang DY, Amann K, Artunc F, Wang K, et al. Role of maternal glucocorticoid inducible kinase SGK1 in fetal programming of blood pressure in response to prenatal diet. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2008;294:R2008-R2013. 103. Watkins AJ, Wilkins A, Cunningham C, Perry VH, Seet MJ, Osmond C, et al. Low protein diet fed
exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring. Journal of Physiology. 2008;586:2231-2244.
104. Watkins AJ, Ursell E, Panton R, Papenbrock T, Hollis L, Cunningham C, et al. Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biology of Reproduction. 2008;78:299-306.
105. Pedersen JF. Ultrasound evidence of sexual difference in fetal size in first trimester. Br Med J. 1980;281:1253.
106. Tanner JM. Fetus into man. 2nd ed. Ware: Castlemead; 1989.
107. Stein AD, Zybert PA, Van Der Pal-De Bruin, Lumey LH. Exposure to famine during gestation, size at birth, and blood pressure at age 59 y: evidence from the Dutch Famine. Eur J Epidemiol. 2006;21:759-765. 108. Painter RC, De Rooij SR, Bossuyt PM, Phillips DI, Osmond C, Barker DJ, et al. Blood pressure response
to psychological stressors in adults after prenatal exposure to the Dutch famine. J Hypertens. 2006;24:1771-1778.
109. Stanner SA, Bulmer K, Andres C, Lantseva OE, Borodina V, Poteen VV, et al. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. British Medical Journal. 1997;315:1342-1348.
110. Huang C, Li Z, Wang M, Martorell R. Early life exposure to the 1959-1961 Chinese famine has long-term health consequences. The Journal of nutrition. 2010;140:1874-1878.
111. Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004;35:1203-1208.
3
112. Roberts I, Kwan I, Evans P, Haig S. Does animal experimentation inform human healthcare?Observations from a systematic review of international animal experiments on fluid resuscitation. BMJ. 2002;324:474-476.
113. Bebarta V, Luyten D, Heard K. Emergency medicine animal research: does use of randomization and blinding affect the results? Acad Emerg Med. 2003;10:684-687.
114. Tonkiss J, Trzcinska M, Galler JR, Ruiz-Opazo N, Herrera VLM. Prenatal malnutrition-induced changes in blood pressure dissociation of stress and nonstress responses using radiotelemetry. Hypertension. 1998;32:108-114.
