Introduction
The Developmental Origins of Health and Disease (DOHaD) hypothesis, proposed by David Barker in 1989, postulated that chronic non-communicable diseases (NCDs) could be driven by environmental insults occurring during intrauterine development.Reference Barker1 Epidemiological evidence suggests that maternal insults during critical windows of fetal development could induce compensatory fetal responses that permanently alter offspring phenotype at birth.Reference Barker2, Reference Barker3 This theoretically impacts on offspring risk for various health conditions, including hypertension, obesity, type 2 diabetes, cardiovascular disease (CVD) and later chronic kidney disease (CKD).Reference Langley-Evans4
Globally, CKD has been recognized as a major NCD.Reference Couser, Remuzzi, Mendis and Tonelli5 A substantial body of evidence indicates that proteinuria, hypertension and CKD in adulthood have childhood antecedents, beginning as early as in utero and prenatally.Reference Ingelfinger, Kalantar-Zadeh and Schaefer6 Nephrogenesis in humans begins at 9 weeks gestation and is completed by approximately 36 weeks gestation, after which time, no further mature nephrons are formed.Reference Bertram, Douglas-Denton, Diouf, Hughson and Hoy7, Reference Dressler8 Therefore, an adverse intrauterine environment at the beginning of life impacts on nephrogenesis, predisposing an individual to an increased risk of subsequent hypertension and renal disease.Reference Brenner, Garcia and Anderson9–Reference Dorey, Pantaleon, Weir and Moritz11 The remaining glomeruli have to maintain normal fluid and electrolyte balance, leading to glomerular hyperfiltration.Reference Brenner, Garcia and Anderson9 Over time, glomerular hypertrophy occurs, followed by maladaptive modifications and eventually leading to glomerulosclerosis.Reference Brenner, Garcia and Anderson9 These adaptations increase the risk of subsequent development of hypertension, impaired kidney function and end-stage renal disease (ESRD) in adulthood, a process termed the ‘Brenner hypothesis.’Reference Brenner, Garcia and Anderson9 This emphasizes the importance of the intrauterine environment for supporting optimal kidney development and function.Reference Luyckx, Perico and Somaschini12
The association between an intrauterine environment characterized by hyperglycemia and later renal disease has been investigated extensively in animal models,Reference Tran, Chen and Chenier13–Reference Chen, Chenier and Tran15 where maternal hyperglycemia is associated with reduced nephron number, raised blood pressure, microalbuminuria and diminished glomerular filtration rate (GFR) in offspring. Tran et al. reported that neonatal offspring (sex not specified) of pregnant mice with severe diabetes (blood glucose concentration ∼30 mM) have an increased risk of congenital malformations and impaired nephrogenesis, leading to smaller kidneys with reduced nephron endowment.Reference Tran, Chen and Chenier13 Similarly, Chen et al. reported that neonatal offspring (both male and female) of diabetic female mice had on average 40% fewer nephrons, compared with offspring of non-diabetic mice.Reference Chen, Chenier and Tran15 These offspring developed hypertension and impaired glucose tolerance and showed signs of renal dysfunction (i.e., microalbuminuria) in adulthood.Reference Chen, Chenier and Tran15 This indicates that exposure to intrauterine hyperglycemia is associated with impaired renal function.
Maternal overweight/obesity is an additional risk factor for developing gestational diabetes mellitus (GDM). Although the majority of studies examining fetal programming of renal disease in adulthood focus on fetal undernutrition, it is apparent that maternal obesity during pregnancy also poses a significant risk to offspring health and wellbeing. Researchers have attempted to model the effects of maternal human obesity in pregnant rats, mostly by feeding a high-fat, high-fructose, typical ‘Western’ diet.Reference Khan, Taylor and Dekou16, Reference Taylor, Khan and Lakasing17 Numerous animal studies have demonstrated that maternal over-nutrition, which leads to maternal obesity, alters nephrogenesis, and increases markers of fibrosis and glomerulosclerosis in offspring kidneys.Reference Wood-Bradley, Barrand, Giot and Armitage18–Reference Glastras, Chen and McGrath21 Male Sprague-Dawley rat offspring exposed to a high-fat maternal diet in utero demonstrated increased inflammation, oxidative stress and fibrosis in their kidneys at 9 weeks of age. These are likely to accelerate the development of CKD later in life.Reference Glastras, Chen and McGrath21 These results from animal studies provide some support for the hypothesis that in humans, maternal obesity has a detrimental impact on later renal health in offspring.
While there is convincing evidence from animal studies of a link between maternal obesity and/or diabetes during pregnancy and offspring kidney structure and function, limited studies have been conducted in humans. To our knowledge, a systematic review of human studies has not yet been conducted. Given the considerable evidence that the origins of many chronic diseases can be traced back to in utero conditions, this is an extremely important issue.Reference Blumfield, Hure and MacDonald-Wicks22, Reference Blumfield, Nowson and Hure23 Understanding the relationship between maternal obesity and/or diabetes during pregnancy with offspring kidney structure and function in humans could therefore inform the development of future interventions aimed at improving maternal health and optimizing infant renal health.
Therefore, the objective of this systematic review was to synthesize the best available evidence on the relationship between maternal obesity and/or diabetes in humans during pregnancy and offspring kidney structure and function. This review considered two main questions:
1. What is known about the relationship between maternal obesity and/or diabetes in humans during pregnancy and offspring kidney structure and function?
2. What are the research gaps related to this area?
Methods
The systematic review protocol was registered on the Prospero database (CRD42016047758),24 and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement.Reference Moher, Liberati, Tetzlaff, Altman and The25
Study Identification
Literature ever published in English up to November 2017 from five relevant databases (CINAHL, Cochrane, EMBASE, MEDLINE and Scopus) were identified in a search using keywords and index terms. The search terms were divided into three groups: (1) Pregnancy/ or pregnan*.mp., Maternal, Mother*, Prenatal.mp.; (2) nutrition.mp., dietary habits.mp. or Food Habits/, food intake.mp. or Eating/, diet.mp. or Diet/, dietary supplements.mp. or Dietary Supplements/, undernutrition.mp. or Malnutrition/, overnutrition.mp. or Overnutrition/ or Nutritional Physiological Phenomena/, diabetes.mp. or Diabetes, Gestational/, Hyperglycemia, Obesity/ or obesity.mp., Weight Gain.mp. or Weight Gain/, Overweight and (3) kidney.mp. or Kidney/, nephron.mp. or Nephrons/, renal.mp. The Boolean phrase AND was used between groups and OR within groups. The results of this systematic review search were separated into two distinct papers for publication due to the number of studies identified in the search. The nutrition aspect of the maternal intrauterine environment and its association with offspring kidney outcomes has been published elsewhere.Reference Lee, Collins, Gordon, Rae and Pringle26 Therefore, the current systematic review focuses on studies investigating the association between maternal obesity and/or diabetes during pregnancy and offspring kidney structure and function in humans.
Inclusion Criteria
Types of Participants
This current review only considered human studies and all participants had to be pregnant (at any stage of gestation) at the time of the study.
Types of Studies
The study types included were experimental studies, including pre–post, pseudo-randomized controlled trials and randomized controlled trials. Observational studies, including cross-sectional studies, case–control studies and prospective and retrospective cohort studies were also considered.
Types of Exposures/Interventions
The type of exposure considered for this current review was maternal obesity and/or diabetes during pregnancy.
Types of Outcome Measures
Studies were considered for inclusion if they measured offspring kidney function and/or structure as a primary or secondary outcome. Kidney structure outcome measures in offspring were: kidney volume, kidney size, kidney mass, kidney structure, glomerular size and nephron endowment. Outcomes related to kidney function in offspring included: proteinuria, urinary albumin/creatinine, microalbuminuria, albuminuria, glomerular filtration rate, urinary protein/creatinine, urinary nephrin/creatinine and urinary sodium/potassium.
Study Selection
All studies identified were retrieved and exported to the reference management system EndNote (version X8; Thomson Reuters, New York, NY, USA). The first phase of study identification included an assessment of study inclusion based on screening of the title, abstract and description/MESH headings. Full texts were retrieved and those papers meeting all inclusion criteria were included in the final review and underwent critical appraisal of study quality and data extraction. All stages were conducted by two independent reviewers with conflicts resolved by a third reviewer who made the final decision.
Study Quality
All included studies were assessed for methodological quality using the American Dietetic Association (ADA) Quality Criteria Checklist,27 which consisted of 10 criteria to assess strength of the research design, relevance and validity. The items assessed included: the method of sample selection, methods of controlling for confounding factors, reliability of outcome measures and statistical analysis. Using this checklist, two independent reviewers rated the overall quality of the studies as positive, neutral or negative. A third reviewer was consulted to resolve differences. No studies were excluded based on quality ratings. To address publication bias, a comprehensive search of the literature was conducted in five major databases. Effort was also taken to retrieve ‘difficult to find studies’ such as utilizing the intra-university library network to request the papers from other universities and printed copies of old papers that are not available online. A meta-analysis was not possible due to the heterogeneity in measures of kidney outcome and function.
Data Extraction and Synthesis
Data extraction was conducted by one reviewer and cross-checked by a second independent reviewer for accuracy and consistency. Participant information, study design and intervention characteristics as well as data related to review outcomes were extracted. A meta-analysis of data was not expected to be possible due to the anticipated heterogeneity in maternal exposures during pregnancy and measures of kidney outcome and function. Therefore, the effect of maternal obesity and/or diabetes during pregnancy on offspring kidney structure and function was described in a narrative synthesis. A structured summary, direction of effect, the strength of the evidence for the effect and whether this was consistent across studies were highlighted in the data synthesis.
Results
Study Selection
Figure 1 illustrates the flow of studies from the initial search to inclusion in the review. The initial database search identified 9501 articles after removal of duplicates, with 8962 records excluded following title and abstract review for eligibility. Despite online inter-library searches, full texts were unavailable for 205 records. Of the 334 full-text articles retrieved, 278 articles were animal studies, with 56 articles on humans. After screening the human studies based on inclusion criteria, 37 were excluded. The primary reasons for exclusion of full-text papers were outcomes not related to offspring kidney structure or function (n=28) and exposure/intervention not related to maternal nutrition or obesity or diabetes during pregnancy (n=8). Of the remaining 19 articles, nine articles focused on maternal obesity or diabetes during pregnancy and offspring kidney outcomes and were included in this current paper.
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram of the study selection process.
Study Characteristics
Included studies (n=9) were published between 1994 and 2014 and were conducted in 12 countries including the United States of America,Reference Nelson, Morgenstern and Bennett28–Reference Hsu, Yamamoto, Henry, De Roos and Flynn30 Netherlands,Reference Bos, Aalders, van Doormaal, Martijn and Okken31, Reference Verburg, Geelhoed and Steegers32 Canada,Reference Dyck, Bingham, Lim, Jiang and Osgood33 France,Reference Abi Khalil, Travert and Fetita34 ItalyReference Cappuccini, Torlone and Ferri35 and Brazil.Reference Neves, Sgarbosa and Calderon36 The most common measures of kidney structure were kidney volume and length, while kidney function measures were albuminuria, albumin/creatinine and GFR. Two studies evaluated the relative risk of developing renal disease in later life.Reference Pavkov, Hanson and Knowler29, Reference Hsu, Yamamoto, Henry, De Roos and Flynn30 All of the studies included approximately equal number of male and female offspring. Four studies did not specify the exact numbers for each sex.Reference Pavkov, Hanson and Knowler29, Reference Bos, Aalders, van Doormaal, Martijn and Okken31, Reference Cappuccini, Torlone and Ferri35, Reference Neves, Sgarbosa and Calderon36 There was a wide range in the age of offspring at the time of assessment, from late gestation to approximately 40 years of age.
All of the included studies were observational study designs (Table 1). Seven observational studies evaluated the relationship between maternal hyperglycemia during pregnancy and offspring kidney structure and function, of which, one was a cross-sectional study,Reference Bos, Aalders, van Doormaal, Martijn and Okken31 four were prospective cohort studiesReference Pavkov, Hanson and Knowler29, Reference Dyck, Bingham, Lim, Jiang and Osgood33, Reference Cappuccini, Torlone and Ferri35, Reference Neves, Sgarbosa and Calderon36 and two were retrospective cohort studies.Reference Nelson, Morgenstern and Bennett28, Reference Abi Khalil, Travert and Fetita34 One prospective cohort study evaluated the relationship between maternal obesity and offspring kidney structure and functionReference Verburg, Geelhoed and Steegers32 and another retrospective cohort study evaluated the relationship between both maternal hyperglycemia and obesity during pregnancy and offspring kidney structure and function.Reference Hsu, Yamamoto, Henry, De Roos and Flynn30 Factors that prevented meta-analysis from being performed included the heterogeneity of outcome measures for kidney structure and function and the large variation in the age at follow-up of offspring.
Table 1 Description of observational studies: diabetes and/or obesity
GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test; IQR, interquartile range; ESRD, end-stage renal disease; IDM, insulin-dependent diabetic; InfDM+, infants of diabetic mothers; InfDM −, infants of non-diabetic mothers; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; CKD, chronic kidney disease
Risk of Bias of Included Studies
Only one studyReference Verburg, Geelhoed and Steegers32 was classified as of high methodological quality, with inclusion/exclusion criteria and demographics of subjects clearly described. In this study,Reference Verburg, Geelhoed and Steegers32 important confounding factors were accounted for by appropriate adjustments in the statistical analyses. Six (66.7%) studiesReference Nelson, Morgenstern and Bennett28, Reference Hsu, Yamamoto, Henry, De Roos and Flynn30, Reference Dyck, Bingham, Lim, Jiang and Osgood33–Reference Neves, Sgarbosa and Calderon36 were rated as of neutral quality, as it was unclear whether data collectors were blinded to study outcomes and risk factor assessments. It was also unclear whether important confounders were accounted for in statistical analyses. Two (22.2%) studiesReference Pavkov, Hanson and Knowler29, Reference Bos, Aalders, van Doormaal, Martijn and Okken31 were rated as of negative quality, as the criteria for study subject selection bias and generalizability were not met. Confounding factors were not clearly identified or taken into account in the statistical analyses, lack of participant and data collector blinding to study outcomes, and limitations were not clearly identified and discussed (Table 2).
Table 2 Results of study quality based on the American Dietetic Association quality criteriaFootnote a
NA: not applicable
a American Dietetic Association quality criteria: Relevance questions: (1) Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (NA for some Epi studies). (2) Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? (3) Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice? (4) Is the intervention or procedure feasible? (NA for some epidemiological studies); Validity questions: (1) Was the research question clearly stated? (2) Was the selection of study subjects/patients free from bias? (3) Were study groups comparable? (4) Was method of handling withdrawals described? (5) Was blinding used to prevent introduction of bias? (6) Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were intervening factors described? (7) Were outcomes clearly defined and the measurements valid and reliable? (8) Was the statistical analysis appropriate for the study design and type of outcome indicators? (9) Are conclusions supported by results with biases and limitations taken into consideration? (10) Is bias due to study’s funding or sponsorship unlikely?
b Studies were rated as ‘positive’ if they were assessed as a ‘Yes’ to all of the four ‘essential’ criteria, as follows: (1) Was selection of study subjects free from bias?; (2) Were study groups comparable?; (3) Were interventions and any comparisons described in detail?; (4) Were outcomes clearly defined and the measurements valid and reliable?; and, at least one additional ‘yes’ from the other six criteria. If six or more of the criteria were assessed as a ‘No’, the study was rated ‘negative’. Studies were rated ‘neutral’ if the majority of the 10 criteria were met, but one of the ‘essential’ criteria were not met.
Relationship Between Maternal Obesity and/or Diabetes During Pregnancy and Offspring Kidney Structure or Function
Nine observational studies investigated the effect of maternal diabetes or obesity during pregnancy on offspring kidney structure and function.Reference Nelson, Morgenstern and Bennett28–Reference Neves, Sgarbosa and Calderon36 Neves et al. found that maternal hyperglycemia in utero was associated with a higher fetal kidney volume, measured between 22–38 weeks of gestation.Reference Neves, Sgarbosa and Calderon36 The median fetal kidney volume in pregnancies affected by hyperglycemia was significantly greater than the 75th percentile kidney volume in normoglycemic pregnancies.Reference Neves, Sgarbosa and Calderon36 In a large population-based prospective cohort study of 1215 women from the Netherlands, Verburg et al. examined the association between maternal characteristics with fetal kidney volume in late pregnancy (30.4 weeks gestation).Reference Verburg, Geelhoed and Steegers32 Maternal pre-pregnancy height and weight were positively associated with fetal kidney size; however, maternal obesity (measured using pre-pregnancy Body Mass Index) and diabetes during pregnancy (pre-existing type 1 or type 2 or pregnancy-induced diabetes) was not associated with fetal kidney size. A cross-sectional study (20 infants in each group) by Bos et al. found that the kidney size of infants born to mothers with tightly controlled insulin-dependent diabetes was not different from the kidney size of healthy control infants in the first week of life.Reference Bos, Aalders, van Doormaal, Martijn and Okken31 Only kidney size was assessed in this study and kidney function was not assessed (Table 3).
Table 3 Results of observational studies: diabetes and/or obesity
UAE, urinary albumin excretion; IDE, intrauterine diabetes exposure; IDM, insulin-dependent diabetic; ACRs, albumin:creatinine ratios; EPH syndrome: increase in blood pressure, proteinuria, edema; DM, diabetes mellitus; GDM, gestational diabetes mellitus; InfDM+, infants of diabetic mothers; InfDM −, infants of non-diabetic mothers; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; CKD, chronic kidney disease; BMI, body mass index; HPW, healthy pregnant women; SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate; ESRD, end-stage renal disease; CI, confidence interval; OD, overall diabetes.
Dyck et al. measured albumin/creatinine in infants of mothers with diabetes (InfDM +: type 1 or type 2 or GDM) and infants of mothers without diabetes (InfDM −) and found that InfDM + had significantly lower albumin/creatinine than InfDM − at one day of age after other variables were adjusted for (P=0.05). However at 9 months, there was no significant difference between groups.Reference Dyck, Bingham, Lim, Jiang and Osgood33 Mean urinary albumin and urinary creatinine were also significantly higher in InfDM − neonates than in InfDM + neonates at one day of age.Reference Dyck, Bingham, Lim, Jiang and Osgood33 Cappuccini et al. found that children (measured at 3 years of age) exposed to maternal hyperglycemia in utero throughout pregnancy had significantly lower mean kidney cortex volume and higher microalbuminuria levels compared with controls.Reference Cappuccini, Torlone and Ferri35
Results from Abi Khalil et al., who compared adult offspring without diabetes (mean age 24–25 years) of mothers with type 1 diabetes during pregnancy to a control group of adult offspring of fathers with type 1 diabetes, found reduced renal function in the former group, as measured by GFR, mean arterial pressure, renal plasma flow and renal vascular resistance, which was thought to be a consequence of a reduction in glomerular number, leading to hyperfiltration.Reference Abi Khalil, Travert and Fetita34
Two epidemiological studies focused on the Gila River Pima Indian population with type 2 diabetes (offspring aged 12–77 years old).Reference Nelson, Morgenstern and Bennett28, Reference Pavkov, Hanson and Knowler29 Nelson et al. found that offspring with type 2 diabetes who were exposed to diabetes in utero (mother had pre-existing diabetes at the time of pregnancy or developed it during pregnancy) had a higher risk of developing albuminuria in adulthood, a key marker of renal disease.Reference Nelson, Morgenstern and Bennett28 Elevated urinary albumin excretion (UAE) was found in 58% of offspring (mean age 24±9 years old) born to mothers with diabetes during pregnancy, 43% of offspring (mean age 38±10 years old) from mothers who developed diabetes after pregnancy and 40% of offspring (mean age 44±15 years old) from mothers without diabetes.Reference Nelson, Morgenstern and Bennett28 The odds of elevated UAE were almost four times higher among offspring exposed to diabetes in utero. Reference Nelson, Morgenstern and Bennett28 In the same population (Gila River Pima Indian population with type 2 diabetes), Pavkov et al. found that intrauterine diabetes exposure was associated with a four-fold increase in the incidence of ESRD in young adults (median age 26.7 years old).Reference Pavkov, Hanson and Knowler29
One large population-based, case–control study of 1994 patients with childhood CKD (<21 years of age at diagnosis) and 20,032 controls found that maternal pre-gestational diabetes mellitus (PDM), GDM, overweight and obesity were associated with significantly increased risk of CKD in offspring at <21 years of age (19, 54, 24 and 26% increased risk, respectively, compared with the controls).Reference Hsu, Yamamoto, Henry, De Roos and Flynn30
Discussion
In the past decade, fetal exposure to maternal obesity and/or diabetes has been identified as a risk factor for the development of NCDs in offspring once they reach adulthood.Reference Ma, Chan, Tam, Hanson and Gluckman37 CKD is a major global health issue due to its high prevalence and associated risk for CVD and premature mortality.Reference Lozano, Naghavi and Foreman38, Reference Mills, Xu and Zhang39 The Global Burden of Disease Study 2013 ranked CKD as the 19th highest condition attributed to years of life lost.40 In addition, there was a 134.6% increase in deaths from 1990 directly caused by CKD.40 Minority and Indigenous groups in many developed and developing countries, including Indigenous Australians, Maori, Pacific, and Torres Strait Islanders in New Zealand and First Nation Canadians are at an increased risk of developing CKD and disease progression.Reference Nicholas, Kalantar-Zadeh and Norris41 To our knowledge, this is the first review to systematically examine the evidence for the effects of maternal obesity and/or diabetes during pregnancy on offspring kidney structure and function in humans. All of the studies included both male and female offspring, therefore limiting the sex bias evident in numerous animal studies.Reference Dickinson, Moss and Gatford42 There was a wide range in the age of offspring at the time of assessment, from late gestation to approximately 40 years of age. No age restriction was set in order to provide a comprehensive summary of evidence examining the relationship between maternal diabetes and/or obesity and offspring kidney structure and function throughout the whole lifespan. The heterogeneity of this age range meant that combining the results of separate studies in a meta-analysis was not possible.
Although the influence of maternal obesity or diabetes during pregnancy on fetal renal development has been clearly demonstrated in numerous experimental studies in large (e.g., sheep and pig) and small (e.g., mouse, rat and guinea pig) animal models,Reference Dorey, Pantaleon, Weir and Moritz11 human data on fetal programming of renal structure and function by maternal obesity or diabetes are lacking, with only nine human studies to date identified in this review. The limited evidence base related to these maternal risk factors for offspring CKD is a major knowledge gap.
Maternal Diabetes and Offspring Kidney Structure or Function
The prevalence of GDM and pre-existing diabetes (type 1 or type 2 diabetes) among young women of reproductive age is increasing, particularly in developing countries and is largely driven by obesity.Reference Kampmann, Madsen and Skajaa43–Reference Mitanchez, Yzydorczyk and Siddeek45 Pregnancies complicated by diabetes (type 1, type 2 or GDM) are associated with an increased risk of adverse outcomes, including congenital malformations, macrosomia, birth trauma and maternal preeclampsia.Reference Mitanchez, Yzydorczyk and Siddeek45 Maternal diabetes is a risk factor for large-for-gestational-age (LGA) birthweightReference Luyckx and Brenner46 and findings from population-based studies indicate a U-shaped relationship between birthweight and risk of CKD or ESRD.Reference Lackland, Bendall, Osmond, Egan and Barker47, Reference Vikse, Irgens, Leivestad, Hallan and Iversen48
In rat models, exposure to hyperglycemia in utero impairs nephrogenesis, leading to reduced nephron numbersReference Amri, Freund, Vilar, Merlet-Benichou and Lelievre-Pegorier49 and alterations in insulin-like growth factor (IGF) and IGF receptor expression in fetal kidneys.Reference Amri, Freund, Duong Van Huyen, Merlet-Benichou and Lelievre-Pegorier50 Maternal hyperglycemia strongly affects the developing metanephros, leading to increased apoptosis in tubules and podocytes, thus increasing the risk of renal agenesis and dysgenesis.Reference Tran, Chen and Chenier13 Five studies found that exposure to a hyperglycemic intrauterine environment contributed to reduced renal function as measured by GFR, mean arterial pressure, renal plasma flow, renal vascular resistance and microalbuminuria and an increased risk of offspring CKD at ages ranging from 3 to 45 years.Reference Nelson, Morgenstern and Bennett28–Reference Hsu, Yamamoto, Henry, De Roos and Flynn30, Reference Abi Khalil, Travert and Fetita34, Reference Cappuccini, Torlone and Ferri35 Therefore, offspring exposed to hyperglycemia in utero could acquire a nephron deficit during nephrogenesis, which may influence the rate of progression of chronic renal diseaseReference Jones, Bilous, Flyvbjerg and Marshall51 and hypertension in adulthood.Reference Chen, Chenier and Tran15, Reference Fetita, Sobngwi, Serradas, Calvo and Gautier52 Additional longitudinal human cohort studies are warranted to further substantiate these findings.
Neves et al. reported that offspring exposed to hyperglycemia throughout pregnancy have significantly larger fetal kidney volumes, measured in the third trimester.Reference Neves, Sgarbosa and Calderon36 On the contrary, Verburg et al. found in a population-based cohort that maternal diabetes (pre-existing type 1 or type 2 or pregnancy-induced diabetes) did not influence fetal kidney volume in late pregnancy.Reference Verburg, Geelhoed and Steegers32 Cappuccini et al. found that there were lower mean renal cortex volumes and higher levels of microalbuminuria in 3-year-old children of diabetic mothers.Reference Cappuccini, Torlone and Ferri35 Human maternal diabetes is normally associated with LGA as a result of organomegaly and increased fat deposition in the fetus.Reference Ben-Haroush, Chen, Hadar, Hod and Yogev53 One possible explanation is that maternal hyperglycemia leads to fetal hyperinsulinemia. As insulin is a regulator of cell growth,Reference Hill, Petrik and Arany54 it provides a stimulating environment for fetal organomegaly. Kidney volume can be used as a surrogate clinical indicator of nephron number, where lower volumes possibly represent kidneys with reduced nephron numbers.Reference Nyengaard and Bendtsen55, Reference Abitbol and Ingelfinger56 Furthermore, an inverse relationship between renal size and the incidence of hypertensionReference Keller, Zimmer, Mall, Ritz and Amann57–Reference Singh, White and Hoy59 or renal function has been reportedReference Widjaja, Oxtoby and Hale60–Reference Kariyanna, Light and Agarwal62 in adulthood. Increase in kidney size due to overgrowth of the proximal tubule and glomerular hypertrophy can also be seen in adults with diabetes as a result of renal hyperfiltration.Reference Christiansen, Gammelgaard, Frandsen and Parving63–Reference Rigalleau, Garcia and Lasseur66 To the best of our knowledge, these are the only three studies to date that have assessed fetal kidney or kidney cortex volume in late pregnancy or in early childhood in offspring exposed to maternal hyperglycemia, thus further investigation to elucidate these relationships is warranted.
Maternal Obesity and Offspring Kidney Structure or Function
In the United States and United Kingdom, there are an increasing number of women of childbearing age being classified as being overweight or obese.Reference Thangaratinam, Rogozinska and Jolly67 This is a major concern as over-nutrition and obesity during pregnancy are associated with worse fetal health outcomes and an increased risk of morbidity and mortality from chronic diseases, such as heart disease, stroke and hypertension.Reference Reynolds, Allan and Raja68–Reference Guo, Wu, Chumlea and Roche71 From this review, only two studies investigated the relationship between maternal obesity during pregnancy and offspring renal health.Reference Hsu, Yamamoto, Henry, De Roos and Flynn30, Reference Verburg, Geelhoed and Steegers32 Exposure to an obesogenic intrauterine environment increased the risk of childhood CKD in these offspring.Reference Hsu, Yamamoto, Henry, De Roos and Flynn30 Maternal pre-pregnancy weight was positively associated with fetal kidney volume in late pregnancy, however, maternal obesity (measured using pre-pregnancy body mass index) was not associated with fetal kidney volume. Much of our understanding of the effect the maternal obesity has on offspring kidney outcomes has come from animal models.Reference Flynn, Alexander, Lee, Hutchens and Maric-Bilkan72, Reference Jackson, Alexander and Roach73 A study in rats demonstrated that offspring of obese mothers (fed a maternal diet high in fat and fructose) had glomerulosclerosis and reduced kidney function (increased urine albumin excretion).Reference Jackson, Alexander and Roach73 Maternal obesity can therefore have deleterious programming effects on the fetal kidney, however, there are limited studies and evidence assessing this in humans. In particular, there is a gap in research and knowledge pertaining to nephron development in infants born to mothers with obesity, which urgently warrants further investigation.
Strengths and Limitations
Strengths of this systematic review include: (1) a comprehensive search strategy across five databases with no date or age restrictions, (2) detailed data extraction allowing comparison between studies, (3) assessment of methodological quality in line with the PRISMA statement and (4) development of and adherence to an evidence-based protocol registered with PROSPERO. However, the current review also has limitations that need to be acknowledged. One limitation is the failure to include studies published in languages other than English, and articles that were not published at the time of review article search. An additional limitation is the large amount of heterogeneity between studies, particularly with regard to offspring age at follow-up, outcome measures of kidney function and the variability of cohorts studied. The majority of studies were rated as being of neutral or negative quality, thus the results should be interpreted with caution.
Implication for Practice
Women should be screened early to identify GDM and be treated appropriately relative to diagnosis. This will not only improve maternal health outcomes but might also improve long-term kidney health outcomes in offspring. From the current review, it was found that exposure to maternal hyperglycemia and/or obesity could potentially affect kidney growth, kidney function in terms of GFR and microalbuminuria, and increase the risk of CKD. This indicates the importance of developing clinical strategies and public health policies for screening and managing women with diabetes during pregnancy, especially in low-income and developing countries, and in populations where the burden of maternal diabetes is higher. Maternal overweight/obesity is an additional risk factor for developing diabetes. Therefore, ensuring an adequate maternal diet before and during pregnancy by eating a varied, balanced diet as well as maintaining a healthy bodyweight and/or appropriate gestational weight gain are vital steps in preventing GDM.
Implications for Research
Overall, the number of human studies investigating the DOHaD hypothesis from a kidney health perspective is relatively small, despite increasing interest in this area of research. By gaining more insight into the various adverse intrauterine environments under which kidney disease may develop and the pathophysiological mechanisms involved, we may be able to identify and develop new treatment/intervention strategies to alleviate the progression to chronic renal disease. There are a number of key issues that should be addressed in future research investigating the relationship between maternal diabetes or obesity and offspring kidney structure and function. These are:
1. High-quality longitudinal studies with longer follow-ups beyond childhood;
2. There is a need for consistent measurements of common indicators of renal development and function in the offspring, such as fetal kidney volume, GFR and albuminuria, and at similar offspring follow-up time points to facilitate meta-analysis of results across studies.
Conclusion
This systematic review critically evaluated the current evidence examining the association between maternal obesity and/or diabetes during pregnancy and offspring kidney structure and function in humans. The included studies were primarily observational (cohort studies), providing a low level of evidence to which causality cannot be applied. Across the limited studies to date, the measurement of offspring kidney outcomes was diverse. There was also a lack of consistency in the follow-up time-points at which offspring kidney structure and/or function were assessed, thus limiting comparability between studies. However, if studies are considered collectively, the evidence suggests a detrimental renal programming effect on offspring renal function due to exposure to maternal diabetes and/or obesity during pregnancy, reinforcing the concept of fetal programming of adult disease, which is consistent with the results from animal studies.Reference Amri, Freund, Vilar, Merlet-Benichou and Lelievre-Pegorier49 Further comprehensive longitudinal studies that assess common offspring kidney outcome measures are required to evaluate the relationship between hyperglycemia and/or maternal obesity during pregnancy, with renal programming in the offspring.
Acknowledgments
The authors wish to thank Debbie Booth, Faculty Librarian, University Library, the University of Newcastle for providing assistance with the literature search. Also, the authors wish to thank Rebecca Williams for assistance with identification of eligible and included studies.
Financial Support
Y.Q.L. is supported by a Susan Alberti PhD Scholarship, K.G.P. is supported by an ARC Future Fellowship (FT150100179) and C.E.C. is supported by an NHMRC Senior Research Fellowship and a Faculty of Health and Medicine Gladys M Brawn Senior Fellowship.
Conflicts of Interest
None.
Transparency Declaration
The lead author affirms that this manuscript is an honest, accurate and transparent account of the study being reported, that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and registered with) have been explained. The reporting of this work is compliant with CONSORT/STROBE/PRISMA guidelines.
