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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 55  |  Issue : 3  |  Page : 303-307
Glomerulogenesis: Can it predict the gestational age? A study of 176 fetuses


Department of Pathology, KLE University's Jawaharlal Nehru Medical College, Belgaum, Karnataka, India

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Date of Web Publication29-Sep-2012
 

   Abstract 

Background: Accurate assessment of gestational age of fetuses is essential from both clinical and medico-legal point of view. Crown-rump length, crown-heel length, foot length, and the weight of the fetus are the commonly used parameters for fetal age assessment. However, this estimate often lacks accuracy and sometimes is necessary to combine other data. An analysis of the embryological development of nephrons in the kidney can assist in this determination. Objective : To correlate the gestational age with the histological study of sequential development of nephrons in fetal kidney. Materials and Methods: This study included 176 fetuses delivered between June 2009 and June 2011 and aged from 12 to 40 weeks. The number of glomerular generations counted in hematoxylin and eosin-stained microscopic sections of the kidneys were correlated with the reported period of gestation based on obstetrical methods. Regression analysis was used to determine the statistical significance of the correlation. Results: A high degree of statistically significant correlation was observed between the period of gestation and the number of glomerular generations (P value < 0.0001). Conclusion: The histological assessment of the number of glomerular generations in kidney can be used as a reliable method of estimating fetal age.

Keywords: Fetal autopsy, fetus, gestational age, glomerular generations

How to cite this article:
Chikkannaiah P, Roy M, Kangle R, Patil PV. Glomerulogenesis: Can it predict the gestational age? A study of 176 fetuses. Indian J Pathol Microbiol 2012;55:303-7

How to cite this URL:
Chikkannaiah P, Roy M, Kangle R, Patil PV. Glomerulogenesis: Can it predict the gestational age? A study of 176 fetuses. Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Aug 20];55:303-7. Available from: http://www.ijpmonline.org/text.asp?2012/55/3/303/101734



   Introduction Top


Accurate assessment of the gestational age (GA) is fundamental to counseling a couple and planning appropriate perinatal care in subsequent pregnancies especially in circumstances like malformed fetus or recurrent abortions. GA estimation has medico-legal implications too, especially in cases of criminal abortion, alleged infanticide, and in medical termination of pregnancy. [1] The parameters commonly used for the GA estimation include fetal weight, crown rump length, crown heel length, foot or hand length. [2],[3] However, this estimate often lacks accuracy and requires substantiation by other data. In recent times, the histology of the embryological development of various organs has been studied and attempted to correlate with the gestational age. [4] Hence, this study was undertaken to correlate the GA with the histological study of the sequential development of glomerulus in fetal kidneys.


   Materials and Methods Top


The study was conducted in the Department of Pathology at a Medical College and Teaching Hospital on 176 fetuses of both sexes, aged between 12 and 40 weeks, and delivered from June 2009 to June 2011. The fetuses submitted for autopsy included stillborn and malformed fetuses (excluding renal anomalies) which were detected by routine ultrasound examination and the pregnancy terminated after obtaining the consent of the parents. Separate written consents were also obtained from the parents prior to the fetal autopsy. As maternal health plays an important role in fetal growth, fetal deaths encountered in pregnancies complicated by maternal gestational diabetes and hypertension were excluded from the study.

The reported gestational age of the fetuses calculated by obstetrical methods were obtained from the clinical record. Autopsy was performed as per the standard protocol. The kidneys were removed, bisected longitudinally from the lateral aspect, and bits including the full thickness cortex with adjacent medullary pyramids were fixed in 10% formalin. The kidney tissue bits, following processing and paraffin embedding, were sectioned to obtain 5 μm thick sections, taking care that the plane of cutting passed perpendicular to the glomerular generation layers. The sections were stained with routine hematoxylin and eosin stain and assessed microscopically separately by two pathologists who were uninformed of the reported clinical gestational age of the fetuses. Care was taken to avoid intra/inter observer bias. The glomeruli seen in pairs in the cortex between any two adjacent collecting tubules were counted and only those rows depicting clear and maximum number of glomerular pairs were considered for the study [Figure 1].
Figure 1: Fetal kidney of 19 weeks gestation showing six glomerular generations. (H and E, x40)

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The oldest or more mature glomeruli are located in the deeper cortex close to the juxta-medullary junction, whereas the newly formed rudimentary glomeruli form a subcapsular layer termed the nephrogenic zone. [5] Studies by various authors have established that nephrogenesis in humans begins by 7 th -8 th weeks of gestation and continues up to 34 th -36 th weeks of gestation. [2],[4],[6],[7]

The gestational age of the fetuses (in weeks) was correlated with the number of glomerular generations counted. The study was cleared by the institution ethics committee.

Statistical Analysis

Regression analysis was used to determine the correlation between the period of gestation (in weeks) and the number of glomerular generations and the probability level was estimated. Statistical Package for Social Science (SPSS) software (version 19) was employed for the statistical analysis.


   Results Top


Of the 176 fetuses included in the study, 82 were male and 94 were female fetuses. The number of glomerular generations observed in fetuses of various gestational ages is displayed in [Table 1]. Maximum numbers of fetuses (15) were in the GA of 36-40 weeks and minimum (1) in the GA of 13 weeks.

In the present study, we observed cessation of neoformation of glomerulus at 35-36 weeks of gestation. The significant correlation between the period of gestation and number of glomerular generations as determined by linear regression analysis and probability level is depicted in [Table 2]. A regression equation was developed with "a" as the correction factor and "b" as the regression coefficient. "b" is equivalent to the change in the period of gestation expected for a unit change in the number of glomerular generations. It was calculated to be 2.436, i.e. for every increase by one glomerular generation, there will be an increase in the period of gestation by approximately 2.5 weeks. When the number of glomerular generations is nil, "a" will be the period of gestation and was worked out to be 5.125. The regression showed an excellent determination coefficient (R2 = 0.965 or 96.5%). [Table 2]
Table 1: Number of glomerular generations vs. period of gestation

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Table 2: Relationship between period of gestation and number of glomerular generations assessed by simple regression analysis

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The relationship between the number of glomerular generations and the average gestational age (in weeks) in the present study is summarized in [Table 3]. A scatter diagram has been plotted depicting the same relationship for ready reference by pathologists for calculating fetal age [Figure 2].
Figure 2: Scatter gram depicting relationship between the number of glomerular generations and period of gestation

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Table 3: Number of glomerular generations in relation to gestational age in weeks

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   Discussion Top


The World Health Organization defines fetal death as "Death before the complete expulsion or extraction from the mother of a product of human conception, irrespective of the duration of pregnancy that is not an induced termination of pregnancy." Fetal deaths are further subdivided into "early" (20-27 weeks' gestation) and "late" (≥28 weeks' gestation). Fetuses that die in utero before 20 weeks' gestation are categorized specifically as miscarriages. [8]

Determination of fetal age at autopsy has important clinical, legal, and ethical implications. When encountered with a malformed fetus or recurrent abortions, knowledge of the fetal age becomes essential in guiding future parental and obstetric decision making.[9],[10] With regards to the law, establishing fetal age is a critical step while assessing the viability of the fetus in order to qualify a homicide in court. The World Health Organization has set the viability threshold at 20 weeks of gestation. [11]

The methods most commonly employed for gestational age assessment revolves around various anthropometric measurements, namely fetal weight, crown-rump length, crown-heel length, foot length and hand length. [2],[3],[12] And regression formulas have been derived by several investigators. [1],[13]

Hadlock [14] observed that in early pregnancy the most accurate fetal age estimate is derived from the crown rump length. Munro [15] claimed fetal length and appearance of ossification centers to be the best criteria for gestational age assessment. Multiple anatomic and ultrasound studies have established the significant correlation between foot length and fetal age. [1],[16],[17],[18],[19] The radiological method of determination of gestational age from the diaphyseal lengths of long bones studied by several authors [20],[21],[22] have been validated by Adalian et al. [13] as an important growth index for gestational age assessment at autopsy.

The biometric methods of fetal age estimation, although quite good and easy, give wide confidence intervals for period of gestation. Moreover, some methods suffer from a lack of reliability. [11]

In recent times, several authors have studied the embryological development of the fetal viscera, notably lungs, brain, skin, kidney and attempted to correlate with the fetal age since these organs show definite qualitative and quantitative changes during development. [2],[4], [23],[24],[25],[26],[27],[28]

Emery and Mithal [23] developed a simple method of estimating the gestational age from the radial alveolar count, i.e. the number of alveoli crossed by an imaginary straight line drawn from the center of a terminal bronchiole to the nearest pleural surface of the fetal lung. However, this method requires a pleural section parallel to the bronchiolar tree and the radial alveolar count is exponentially related to gestation only after 18 weeks. [24] Moreover, maternal hypertensive disease can hasten lung maturity, thereby limiting the utility of lungs in fetal age estimation in this condition. [11] A large study by Chi et al. [25] of 507 fetal brains validated and provided pictorial documentation of the pioneering approach by Larroche [26] of estimating gestational age from the brain gyration pattern, particularly between the 20 th and the 36 th week of gestation. The surface of the brain is smooth at 20 weeks gestation, and thereafter, secondary gyri progressively develop. Although gyral and sulcal development is usually unaffected by conditions causing intrauterine growth retardation, nevertheless susceptibility of brain to early autolysis often makes study impossible. [29] Ersch and Stallmach [28] studied 250 skin samples and illustrated the patterns of development of skin that are strongly related to fetal age, easily recognizable, and not affected by intrauterine malnutrition. However, the patterns of skin development vary by site, with a range of 1-2 weeks in different regions of the body, and usually give a rough estimate of the gestational age.

Piercecchi-Marti et al. [11] in a study on 448 fetuses demonstrated that skin and adrenal gland are very good parameters to determine the GA around 20 weeks. They also derived regression formula for three organs, namely kidney, brain and, lung and suggested to combine both histological and anthropometric data to determine fetal age as accurately as possible.

The development of human kidney is a complex process.[5] Three slightly overlapping urinary system develops from the intermediate mesoderm in a cranial to caudal sequence during intrauterine life: the pronephros which is vestigial, the mesonephros which functions briefly but mostly disappears, and the metanephros which forms the permanent kidney. The metanephros or definitive kidney develops from two sources: the metanephric mesoderm and the ureteric bud that develops into the excretory system and collecting system respectively. The ureteric bud undergoes rapid series of dichomotous branching, penetrates the metanephric mesoderm, and induces nephrogenesis. [30] Nephrogenesis in humans begins by 7th-8th weeks of gestation. [6],[30] The developing renal cortex has unique temporal and spatial features of organization. Each generation of nephrons, most easily observed histologically by the glomeruli, forms a layer over the preceding generation. The mature glomeruli are located in the deeper cortex near to the medulla whereas the newly formed rudimentary glomeruli form the subcapsular nephrogenic zone. [5],[31] According to Carlotti et al., [6] nephrogenesis is completed by 32nd-34th week of gestation. However, Fujikura and Froehlich [32] , Nash and Edermann [7] , and Lizardo-Daudt et al. [4] observed that formation of new glomeruli ceases at 35 weeks of gestation. Our findings agree with the aforementioned observations. Individual variation exists and fetuses of the same age may differ by one row of mature glomeruli. [3] Kumar and Pillay. [2] and Piercecchi-Marti et al. [11] in their respective studies noted significant correlation between fetal age and number of glomerular generations. The method of estimation of gestational age from the sequential development of the nephrons is well established and our article reiterates the fact.

The definitive and morphologically distinctive sequential developmental pattern of the glomerulus, commencing as early as 7th-8th week of gestation and continuing up to 35-36 weeks of gestation, makes the fetal kidneys excellent viscera for estimation of period of gestation. Histological examination of the kidney has the added advantage of being still recognizable in cases of advanced maceration, thereby being very useful in fetal age determination for forensic purposes. [11]


   Conclusion Top


The histological assessment of the sequential development of glomerulus in the fetal kidney can be used as a reliable method of estimating gestational age. In practice, the forensic pathologist must substantiate anthropometric data with histological data in order to estimate fetal age with high level of precision.


   Acknowledgments Top


To Mr. Mallapur, Professor, Department of Community Medicine, for his valuable help in the statistical analysis. Presentation at a meeting: APCON 2011 at Government Medical college, Patiala, Punjab, India on 03 December 2011.

 
   References Top

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Correspondence Address:
Panduranga Chikkannaiah
Department of Pathology, KLE University's Jawaharlal Nehru Medical College, Belgaum - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.101734

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