Marilza Vieira Cunha Rudge, Christiane Maria Moreira Gomes Iracema de Mattos Paranhos Calderon, Maria Delgi Ramos Joelcio Francisco Abbade, Marcus Guazzelli Mauricio de Oliveira Marcia Guimarães da Silva
Original Article
INTRODUCTION
Intrauterine growth retard (IUG R) continues to be a significant perinatology problem at the end of this century. The nature of the etiologic agent, the time when the attack occurred during pregnancy and its duration affect the type of IUG R.1
Experimental research carried out in Botucatu (Brazil) has demonstrated that fetuses with IUG R are o b ta ine d using mo d e ls o f p ro te in-c a lo rie malnutrition,1-7 of maternal arterial hypertension8-10 and of severe maternal diabetes.11-15 Placental weight is lower in protein-calorie malnutrition1 6 and in the presence of renovascular arterial hypertension,8,9 but in spo nta neo usly hypertensive ra ts (SHR) the placental weig ht o f newbo rn rats with IUG R is identical to that of the normal young of appropriate weight.1 0
An interesting aspect has been observed in the model of diabetes and pregnancy in rats: the same placental weight and histopathological aspects are asso ciated with o ppo site deviatio ns in fetal growth, i.e. macrosomia in moderate diabetes and IUG R in severe diabetes.11-13
A more in-depth study of the placenta and pa nc re a s o f ne wb o rn ra ts ha s pe rmitte d the understanding o f the deviatio ns in fetal g ro wth occurring in the presence of moderate and severe
Study of the e volution of the place nta and fe tal
pancre as in the pathophysiology of growth
re tardation
intraute rine due to re stricte d mate rnal die t
Discipline of Obstetrics, Faculdade de Medicina de Botucatu, UNESP, Botucatu, Brazil
ABSTRACT
Contex t: Intrauterine growth retard (IUG R) continues to be a significant perinatology problem at the end of this century. The nature of the etiologic agent, the time when the attack occurred during pregnancy and its duration affect the type of IUG R.
O bjective: To study the evo lutio n o f fetal pancreas and placenta between the 1 8 th and 2 1 st day o f preg nancy in rats submitted to maternal pro tein-calo rie restrictio n.
Design: Rando miz ed co ntro lled trial o n labo rato ry animal.
Sa m ple: Fo rty-o ne no rmo g lycemic preg nant W istar rats.
Intervention: Rats were divided into six experimental
g ro ups acco rding to their access to fo o d and date o f cesarean sectio n (1 8 th o r 2 1 st day): co ntro l with free access to fo o d; diet restricted to 2 5 % intro duced o n 1 st day o f preg nancy; and diet restricted to 2 5 % after the 3 rd day o f preg nancy.
M a in m ea surem ents: N ewbo rn weig ht, placenta
weig ht, histo patho lo g ical study (mo rpho lo g ical histo chemistry)
Results: Ma te rna l pro te in-c a lo rie ma lnutritio n c a use d intra ute rine g ro wth re ta rd (IUG R) a fte r the 1 8 th da y o f pre g na nc y. Die ta ry re stric tio n did no t inte rfe re with the mo rpho lo g y o f the fe ta l pa nc re a s a nd the
immuno histo c he mic a l study o f the pla c e nta sho we d tha t g lyc o g e n sto re s we re de c re a se d b e twe e n the 1 8 th a nd 2 1 st da y in the c o ntro l g ro up a nd in a die t re stric te d to 2 5 % fro m the first da y o f pre g na nc y. Die ta ry re stric tio n a fte r the 3 rd da y o f pre g na nc y le d to lo w pla c e nta l g lyc o g e n c o nc e ntra tio ns o n the 1 8 th da y a nd disa ppe a ra nc e o n the 2 1 st da y.
Conclusion: The patho physio lo g y o f IUG R due to maternal pro tein-calo rie restrictio n in rats is related to lo wer placental weig ht and lo w placental g lyco g en sto res.
diabetes. Calderon et al.1 4 demonstrated that the placentas of newborn rats with moderate diabetes presented an evo lutio n o f glyco gen co mpo sitio n similar to that o f the yo ung o f no rmal rats, i.e. glycogen was present on the 18th day of pregnancy and disappeared by the 2 1 st day. Newborn rats with severe diabetes showed increased glycogen deposition in the placenta from the 1 8 th to the 2 1 st day of pregnancy. Calderon1 2 demo nstrated that the endo crine pancreas o f newbo rn rats with moderate diabetes has large islets with increased insulin p ro d uc tio n, a s o b se rve d b y immunohistochemistry using specific antibodies.
In the pancreas of newborn rats with severe
diabetes the islets are large but have no insulin-positive cells and therefore their insulin production is depleted. Since moderate diabetes is a model of fetal macro so mia, we may infer that maternal hyperg lycemia causes fetal hyperg lycemia and hyperinsulinism. This leads to the removal of glycogen depo sited in the placenta which, co nverted into energy, increases the weight o f newbo rn rats. In severe diabetes, a IUG R model, severe maternal hyperglycemia causes intense fetal hyperglycemia leading to depletion of fetal pancreatic function. The lack of insulin production by the fetal pancreas at the end of pregnancy does not permit the removal of glycogen stores from the placenta and the fetus does not grow in an adequate manner.
The use of a restricted diet for the treatment of diabetic rats1 3 showed that non-diabetic pregnant control rats had IUG R, a fact previously observed by o thers.6 ,7 Do ubt remained as to whether the physiopathological mechanism of intrauterine growth retardation due to the restricted diet is similar to that observed in diabetic rats. Study of the evolution of the fetal pancreas and of the placentas of normal pregnant rats submitted to a restricted diet, which has proved to be a model for IUG R,1 7 would permit the evaluation of this physiopathology.
The g e ne ra l o b je c tive o f the p re se nt investigation was to study the physiopathology of intrauterine growth retardation in fetuses in pregnant rats submitted to protein-calorie malnutrition, on the
Figure 2 - Mean weight of the placentas from the control groups, the group submitted to dietary restric-tion from the 1st day and the group submitted to di-etary restriction after the 3rd day of pregnancy, as determined on the 18th and 21st days of pregnancy. Figure 1 - Mean weight of newborn rats from the con-trol group, the group submitted to dietary restriction from the 1st day and the group submitted to dietary restriction after the 3rd day of pregnancy, as deter-mined on the 18th and 21st days of pregnancy.
basis of evolution of the placenta and of the fetal pancreas. Specific objectives were: a) analysis of the pla c enta s o n the 1 8 th a nd 2 1 st da ys o f pregnancy in terms o f weight, mo rpho lo gy and c o mp o sitio n o f g lyc o g e n d e p o sits, a nd b ) morphologic analysis of the pancreas of newborn ra ts o b ta ined o n the 1 8 th a nd 2 1 st da ys o f pregnancy.
METHODS
The stud y w a s c o nd uc te d o n 4 1 no rmo g lycemic preg nant W istar rats supplied by the central animal ho use o f the Bo tucatu Campus, UN ESP.
After pregnancy was co nfirmed,1 1 the rats w e re a ssig ne d a t ra nd o m to the fo llo w ing experimental groups according to the diet used and the gestational age at the time of resolution , i.e. the 1 8 th o r 2 1 st day:
1 ) co ntro l g ro up receiving a standard diet ad libitum and submitted to cesarean sectio n o n the 1 8 th day (n = 7 );
2 ) co ntro l g ro up receiving a standard diet ad libitum and submitted to cesarean sectio n o n the 2 1 st day (n = 1 0 );
3 ) g ro up submitted to a restricted diet intro duced o n the 1 st day o f preg nancy and to cesarean sectio n o n the 1 8 th day (n = 6 );
4 ) g ro up submitted to a restricted diet intro duced o n the 1 st day o f preg nancy and to cesarean sectio n o n the 2 1 st day (n = 6 );
5 ) g ro up submitted to a restricted diet intro duced o n the 3 rd day o f preg nancy and to cesarean sectio n o n the 1 8 th day (n = 6 ).
6 ) g ro up submitted to a restricted diet intro duced o n the 3 rd day o f preg nancy and to cesarean sectio n o n the 2 1 st day (n = 6 ).
Calculatio n o f fo o d ingestio n. The calculatio n o f dietary restrictio n to 2 5 % o f no rmal was based o n the mean weekly ingestio n calculated as g/ 1 0 0 g rat weight co mpared to the gro up receiving a diet ad libitum.1 3
N ewbo rn weig ht. After removal of the uterus and separation of the placenta, newborn rats were weighed and classified as small (SG A), appropriate (AG A) and large (LG A) for gestational age of 1 8 and 2 1 days as co mpared to the mean a nd Standard for the control group.1 1
Histopathology. The placentas were separated from their membranes, weighed and processed for histo p a tho lo g ic a l stud y (mo rp ho lo g y a nd
Figure 5 - Pancreas of newborn rats obtained on the 18th day of pregnancy from the group receiving the diet ad libitum (A), the group submitted to protein-calorie restriction from the 1st day (B) and the group submitted to protein-calorie restriction after the 3rd day of pregnancy (C) - in Hematoxylin-Eosin.
histo chemistry). The material was embedded in paraffin, sectioned and stained with hematoxylin-eosin (HE). The thickness of the maternal-fetal exchange surface and the presence of cytotrophoblastic cells were scored from + to +++ according to intensity.
Histochemical analysis was performed by the p e rio d ic a c id Sc hiff (PA S) re a c tio n fo r the identification of glycogen deposits on the placental membrane on 1 8 th and 2 1 st days of pregnancy.1 4 The intensity of the PAS reaction was scored from + to +++ and compared between the 1 8 th and 2 1 st day in the experimental groups.
The fetal pancreases were resected, pooled
Ta ble 1 - Qua lita tive results of the morphologic study of pa ncrea tic islets from new born ra ts belonging to the control group a nd to the groups submitted to dieta ry restriction from the 1 st da y a nd a fter the 3 rd da y
of pregna ncy, obta ined on the 1 8 th a nd 2 1 st da ys of pregna ncy
G ro ups Islet bo rders Islet size* Q uantity o f vacuo les* Co ntro l at 1 8 th day irreg ular small/ medium ++/ +++ Co ntro l at 2 1 st day reg ular small/ medium +/ ++ Restrictio n fro m 1 st day to 1 8 th day irreg ular medium/ small +/ ++ Restrictio n fro m 1 st day to 2 1 st day reg ular medium/ small +/ ++ Restrictio n fro m 3 rd day to 1 8 th day irreg ular small/ medium +/ ++ Restrictio n fro m 3 rd day to 2 1 st day reg ular small/ medium +/ ++
* The sco res were attributed acco rding to predo minance o n the slides evaluated.
Figure 5 - Pancreas of newborn rats obtained on the 21st day of pregnancy from the group receiving the diet ad libitum (A), the group submitted to protein-calorie restriction from the 1st day (B) and the group submitted to protein-calorie restriction from the 3rd day of pregnancy (C) - in Hematoxylin-Eosin.
A B C
for each litter and processed for morphohistology. The material was stained with HE and morphology was compared between the experimental groups. Ten Langerhans islets per slide were analyzed in terms of size, borders and quantity of vacuoles in the cell cyto plasm.1 2 Size was sco red as small, medium or large, the borders were scored as regular or irregular, and the quantity of vacuoles as reduced (+), moderate (++) or intense (+++).1 1 ,1 2
Photomicrographs of the major histopathologic and histochemical features of the placentas and of the fetal pancreases were obtained.
each other, the percentage of SGA young was higher in the group submitted to dietary restriction from the 1 st day of pregnancy. O n the 2 1 st day there was a clear occurrence of retarded intrauterine growth in the young from malnourished mothers (Figure 3 ).
The pancreases of the newborn rats showed characteristics of pancreatic islet maturation that were similar for all six groups studied (Table 1 and Figures 4 and 5 ).
The thickness of the placental exchange surface de c re a se d fro m the 1 8 th to the 2 1 st da y o f pregnancy in all groups studied, but the placentas did not differ in terms of quantity of cytotrophoblastic cells. Placental glycogen stores were normal on the 1 8 th day and decreased by the 2 1 st day o f pregnancy in the control groups and in the groups with dietary restrictio n intro duced o n the 1 st day o f pregnancy. In contrast, placental glycogen stores ha d a lre a d y d e c re a se d b y the 1 8 th d a y o f pregnancy in rats submitted to dietary restriction on the 3 rd day of pregnancy (Table 2 and Figures 6 and 7 ).
DISCUSSION
Maternal pro tein-calo rie restrictio n reduces offspring size. This effect has also been reported in studies using protein-calorie malnutrition, in which g re a te r o c c urre nc e o f a b o rtio n a nd/ o r fe ta l resorption is attributed to maternal malnutrition.1 6 ,1 9 The restricted diet, reducing offspring size, is however seen to be sufficient to maintain fetal weight up to the 1 8 th day of pregnancy. This is probably due to weight and placental weight were analyzed by fully
randomized factorial analysis of variance.1 8 No n-parametric tests were used for SG A, AG A and LG A data,1 8 with calculation of the
χ
2 statistic and with level of significance set at p < 0 .0 5 for all tests.RESULTS
The 4 1 rats produced 4 7 1 young; the mean number of newborns per rat was 1 2 .9 in the control g ro up, 9 .8 in the g ro up submitted to dietary restriction from the 1 st day of pregnancy, and 1 0 .0 in the group submitted to dietary restriction after the 3 rd da y o f pre g na nc y. O n the 1 8 th da y o f pregnancy, mean newborn weight was higher in the group submitted to dietary restriction after the 3rd day. W hen pregnancy was resolved on the 21st day, fetal weight was decreased in the group of pregnant rats submitted to dietary restriction, and more intensely in the group in which restriction was started after the 3 rd day (Figure 1 ). The placentas of rats submitted to dietary restriction were larger than tho se o f the co ntro l o n the 1 8 th day o f pregnancy. At the end of pregnancy, the weight of the placentas of rats submitted to dietary restriction from the 1 st day of pregnancy was the same as the weight of control rats and higher than that of the group submitted to dietary restriction after the 3 rd day (Figure 2 ).
O n the 1 8 th day of pregnancy, no increase incidence of SG A newborn rats was observed in the restricted gro ups, co mpared to the co ntro ls. W hen the restricted groups were compared with
Ta ble 2 - Qua lita tive results of the morphometric a nd histochemica l study of the pla centa s from control ra ts, ra ts submitted to dieta ry restriction from the 1 st a nd 3 rd da ys of pregna ncy, a s determined on the
1 8 th a nd 2 1 st da ys of pregna ncy
G ro ups Cyto tro pho blastic cells* Exchang e surface thickness* G lyco g en intensity* Co ntro l at 1 8 th day +++ ++++ +++ Co ntro l at 2 1 st day +++ ++/ +++ + Restrictio n fro m 1 st day to 1 8 th day +++ ++++ +++ Restrictio n fro m 1 st day to 2 1 st day +++ +++/ ++++ + Restrictio n fro m 3 rd day to 1 8 th day +++ ++++ + Restrictio n fro m 3 rd day to 2 1 st day +++ +++ absent/ +
the vicarious action of the placenta occurring with its increased weight (Figures 1 and 2 ). The evolution of pregnancy up to the 2 1 st day shows that protein-calorie restriction is a model for IUG R (Figure 3 ) associated with decreased placental weight (Figure 2 ), confirming previous reports.6 ,7 ,1 3 ,1 7
The co rrelatio n o f fetal weight with placental weig ht has been clinically do cumented in studies e va lua ting a ppro pria te , sma ll a nd la rg e fo r g estatio nal ag e newbo rns.2 0 These investig ato rs co ncluded that in the presence o f intrauterine ma lnutritio n lo w-weig ht newb o rns ha ve sma ll placentas, sho wing a clear relatio nship between fetal nutritio n and placental weig ht. Experimental stud ie s o n ma lno urishe d ra ts thro ug ho ut pregnancy have demo nstrated lo wer birth weight, a hig her neo natal mo rtality rate, and placental damag e co nsisting o f reduced weig ht, number o f cells and pro tein amo unts.4 ,5
In the present study, between the 1 8 th and the 2 1 st day o f pregnancy the placenta sho wed a decrease in membrane thickness in all groups (Table 2 and Figures 6 and 7 ). Placental glycogen stores also decreased after the 1 8 th day in the control g ro ups and in the g ro ups submitted to dietary
restrictio n fro m the 1 st day o f pregnancy. In the groups submitted to dietary restriction after the 3 rd day of pregnancy, glycogen stores were already smaller on the 1 8 th day and disappeared by the 2 1 st day of pregnancy (Table 2 and Figures 6 and 7 ). Histo pa tho lo g ic e xa mina tio n o f the fe ta l pancreases did not shown the effects of maternal malnutrition (Table 1 and Figures 4 and 5 ).
The p re se nt re sults sho w tha t the physio patho lo g ical mechanism o f IUG R in the presence o f maternal dietary restrictio n seems to d iffe r fro m tha t o c c urring in d ia b e te s. In d ia b e te s, p la c e nta l g lyc o g e n sto re s a re no t utilized and co nverted to energ y fo r fetal g ro wth, due to the lack o f fetal insulin. The actio n o f severe ma te rna l hyp e rg lyc e mia d e p le te s the fe ta l pa nc rea s, whic h lo ses the a b ility to pro duc e insulin a t the e nd o f p re g na nc y.1 2 , 1 4 In the p re se nc e o f intra ute rine p ro te in-c a lo rie malnutritio n the fetal pancreas develo ps no rmally, d e mo nstra ting tha t insulin, the fe ta l g ro w th ho rmo ne, is no t sufficient, per se, to g uarantee appro priate fetal develo pment. Small placentas with lo w g lyco g en depo sits seem to play the mo st impo rtant ro le in the etio lo g y o f IUG R due to
Figure 6 - Placentas of rats receiving the diet ad libitum (A) and of rats submitted to protein-calorie restriction from the 1st day (B) and after the 3rd day of pregnancy (C), obtained on the 18th day of pregnancy - in Hematoxylin-Eosin and Periodic Acid Schiff.
pro tein-calo rie malnutritio n intro duced after the 3 rd day o f preg nancy.
In the g ro ups submitted to dietary restrictio n fro m the 1 st day o f preg nancy, fetal develo pment was no rmal up to the 1 8 th day because o f the vic a rio us a c tio n o f the p la c e nta a nd o f the g lyco g en sto res. The co ntinuatio n o f maternal malnutritio n up to the 2 1 st day was asso ciated w ith d e c re a se d fe ta l w e ig ht a nd inc re a se d incidence o f intrauterine g ro wth retardatio n even tho ug h placental weig ht was maintained and g lyco g en sto res evo lved no rmally. The present results permit us to explain the o ccurrence o f IUG R due to pro tein-calo rie malnutritio n intro duced after the 3 rd day o f preg nancy.
CONCLUSIONS
Maternal protein-calorie malnutrition was the c a use o f IUG R in ra ts, w ith the fo llo w ing physiopathologic peculiarities:
1 ) when dietary restrictio n was started o n the 1 st day o f preg nancy fetal develo pment was no rmal up to the 1 8 th day because o f the vic a rio us a c tio n o f the p la c e nta a nd the
quantity o f g lyco g en sto red in the placenta. Fro m the 1 8 th to the 2 1 st day, fetal weig ht reduced, with an increased incidence o f SG A ne w b o rns w itho ut d e c re a se d sto re s o f placental g lyco g en.
2 ) W hen dietary restrictio n was started after the 3 rd d a y o f p re g na nc y, re g a rd le ss o f the vicario us actio n o f the placenta up to the 1 8 th day, fetal develo pment was impaired during the fina l p e rio d (1 8 th to 2 1 st d a y), w ith p la c e nta l w e ig ht d e c re a sing a nd the pe rc e nta g e o f SG A ne wb o rns inc re a sing . Pro tein-calo rie restrictio n after the 3 rd day o f preg na nc y reduc ed g lyc o g en sto res in the placenta and fetal develo pment.
3 ) Pro tein-calo rie malnutritio n did no t interfere with the development of the fetal endocrine pancreas.
REFERENCES
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Figure 7 - Placentas of rats receiving the diet ad libitum (A) and of rats submitted to protein-calorie restriction from the 1st day (B) and after the 3rd day of pregnancy (C), obtained on the 21st day of pregnancy - in Hematoxylin-Eosin and Periodic Acid Schiff.
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6. Trindade CEP. Repercussõ es da desnutrição intra-uterina em amino ácido s livres do cérebro : estudo em rato s recém-nascido s e jo vens. Bo tucatu: UNESP 1980. 222p. “Livre Do cência” Thesis - Faculdade de Medicina, Universidade Estadual Paulista.
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10. Peraço li JC. Hipertensão arterial e gravidez: estudo experimental em ratas espo ntaneamente hipertensas (SHR). Bo tucatu 1990. 106p. Do cto ral Thesis. Faculdade de Medicina de Bo tucatu, UNESP.
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RESUMO
Contex to: O retardo do crescimento intra-uterino (RCIU) continua sendo importante problema em perinatologia neste final de século. A natureza do agente etiológico, o período da gestação em que ocorreu o insulto e a sua duração influenciam o tipo de RCIU.
O bjetivo: Estudar a fisio pato lo g ia do retardo de crescimento intrauterino (RCIU) em ratas, deco rrente da restrição pro téico -caló rica materna, em relação à evo lução do pâncreas fetal e placenta entre o 1 8o e 2 1o dias de prenhez . Tipo de estudo:
Ensaio clínico rando miz ado em animal de labo rató rio . Pa rticipa ntes: 4 1 ratas prenhes, no rmo g licêmicas, da raça W istar.
Intervençã o: Co nstituíram-se seis g rupo s experimentais: co ntro le, co m dieta “ ad libitum” e cesárea, respectivamente, no 1 8 º e 2 1 º dias; g rupo s dieta restritiva a 2 5 % intro duz ida no 1o dia da prenhez e cesárea no 1 8o e 2 1o dias; g rupo s co m a mesma restrição , po rém iniciada no 3o dia, co m cesárea no 1 8o e 2 1o dias. Va riá veis estuda da s: O s recém-nascido s fo ram classificado s, em relação à média mais o u meno s um desvio padrão do g rupo co ntro le, em peso pequeno (PIP), adequado (AIP) e g rande (G IP) para a idade de prenhez ; as placentas fo ram pesadas e pro cessadas para estudo histo pato ló g ico , incluindo mo rfo lo g ia e histo química, e o s pâncreas fetais, para estudo mo rfo ló g ico . Resulta dos: A desnutrição pro téico -caló rica materna causo u RCIU apó s o 1 8o dia da prenhez . Antes desse perío do não o co rreu RCIU, po rque a desnutrição materna diminuiu o número da pro le e a placenta to rno u-se vicariante. A restrição alimentar não interferiu co m a mo rfo lo g ia do pâncreas fetal, e o estudo imuno histo químico da placenta mo stro u que, quando a restrição é intro duz ida no 1o dia de prenhez , o s esto ques de g lico g ênio também não so frem alteraçõ es, diminuindo entre o 1 8o e 2 1o dias, co mo na prenhez no rmal. A restrição no 3o dia curso u co m baixas co ncentraçõ es de g lico g ênio placentário no 1 8o dia e desaparecimento no 2 1o dia. Conclusã o: A fisio pato lo g ia do RCIU, deco rrente da restrição pro téico -caló rica materna em ratas, está relacio nada co m meno r peso placentário e baixo s esto ques de g lico g ênio placentário .
M arilza Vieira Cunha Rudge - Full Professor of O bstetrics
Christia ne M a ria M oreira Gom es - Underg raduate
student o f Medicine
Ira cem a de M a ttos Pa ra nhos Ca lderon - PhD
M a ria Delgi Ra m os - PhD
Joelcio Fra ncisco Abba de - Msc
M a rcus Gua zzelli M a uricio de O liveira - Resident o f G yneco lo g y and O bstetrics
M a rcia Guim a rã es da Silva - G raduate Scho o l o f Medicine o f Bo tucatu - UN ESP
Sources of Funding: CN Pq, PIBIC
Conflict of interest: N o t declared
La st received: 2 9 September 1 9 9 8
Accepted: 7 January 1 9 9 9
Address for correspondence:
