ABSTRACT:

Introduction:

Epidemiological studies have shown associations between placental measurements and perinatal and later life outcomes.

Objectives:

To report placental measurements and evaluate their association with birth weight in a Brazilian birth cohort.

Methods:

Retrospective cohort study with 958 mothers, placentas, and newborns delivered at the Ribeirão Preto Medical School Hospital, Universidade de São Paulo, Brazil, in 2010 and 2011. The information was collected from interviews, medical records, and pathology reports. The placental measurements were: weight, largest and smallest diameters, eccentricity, thickness, shape, area, and birth weight/placental weight and placental weight/birth weight ratios. We analyzed the associations between birth weight and placental measurements using multiple linear regression.

Results:

Placental weight alone accounted for 48% of birth weight variability (p < 0.001), whereas placental measurements combined (placental weight, largest and smallest diameters, and thickness) were responsible for 50% (p < 0.001). When adjusted for maternal and neonatal characteristics, placental measurements explained 74% of birth weight variability (p < 0.001).

Conclusion:

Placental measurements are powerful independent predictors of birth weight. Placental weight is the most predictive of them, followed by the smallest diameter.

Keywords:
Placenta; Birth weight; Perinatology; Anthropometry; Body weights and measures; Observational study.

RESUMO:

Introdução:

Estudos epidemiológicos demonstraram associações entre medidas placentárias, resultados perinatais e futuros.

Objetivos:

Descrever medidas placentárias e avaliar suas associações com peso ao nascer numa coorte de nascimentos brasileira.

Metodologia:

Estudo de coorte retrospectiva de 958 mães, placentas e recém-nascidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Brasil, em 2010 e 2011. As informações foram coletadas por entrevistas, prontuários médicos e laudos de patologia. As medidas placentárias foram: peso, diâmetros maior e menor, excentricidade, espessura, forma, área, relações peso ao nascer/ peso da placenta e peso da placenta/ peso ao nascer. As associações entre peso ao nascer e medidas placentárias foram examinadas por meio de regressão linear múltipla.

Resultados:

O peso da placenta foi responsável por 48% da variabilidade do peso ao nascer (p < 0,001), enquanto o conjunto de medidas placentárias (peso, diâmetros maior e menor e espessura) foi responsável por 50% (p < 0,001). Quando ajustadas pelas características maternas e neonatais, as medidas placentárias explicaram 74% da variabilidade do peso ao nascer (p < 0,001).

Conclusão:

medidas placentárias são preditores independentes do peso ao nascer. O peso placentário é o mais forte preditor dentre elas, seguido pelo diâmetro menor.

Palavras-chave:
Placenta; Peso ao nascer; Perinatologia; Antropometria; Pesos e medidas corporais; Estudo observacional.

INTRODUCTION

The placenta remains an under-researched and poorly understood human organ. It is the interface between the pregnant woman and the fetus; the source of oxygen and nutrients to the latter, so deficits in its function impair fetal development¹1. Turowski G, Tony Parks W, Arbuckle S, Jacobsen AF, Heazell A. The structure and utility of the placental pathology report. APMIS 2018; 126(7): 638-46. https://doi.org/10.1111/apm.12842
https://doi.org/https://doi.org/10.1111/... . The placenta is subject to the same intrauterine environment as the fetus; thus, maternal diseases and inadequate nutrition limit the growth of both. Consequently, understanding placental growth and function is essential to clarify the mechanisms through which different exposures affect the developing fetus²2. Gill JS, Woods MP, Salafia CM, Vvedensky DD. Probability distributions for measures of placental shape and morphology. Physiol Meas 2014; 35(3): 483-500. https://doi.org/10.1088/0967-3334/35/3/483
https://doi.org/https://doi.org/10.1088/... .

Placental measurements (PMs) have been studied as indicators of its growth and function. Epidemiological studies have shown associations between PMs and perinatal and later life outcomes³3. Cardoso V, Mazzitelli N, Veiga MA, Furlán R, Grandi C. Medidas del crecimiento placentario y su relación con el peso de nacimiento y la edad gestacional. Revisión bibliográfica. Rev Hosp Mat Inf Ramón Sardá 2012; 31(2): 69-74.. Placental weight (PW), for instance, relates to the risk of stillbirth, 5-minute Apgar score lower than 7, neonatal seizures, and ventilation for more than 3 minutes after birth⁴4. Hutcheon JA, McNamara H, Platt RW, Benjamin A, Kramer MS. Placental weight for gestational age and adverse perinatal outcomes. Obstet Gynecol 2012; 119(6): 1251-8. https://doi.org/10.1097/AOG.0b013e318253d3df
https://doi.org/https://doi.org/10.1097/... . PMs are also associated with adult diseases, namely hypertension⁵5. Barker DJP, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol 2010; 54(2-3): 525-30. https://doi.org/10.1387/ijdb.082760db
https://doi.org/https://doi.org/10.1387/... , diabetes⁶6. Forsén T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med 2000; 133(3): 176-82. https://doi.org/10.7326/0003-4819-133-3-200008010-00008
https://doi.org/https://doi.org/10.7326/... , coronary heart disease, stroke⁷7. Martyn CN, Barker DJP, Osmond C. Mothers’ pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 1996; 348(9037): 1264-8. https://doi.org/10.1016/s0140-6736(96)04257-2
https://doi.org/https://doi.org/10.1016/... , and colorectal cancer⁸8. Barker DJP, Osmond C, Thornburg KL, Kajantie E, Eriksson JG. The shape of the placental surface at birth and colorectal cancer in later life. Am J Hum Biol 2013; 25(4): 566-8. https://doi.org/10.1002/ajhb.22409
https://doi.org/https://doi.org/10.1002/... . Studies on the developmental origins of health and disease postulate that PMs signal fetal and placental adaptations to environmental insults⁹9. Barker DJ, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. Beyond birthweight: the maternal and placental origins of chronic disease. J Dev Orig Heal Dis 2010; 1(6): 360-4. https://doi.org/10.1017/S2040174410000280
https://doi.org/https://doi.org/10.1017/... .

The main PMs under investigation are weight, largest diameter, smallest diameter, thickness, eccentricity, and surface area. Each of them has a critical period of development and respond differently to negative stimuli³3. Cardoso V, Mazzitelli N, Veiga MA, Furlán R, Grandi C. Medidas del crecimiento placentario y su relación con el peso de nacimiento y la edad gestacional. Revisión bibliográfica. Rev Hosp Mat Inf Ramón Sardá 2012; 31(2): 69-74.. The surface area is proportional to the number of uterine spiral arteries available for fetal nutrition; thickness reflects the level of villous ramification; and changes in eccentricity signal uterine constraint of placental growth¹⁰10. Benirschke K, Burton GJ, Baergen RN. Placental Shape Aberrations. In: Pathology of the Human Placenta. 6th ed. Berlin: Springer-Verlag ; 2012. p. 377-93..

Small placentas are more likely to be dysfunctional, and PW is closely correlated to birth weight (BW). Studies conducted in populations from various geographic and historic backgrounds confirm such association¹¹11. Salafia CM, Zhang J, Charles AK, Bresnahan M, Shrout P, Sun W, et al. Placental characteristics and birthweight. Paediatr Perinat Epidemiol 2008; 22(3): 229-39. https://doi.org/10.1111/j.1365-3016.2008.00935.x
https://doi.org/https://doi.org/10.1111/... ^,1212. Haeussner E, Schmitz C, Von Koch F, Frank HG. Birth weight correlates with size but not shape of the normal human placenta. Placenta 2013; 34(7): 574-82. https://doi.org/10.1016/j.placenta.2013.04.011
https://doi.org/https://doi.org/10.1016/... ^,1313. Grandi C, Veiga A, Mazzitelli N, Cavalli R, Cardoso V. Placental Growth Measures in Relation to Birth Weight in a Latin American Population. Rev Bras Ginecol Obs 2016; 38(8): 373-80. http://dx.doi.org/10.1055/s-0036-1586721
https://doi.org/http://dx.doi.org/10.105... . Besides, placental to birth weight ratio (PW/BW) is an important marker of fetal growth and a proxy of placental efficiency. Other ratios of interest to estimate placental efficiency are the largest and smallest diameter to BW¹⁴14. Molteni RA, Stys SJ, Battaglia FC. Relationship of fetal and placental weight in human beings: fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reprod Med 1978; 21(5): 327-34..

Placental morphometry has been extensively explored in developed countries, where PW percentile curves have been reported¹⁵15. Thompson J, Irgens L, Skjaerven R, Rasmussen S. Placenta weight percentile curves for singleton deliveries. BJOG 2007; 114(6): 715-20. https://doi.org/10.1111/j.1471-0528.2007.01327.x
https://doi.org/https://doi.org/10.1111/... ^,1616. Wallace JM, Bhattacharya S, Horgan GW. Gestational age, gender and parity specific centile charts for placental weight for singleton deliveries in Aberdeen, UK. Placenta 2013; 34(3): 269-74. https://doi.org/10.1016/j.placenta.2012.12.007
https://doi.org/https://doi.org/10.1016/... . However, there is limited data from Latin American populations, including Brazilian ones¹³13. Grandi C, Veiga A, Mazzitelli N, Cavalli R, Cardoso V. Placental Growth Measures in Relation to Birth Weight in a Latin American Population. Rev Bras Ginecol Obs 2016; 38(8): 373-80. http://dx.doi.org/10.1055/s-0036-1586721
https://doi.org/http://dx.doi.org/10.105... ^,1717. Salge AKM, Xavier RM, Ramalho WS, Rocha EL, Coelho ASF, Guimarães JV, et al. Placental and umbilical cord macroscopic changes associated with fetal and maternal events in the hypertensive disorders of pregnancy. Clin Exp Obstet Gynecol 2013; 40(2): 198-202.^,1818. Souza M, Brizot M, Biancolin S, Schultz R, Carvalho M, Francisco R, et al. Placental weight and birth weight to placental weight ratio in monochorionic and dichorionic growth-restricted and non-growth-restricted twins. Clinics 2017; 72(5): 265-71. http://dx.doi.org/10.6061/clinics/2017(05)02
https://doi.org/http://dx.doi.org/10.606... .

The present study aimed to describe the placental morphometry of a Brazilian birth cohort and investigate its relationship with BW.

METHODS

This was an observational study conducted at the Ribeirão Preto Medical School Hospital, Universidade de São Paulo, Brazil, in 2010 and 2011. It is part of the project “Etiological factors of preterm birth and consequences of perinatal factors in child health: birth cohorts in two Brazilian cities,” known as BRISA (Brazilian Ribeirão Preto and São Luís Birth Cohort). Exclusion criteria were gestational age (GA) under 22⁺⁰ weeks or over 42⁺⁶ weeks, multiple gestation, and PW under 100 g or over 2500 g, which were considered implausible values.

Trained personnel interviewed 1067 consecutive women to trace their demographic, social, and health profile. Pediatricians examined the newborns after birth. Pathologists evaluated the placentas according to standard procedures¹1. Turowski G, Tony Parks W, Arbuckle S, Jacobsen AF, Heazell A. The structure and utility of the placental pathology report. APMIS 2018; 126(7): 638-46. https://doi.org/10.1111/apm.12842
https://doi.org/https://doi.org/10.1111/... , blinded from maternal and neonatal data. All information was collected from the interview questionnaires, medical records, and pathology reports. Education level was estimated by the years of school attendance, whereas the socioeconomic status was assessed by the occupation of the main income earner in the household¹⁹19. Olsen J, Frische G. Social differences in reproductive health. A study on birth weight, stillbirths and congenital malformations in Denmark. Scand J Soc Med 1993; 21(2): 90-7. https://doi.org/10.1177/140349489302100206
https://doi.org/https://doi.org/10.1177/... . Body mass index (BMI) was calculated using the formula weight/height². GA was calculated by the most reliable information available, either the last menstrual period or early obstetric ultrasound²⁰20. Verburg BO, Steegers EAP, De Ridder M, Snijders RJM, Smith E, Hofman A, et al. New charts for ultrasound dating of pregnancy and assessment of fetal growth: Longitudinal data from a population-based cohort study. Ultrasound Obstet Gynecol 2008; 31(4): 388-96. https://doi.org/10.1002/uog.5225
https://doi.org/https://doi.org/10.1002/... . BW was classified as very low (VLBW, < 1,500 g) and low (LBW, < 2,500 g). Weight for GA and ponderal index (weight/length³) were also assessed²¹21. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13: 59. https://doi.org/10.1186/1471-2431-13-59
https://doi.org/https://doi.org/10.1186/... ^,2222. Barker DJP, Godfrey KM, Osmond C, Bull A. The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life. Paediatr Perinat Epidemiol 1992; 6(1): 35-44. https://doi.org/10.1111/j.1365-3016.1992.tb00741.x
https://doi.org/https://doi.org/10.1111/... .

The placentas were weighed in grams on an electronic scale after cutting the cord and membranes. Length was considered the largest diameter measured with a transparent ruler in cm, whereas the diameter perpendicular to the length was defined as the smallest diameter (breadth), measured in the same way¹1. Turowski G, Tony Parks W, Arbuckle S, Jacobsen AF, Heazell A. The structure and utility of the placental pathology report. APMIS 2018; 126(7): 638-46. https://doi.org/10.1111/apm.12842
https://doi.org/https://doi.org/10.1111/... . Thickness was measured at the center of the placenta by a graduated needle, in millimeters. Eccentricity was estimated by the ratio of the largest to the smallest diameter, measuring the relative asymmetry of placental growth. Placental area (cm²) was calculated assuming an elliptical surface by the formula largest diameter × smallest diameter × π/4⁵. Placental shape was obtained by the difference between the largest and smallest diameters: A difference of 3 cm or more characterized an oval placenta, whereas a difference of less than 3 cm characterized a round placenta²³23. Winder NR, Krishnaveni GV, Veena SR, Hill JC, Karat CLS, Thornburg KL, et al. Mother’s lifetime nutrition and the size, shape and efficiency of the placenta. Placenta 2011; 32(11): 806-10. https://doi.org/10.1016/j.placenta.2011.09.001
https://doi.org/https://doi.org/10.1016/... .

PW was compared in different GA groups (22-28 weeks; 29-32 weeks; 33-36 weeks; and 37-42 weeks). Also, the placental weight Z scores of term and preterm neonates were established according to Thompson et al.¹⁵15. Thompson J, Irgens L, Skjaerven R, Rasmussen S. Placenta weight percentile curves for singleton deliveries. BJOG 2007; 114(6): 715-20. https://doi.org/10.1111/j.1471-0528.2007.01327.x
https://doi.org/https://doi.org/10.1111/... .

BW (g) to PW (g) ratio (BW/PW) indicated the adequacy of fetal nutrition²⁴24. Burkhardt T, Schäffer L, Schneider C, Zimmermann R, Kurmanavicius J. Reference values for the weight of freshly delivered term placentas and for placental weight-birth weight ratios. Eur J Obstet Gynecol Reprod Biol 2006; 128(1-2): 248-52. https://doi.org/10.1016/j.ejogrb.2005.10.032
https://doi.org/https://doi.org/10.1016/... . PW (g) to BW (g) ratio (PW/BW), a proxy of placental efficiency (“efficiency 1”), was expressed as percentage [(PW/BW) × 100]. Finally, two other measurements of placental efficiency were calculated using the ratios of length (“efficiency 2”) and breadth (“efficiency 3”) to BW²³23. Winder NR, Krishnaveni GV, Veena SR, Hill JC, Karat CLS, Thornburg KL, et al. Mother’s lifetime nutrition and the size, shape and efficiency of the placenta. Placenta 2011; 32(11): 806-10. https://doi.org/10.1016/j.placenta.2011.09.001
https://doi.org/https://doi.org/10.1016/... .

The descriptive statistics included the mean, proportion, standard deviation (SD), and 95% confidence interval (CI). Student’s t-test and analysis of variance (ANOVA) compared the means. Pearson correlation coefficients explored the relationship between PW and four outcomes of fetal growth: BW, birth length, head circumference, and ponderal index.

We found no strong correlations among the PMs, so we fitted unadjusted and multiple linear equations to explore the prediction of BW by them. The effect point estimates with 95%CI and R² were obtained. When a PM included the dependent variable (BW) as well as any other predictor, it was excluded from the adjusted models. The goodness of fit of each regression model was assessed according to Royston and Wright²⁵25. Royston P, Wright EM. Goodness-of-fit statistics for age-specific reference intervals. Stat Med 2000; 19(21): 2943-62. https://doi.org/10.1002/1097-0258(20001115)19:21%3C2943::aid-sim559%3E3.0.co;2-5
https://doi.org/https://doi.org/10.1002/... , leaving four PMs (PW, largest and smallest diameters, and disc thickness) as predictors. Three models were then defined:

Type of delivery (cesarean or vaginal) was not firstly taken into consideration because it could be a downstream consequence of maternal risk factors and placental size (e.g., preeclampsia may result in a small placenta, and fetal compromise resulting from the small placenta can increase the risk of cesarean delivery). However, since cesarean delivery could affect PW through mechanisms independent of underlying pathological processes, secondary analyses were conducted so that models could be additionally adjusted for this factor²⁶26. McNamara H, Hutcheon JA, Platt RW, Benjamin A, Kramer MS. Risk factors for high and low placental weight. Paediatr Perinat Epidemiol 2014; 28(2): 97-105. https://doi.org/10.1111/ppe.12104
https://doi.org/https://doi.org/10.1111/... .

The sample size calculation determined that 51 subjects were necessary to obtain a statistical power of 80%, with α set at 0.05 and an expected adjusted coefficient of determination (R²) of 0.40. Stata 13.0^® (College Station, Texas, USA) and SAS/STAT^® (SAS Institute Inc., Cary, NC, 2010) performed all statistical calculations, and significance was set at 0.05 level.

The presentation of research results followed the STROBE international guidelines for observational studies in epidemiology²⁷27. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. Int J Surg 2014; 12(12): 1495-9. https://doi.org/10.1016/j.ijsu.2014.07.013
https://doi.org/https://doi.org/10.1016/... .

The Research Ethics Committee approved this project (process number 11,157/2008). The women were informed about the study protocol and signed an informed consent form.

RESULTS

From the original 1067 subjects, 77 were excluded for lack of placental data, 1 for hydropic placenta, and 31 for multiple pregnancy, resulting in a final study population of 958 trios of mothers, placentas, and newborns.

Tables 1, 2, and 3 present the maternal, neonatal, and placental characteristics, respectively.

Adolescent mothers corresponded to 12.7% of the sample, while 14.6% were 35 years old or older. About half of them were white, which is compatible with the Brazilian ethnic distribution. Despite 98.3% having attended school, only 8.8% reached higher education. Most families were headed by manual workers, who have low incomes, and most women used the Brazilian public health system; only 5.7% paid for private medical care. Nearly 20% of the women did not live with a partner.

The frequency of primiparity was 39.6%. Approximately half of the women were overweight or obese. The frequencies of hypertension, diabetes, alcohol consumption, and tobacco use during pregnancy were high - 27.4, 17.3, 27.3, and 18.6%, respectively. Besides, 42.8% had cesarean deliveries (Table 1).

Mean GA was 38 weeks, and 25.6% of the births were preterm; 50.5% of the newborns were female. Mean BW was 3,047 g, 6.2% had a VLBW, and 15.6% were small for gestational age (SGA)²¹21. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13: 59. https://doi.org/10.1186/1471-2431-13-59
https://doi.org/https://doi.org/10.1186/... , which occurred with a similar frequency among term (13.5%) and preterm infants (13.8%). The mean ponderal index was 2.8 g/cm³ (Table 2).

Mean PW was 579 g, mean largest diameter was 17 cm, mean smallest diameter was 15.1 cm, and mean thickness was 2.5 cm. Mean eccentricity was 1.1, and mean surface area was 205 cm². The shape of 77.4% of the placentas was round. Mean BW/PW was 5.3, and mean PW/BW was 19.8 (Table 3). All PMs except PW/BW were consistently higher in males than females, without statistical significance (data not shown).

Correlation coefficients of PW with BW, birth length, head circumference, and ponderal index were 0.67, 0.49, 0.48, and 0.24, respectively, all statistically significant. Indices of placental efficiency showed no significance.

BW was weakly correlated with length (r = 0.464, R² = 0.215, p < 0.001), breadth (r = 0.421, R² = 0.177, p < 0.001), and placental surface area (r = 0.476, R² = 0.226, p < 0.001).

Table 4 displays the results of the regression models of BW. Model 1(unadjusted) with PW, largest diameter, smallest diameter, and thickness as single predictors had an R² of 0.48, 0.24, 0.27, and 0.02, respectively; all of them were significant at the 0.001 level. Model 2 (multivariate) considered these four PMs together as predictors, without other adjustments, and its R² was 0.50, but only the effects of PW and smallest diameter were statistically relevant. Finally, model 3 (full multivariate), which was further adjusted for maternal variables (parity, BMI before pregnancy, gestational diabetes, hypertension, and tobacco use), GA, and gender, resulted in an R² of 0.74. Again, only PW and smallest diameter had statistically relevant effects on BW in opposition to largest diameter and thickness.

In a secondary analysis conducted to explore the main results further, PMs explained 50% of BW variability among preterm births compared with 37% at term, and maternal characteristics explained 64.8% of the BW variance after adjustment for GA and gender (p < 0.001). The additional adjustment of the full model for type of delivery had a minimal impact on the R², and we found no significant association between cesarean delivery and BW.

DISCUSSION

As expected, weight, largest diameter, smallest diameter, and thickness of the placenta were positively associated with BW. In addition, four PMs explained 50% of the BW variability, yet only PW and smallest diameter showed statistical significance. After adjustment for maternal and infant factors, R² raised to 74%. This result is in agreement with previous Argentinian findings¹³13. Grandi C, Veiga A, Mazzitelli N, Cavalli R, Cardoso V. Placental Growth Measures in Relation to Birth Weight in a Latin American Population. Rev Bras Ginecol Obs 2016; 38(8): 373-80. http://dx.doi.org/10.1055/s-0036-1586721
https://doi.org/http://dx.doi.org/10.105... . In contrast, an American study with a similar methodology found that the adjustment for covariates diminished the power of association between PM and BW²⁸28. Freedman AA, Hogue CJ, Marsit CJ, Rajakumar A, Smith AK, Goldenberg RL, et al. Associations Between the Features of Gross Placental Morphology and Birthweight. Pediatr Dev Pathol 2018; 22(3): 194-204. https://doi.org/10.1177/1093526618789310
https://doi.org/https://doi.org/10.1177/... .

PW had the strongest bivariate association with BW (R² 48%). However, in the multivariate models (2 and 3), PW point estimates declined significantly from four to six times, while in the three models, the smallest diameter presented the highest BW gain for each unit (cm) increase.

The mean PW Z score was lower than that of a previous population study²⁶26. McNamara H, Hutcheon JA, Platt RW, Benjamin A, Kramer MS. Risk factors for high and low placental weight. Paediatr Perinat Epidemiol 2014; 28(2): 97-105. https://doi.org/10.1111/ppe.12104
https://doi.org/https://doi.org/10.1111/... ; this might be attributable to the high-risk population of the investigation.

Although BW was correlated with PW, Figure 1 shows a wide variation in PW for any given BW; e.g., infants weighing around 3000 g had placentas ranging from 300 to 900 g. This finding suggests a wide variation in placental efficiency, which corroborates previous data¹³13. Grandi C, Veiga A, Mazzitelli N, Cavalli R, Cardoso V. Placental Growth Measures in Relation to Birth Weight in a Latin American Population. Rev Bras Ginecol Obs 2016; 38(8): 373-80. http://dx.doi.org/10.1055/s-0036-1586721
https://doi.org/http://dx.doi.org/10.105... .

The caloric intake and dietary composition during pregnancy affect the size of the human placenta at term²⁹29. Thame M, Osmond C, Bennett F, Wilks R, Forrester T. Fetal growth is directly related to maternal anthropometry and placental volume. Eur J Clin Nutr 2004; 58: 894-900. https://doi.org/10.1038/sj.ejcn.1601909
https://doi.org/https://doi.org/10.1038/... . It is positively related to maternal BMI across the normal spectrum. In the adjusted model³3. Cardoso V, Mazzitelli N, Veiga MA, Furlán R, Grandi C. Medidas del crecimiento placentario y su relación con el peso de nacimiento y la edad gestacional. Revisión bibliográfica. Rev Hosp Mat Inf Ramón Sardá 2012; 31(2): 69-74., BMI before pregnancy was positively associated with PW; on average, PW increased 4.5 g per 1 Kg/m² increment in BMI (p < 0.001) (data not shown).

The smallest diameter was more strongly correlated to BW than the largest diameter in the three models. Other studies have also found this difference²⁸28. Freedman AA, Hogue CJ, Marsit CJ, Rajakumar A, Smith AK, Goldenberg RL, et al. Associations Between the Features of Gross Placental Morphology and Birthweight. Pediatr Dev Pathol 2018; 22(3): 194-204. https://doi.org/10.1177/1093526618789310
https://doi.org/https://doi.org/10.1177/... . Previous research has concluded that the smallest diameter is more sensitive to the pregnancy nutritional status than the largest one³⁰30. Alwasel SH, Abotalib Z, Aljarallah JS, Osmond C, Al Omar SY, Harrath A, et al. The breadth of the placental surface but not the length is associated with body size at birth. Placenta 2012; 33(8): 619-22. https://doi.org/10.1016/j.placenta.2012.04.015
https://doi.org/https://doi.org/10.1016/... . Barker et al. identified that placental growth along the major axis is qualitatively different from growth along the minor axis. They postulated that the minor axis is more important for nutrient transfer to the fetus, partially explaining current results⁵5. Barker DJP, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol 2010; 54(2-3): 525-30. https://doi.org/10.1387/ijdb.082760db
https://doi.org/https://doi.org/10.1387/... .

A previous study revealed that neonatal ponderal index, head, chest, abdomen, and thigh circumferences are all highly associated with placental breadth, while none of them are related to placental length³⁰30. Alwasel SH, Abotalib Z, Aljarallah JS, Osmond C, Al Omar SY, Harrath A, et al. The breadth of the placental surface but not the length is associated with body size at birth. Placenta 2012; 33(8): 619-22. https://doi.org/10.1016/j.placenta.2012.04.015
https://doi.org/https://doi.org/10.1016/... .

Freedman et al. found that the surface area had more impact on BW than other PM²⁸28. Freedman AA, Hogue CJ, Marsit CJ, Rajakumar A, Smith AK, Goldenberg RL, et al. Associations Between the Features of Gross Placental Morphology and Birthweight. Pediatr Dev Pathol 2018; 22(3): 194-204. https://doi.org/10.1177/1093526618789310
https://doi.org/https://doi.org/10.1177/... . However, this study did not include surface area in its regression models for it being a composite measurement derived from the largest and smallest diameters.

The surface area of the maternal-fetal interface increases in line with PW during pregnancy due to the growing length and branching of the fetal villi³¹31. Burton GJ, Fowden AL, Thornburg KL. Placental Origins of Chronic Disease. Physiol Rev 2016; 96(4): 1509-65. https://doi.org/10.1152/physrev.00029.2015
https://doi.org/https://doi.org/10.1152/... . Besides, the mean chorionic plate eccentricity could explain the round placental shape predominance (77%). In addition, this may have contributed to 74.5% of the newborns being classified as appropriate for gestational age (AGA). This is also consistent with the hypothesis that tissue along the smallest diameter plays a key role in nutrient transfer from mother to fetus³²32. Yampolsky M, Salafia CM, Shlakhter O, Haas D, Eucker B, Thorp J. Modeling the variability of shapes of a human placenta. Placenta 2008; 29(9): 790-7. https://doi.org/10.1016/j.placenta.2008.06.005
https://doi.org/https://doi.org/10.1016/... .

At present, data show that elliptical placentas tend to be less efficient than circular ones, yet more research is necessary to understand the underlying biological reasons. The degree to which a placenta deviates from being perfectly round has a predictive value for specific diseases. A suitable explanation is that placental shape is a proxy indicator of placentation processes related to its transport and other physiological functions³³33. Biswas S, Ghosh SK. Gross morphological changes of placentas associated with intrauterine growth restriction of fetuses: A case control study. Early Hum Dev 2008; 84(6): 357-62. https://doi.org/10.1016/j.earlhumdev.2007.09.017
https://doi.org/https://doi.org/10.1016/... .

Previous studies conclude that a placenta with a low average thickness has decreased functional efficiency, leading to a smaller newborn for a given PW¹⁵15. Thompson J, Irgens L, Skjaerven R, Rasmussen S. Placenta weight percentile curves for singleton deliveries. BJOG 2007; 114(6): 715-20. https://doi.org/10.1111/j.1471-0528.2007.01327.x
https://doi.org/https://doi.org/10.1111/... ^,2323. Winder NR, Krishnaveni GV, Veena SR, Hill JC, Karat CLS, Thornburg KL, et al. Mother’s lifetime nutrition and the size, shape and efficiency of the placenta. Placenta 2011; 32(11): 806-10. https://doi.org/10.1016/j.placenta.2011.09.001
https://doi.org/https://doi.org/10.1016/... ^,2828. Freedman AA, Hogue CJ, Marsit CJ, Rajakumar A, Smith AK, Goldenberg RL, et al. Associations Between the Features of Gross Placental Morphology and Birthweight. Pediatr Dev Pathol 2018; 22(3): 194-204. https://doi.org/10.1177/1093526618789310
https://doi.org/https://doi.org/10.1177/... . However, this and another Latin American study have found a low explanatory power of BW by placental thickness¹³13. Grandi C, Veiga A, Mazzitelli N, Cavalli R, Cardoso V. Placental Growth Measures in Relation to Birth Weight in a Latin American Population. Rev Bras Ginecol Obs 2016; 38(8): 373-80. http://dx.doi.org/10.1055/s-0036-1586721
https://doi.org/http://dx.doi.org/10.105... . The speculated reason is that this measurement incompletely captures the variability that characterizes the human placenta.

Fetal growth restriction (FGR) has been associated not only to PW and length but also to other gross morphological changes such as type of placental cord insertion and presence of knots in the umbilical cord³⁴34. Sornes T. Umbilical cord knots. Acta Obstet Gynecol Scand 2000; 79(3): 157-9. https://doi.org/10.1080/j.1600-0412.2000.079003157.x
https://doi.org/https://doi.org/10.1080/... ^,3535. Wilson ME, Ford SP. Comparative aspects of placental efficiency. Reprod Suppl 2001; 58: 223-32..

Placental efficiency, defined as the amount of fetal body mass accumulated per gram of placenta, is a key indicator of the resilience and susceptibility of the offspring to chronic diseases in later life. It also provides an overview of placental function³⁶36. Wallace JM, Horgan GW, Bhattacharya S. Placental weight and efficiency in relation to maternal body mass index and the risk of pregnancy complications in women delivering singleton babies. Placenta 2012; 33(8): 611-8. https://doi.org/10.1016/j.placenta.2012.05.006
https://doi.org/https://doi.org/10.1016/... . This index is simple to calculate in epidemiological studies. Moreover, it encapsulates numerous factors, such as placental exchange surface area, transporter density and activity, and blood flow rates, which all require more detailed individual stereological, molecular, and physiological research. In the present study, the BW/PW ratio was higher in term than preterm, reflecting the high demand of the fetus across the entire pregnancy³⁷37. Macdonald M, Natale R, Regnault T, Koval J, Campbell M. Obstetric conditions and the placental weight ratio. Placenta 2014; 35(8): 582-86. https://doi.org/10.1016/j.placenta.2014.04.019
https://doi.org/https://doi.org/10.1016/... .

Among the three proxies of placental efficiency, PW/BW ratio showed the greatest value and was higher in preterm than term infants, demonstrating that it can be a useful tool to evaluate the placenta functionality.

The main strength of the current study is its population size, one of the largest among recent Latin American investigations into placental morphometry. On the other hand, a limitation is that it took place at a high-complexity maternity ward, which mainly treats unhealthy pregnancies. The main conditions observed were chronic diseases, such as hypertension and diabetes, and obstetric complications, such as preterm labor and fetal malformations. Another potential drawback is the information bias, since the data about gestational exposure were self-declared by the mothers, instead of checked in medical records. Although random measurement error in an outcome variable (BW) should not influence the point estimates of regression models, bias could have been introduced if placentas of complicated pregnancies were prepared for measuring with more scrutiny than those of uncomplicated pregnancies³⁸38. Hutcheon JA, Chiolero A, Hanley JA. Random measurement error and regression dilution bias. Br Med J 2010; 340: c2289. https://doi.org/10.1136/bmj.c2289
https://doi.org/https://doi.org/10.1136/... .

More comprehensive placental phenotyping is necessary to expand the current knowledge: sequential PMs during pregnancy by ultrasound, calculation of structural parameters, such as surface area and internal distance; characterization of maternal and fetal circulations; analysis of the expression and activity of different transporters; measurement of endocrine function and enzyme activities; assessment of placental metabolism and regulatory signaling pathways; and, ideally, investigation into single-cell transcriptomics and epigenetics³¹31. Burton GJ, Fowden AL, Thornburg KL. Placental Origins of Chronic Disease. Physiol Rev 2016; 96(4): 1509-65. https://doi.org/10.1152/physrev.00029.2015
https://doi.org/https://doi.org/10.1152/... .

CONCLUSION

PMs are powerful independent predictors of BW. PW is the most predictive of them, followed by the smallest diameter. PMs should be estimated during pregnancy and at the time of birth to assess the nutritional status of the fetus.

Since distinct environmental insults affect each PM differently, studying them may contribute to understanding both perinatal outcomes and maternal-placental programming of chronic diseases.

ACKNOWLEDGMENTS

We acknowledge the women, children, and families who generously provided information to our research project. We thank Marco Antônio Barbieri and Heloisa Bettiol for designing the birth cohorts at Ribeirão Preto and mentoring our study group. Finally, we thank Rafaela Furlan for her precious help in this study.

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