Abstract
Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.
Keywords: cryptorchidism, hypospadias, placenta, testicular dysgenesis syndrome
Cryptorchidism and hypospadias are the 2 most common congenital anomalies of the genitourinary tract in males (1–3). The 2 conditions, together with impaired spermatogenesis and testicular germ-cell tumors, comprise the testicular dysgenesis syndrome and are thought to share a common in utero etiology (4). While low birth weight and preterm birth have been associated with both conditions, the etiology of cryptorchidism and hypospadias remains unclear (5). The in utero hormonal milieu, however, is critical to the development of the male phenotype. During the first trimester of pregnancy, the fetal testis is stimulated by human chorionic gonadotropin (hCG), elaborated by the placenta, to produce testosterone (6–8). Insufficient testosterone production can affect testicular descent and urethral fusion and thus may result in abnormal genitourinary development. Previous studies have suggested that the weight of the placenta at birth is correlated with placental function (9–11). Placental characteristics other than weight have not been as widely examined and may be associated with placental insufficiency. Such factors include but are not limited to placental thickness, placental calcification, placental infarcts, amnion cell metaplasia, and changes to the intervillous space (12).
Several prior studies have examined the association between placental weight and hypospadias (13–17) but results have been inconsistent, and only 1 of the studies (14) also examined cryptorchidism. Most prior studies have included only a small number of cases and have been limited to white boys. Although it is unclear whether rates of cryptorchidism and hypospadias differ by race in the United States (18), rates of testicular cancer are 5 times higher in white men than in black men (19), suggesting that rates of cryptorchidism and hypospadias may differ by race as well. An examination of the prevalence of cryptorchidism in the CPP found that white babies had higher rates than black babies (18), further suggesting that racial disparities in these anomalies may exist. Thus, we sought to examine the associations between placental weight and the risks of cryptorchidism and hypospadias by race. In addition, other placental characteristics were also examined.
METHODS
Study participants
The CPP has been described in detail previously (20). In brief, the CPP was a mother-child cohort study conducted in the United States. Pregnant women were recruited between 1959 and 1965 at 12 study centers: Baltimore, Maryland; Boston, Massachusetts; Buffalo, New York; Memphis, Tennessee; Minneapolis, Minnesota; New Orleans, Louisiana; New York, New York (2 centers); Philadelphia, Pennsylvania; Portland, Oregon; Providence, Rhode Island; and Richmond, Virginia. The selection of study participants varied among the study centers: At 11 study centers, participants were recruited from the prenatal clinics of a university hospital, while at 1 study center (Buffalo) pregnant women were recruited from 13 private obstetrical/gynecological practices. Women were ineligible to participate in the study if they were incarcerated, if they planned to leave the study area upon delivery, if they were planning to place their child for adoption, or if they delivered on their study recruitment date. At registration, the characteristics of the women in the sample were essentially the same as those in the sampling frame. Approximately 42,000 women were enrolled, and 55,000 children were born to the participating women. Four percent of the study mothers were lost to follow-up before delivery. The children were systematically assessed for the presence of congenital anomalies and other outcomes until they reached 7 years of age. Seventy-five percent of the study children were followed up to age 7 years.
For the present analysis, only male babies born to black or white mothers were included. Other inclusion criteria were 1) singleton birth, 2) infant survival for at least 1 year, and 3) gestational age at delivery greater than 26 weeks. A total of 24,212 boys satisfied the study inclusion criteria. Among the 24,212 eligible boys, 1,741 were missing data on hypospadias. In total, 413 boys were classified as having cryptorchidism and 145 boys were classified as having hypospadias.
The primary exposure variable evaluated was placental weight. Other placental characteristics were considered exploratory variables and included 1) placental thickness, 2) placental infarcts, 3) neutrophils in the amnion of the placental surface, 4) hemorrhage of maternal surface of the placenta, 5) laceration of maternal surface of the placenta, 6) intervillous thrombosis, 7) calcification of the placenta, and 8) the presence of macrophages in the amniotic fluid. Data on placental measures were systematically collected according to a protocol prepared specifically for the CPP (21). Placental characteristics from both the gross examination and the microscopic examination were included in the present study.
Cryptorchidism was defined as having unilateral or bilateral undescended testes at any point between birth and 1 year of age. The diagnosis of cryptorchidism was made by pediatricians on the basis of serial examinations that included palpation and inspection of the male genitalia. Boys first diagnosed with cryptorchidism after 1 year of age or who had spontaneously descending testes within the first year of life were excluded from the analysis. Hypospadias was defined as having a diagnosis at any time within the first 7 years of life. The degree of hypospadias was not captured in the medical records.
Statistical analysis
We used χ2 tests and t tests to compare the distributions of the categorical covariates and the mean values of the continuous covariates, respectively. Adjusted odds ratios and 95% confidence intervals for the associations between selected placental characteristics and the risk of each anomaly were estimated using unconditional logistic regression. The overall model adjusted for maternal factors that have been previously found to be associated with these anomalies, including age, body mass index (weight (kg)/height (m)2), smoking status, and race, while the race-specific models adjusted for the same factors except race (18). Five-knot restricted cubic regression splines were used to determine whether there were nonlinear relationships with placental weight (22). To account for potential correlation between births from the same mother, we used statistical procedures for the χ2 tests, 2-sample t tests, and logistic regression analyses that allow for cluster sampling, in which births to the same mother are treated as a cluster and robust variance estimation is used to compute standard errors. These procedures are also used for conducting analyses of cluster samples in surveys; for our case, the sample weights were set to 1, under the assumption that the cohort was a simple random sample (23).
All statistical analyses were performed using SAS, version 9.3 (SAS Institute, Inc., Cary, North Carolina). The computations were conducted using the SAS survey procedures proc surveylogistic, proc surveyfreq, and proc surveyreg. All tests were 2-sided, with P < 0.05 defined as being statistically significant.
RESULTS
Perinatal characteristics of the study population are shown in Table 1. For both anomalies, mean birth weight was significantly lower in cases than in controls (cryptorchidism: P = 0.01; hypospadias: P = 0.003). For cryptorchidism, mean gestational age was significantly lower in cases than in controls (P = 0.02) and mean maternal age was significantly higher in case mothers than in control mothers (P = 0.003). There were no statistically significant differences in prepregnancy body mass index or smoking status between case mothers and control mothers for either anomaly. Data on the same factors and the placental characteristics of interest are shown by race in Web Table 1 (available at https://academic.oup.com/aje) and by case status in Web Table 2.
Table 1.
Distribution of Maternal and Neonatal Characteristics, Collaborative Perinatal Project, 1959–1965
| Maternal/Neonatal Variable | Cryptorchidism | Hypospadias | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cases (n = 413) | Noncases (n = 23,799) | P Value | Cases (n = 145) | Noncases (n = 22,326) | P Value | |||||
| No.a | % | No. | % | No. | % | No. | % | |||
| Birth weight category, g | ||||||||||
| 500–2,499 | 60 | 14.5 | 1,861 | 7.8 | 31 | 21.4 | 1,773 | 7.9 | ||
| 2,500–3,999 | 327 | 79.2 | 20,298 | 85.3 | 106 | 73.1 | 19,040 | 85.3 | ||
| ≥4,000 | 26 | 6.3 | 1,599 | 6.7 | <0.0001 | 8 | 5.5 | 1,493 | 6.7 | <0.0001 |
| Birth weight, gb | 3,156.2 (627.9) | 3,244.4 (539.0) | 0.01 | 3,075.6 (664.2) | 3,242.5 (540.4) | 0.003 | ||||
| Gestational age category, weeks | ||||||||||
| <39 | 168 | 40.7 | 8,356 | 35.1 | 51 | 35.2 | 7,894 | 35.4 | ||
| ≥39 | 245 | 59.3 | 15,443 | 64.9 | 0.01 | 94 | 64.8 | 14,432 | 64.6 | 0.83 |
| Gestational age, weeksb | 38.6 (3.2) | 40.0 (2.9) | 0.02 | 38.6 (3.2) | 39.0 (2.9) | 0.21 | ||||
| Maternal BMI categoryc | ||||||||||
| <18.5 | 31 | 7.5 | 2,055 | 8.6 | 17 | 11.7 | 1,914 | 8.6 | ||
| 18.5–24.9 | 256 | 62.0 | 15,063 | 63.3 | 94 | 64.8 | 14,158 | 63.4 | ||
| 25.0–29.9 | 51 | 12.3 | 3,269 | 13.7 | 14 | 9.7 | 3,102 | 13.9 | ||
| ≥30.0 | 31 | 7.5 | 1,427 | 6.0 | 0.45 | 11 | 7.6 | 1,372 | 6.1 | 0.27 |
| Maternal BMIb,c | 23.1 (4.5) | 22.7 (4.3) | 0.17 | 22.3 (4.0) | 22.8 (4.3) | 0.17 | ||||
| Maternal age group, years | ||||||||||
| ≤19 | 70 | 16.9 | 5,613 | 23.6 | 33 | 22.8 | 5,259 | 23.6 | ||
| 20–29 | 244 | 59.1 | 13,737 | 57.7 | 82 | 56.6 | 12,820 | 57.4 | ||
| 30–39 | 87 | 21.1 | 4,061 | 17.1 | 28 | 19.3 | 3,866 | 17.3 | ||
| ≥40 | 12 | 2.9 | 388 | 1.6 | 0.002 | 2 | 1.4 | 381 | 1.7 | 0.92 |
| Maternal age, yearsb | 25.1 (6.3) | 24.2 (6.0) | 0.003 | 24.5 (5.8) | 24.2 (6.1) | 0.50 | ||||
| Maternal smoking status | ||||||||||
| Nonsmoker | 213 | 51.6 | 12,503 | 52.5 | 85 | 58.6 | 11,880 | 53.2 | ||
| Smoker | 198 | 47.9 | 11,057 | 46.5 | 0.62 | 60 | 41.4 | 10,304 | 46.2 | 0.22 |
Abbreviation: BMI, body mass index.
a Numbers for certain subgroups in the table do not sum to totals because of missing data.
b Values are expressed as mean (standard deviation).
c Maternal prepregnancy BMI, calculated as weight (kg)/height (m)2.
The associations between placental weight and risk of cryptorchidism and hypospadias are presented in Table 2, overall and by race. Overall, there were no statistically significant associations between placental weight and the risks of cryptorchidism and hypospadias in the categorical analysis. Among white boys, there was a significantly decreased risk of cryptorchidism among those in the highest tertile of placental weight (odds ratio (OR) = 0.66, 95% confidence interval (CI): 0.46, 0.95) as compared with the middle tertile (referent group). Among black boys, there was a significantly increased risk of cryptorchidism among those in the lowest tertile of placental weight (OR = 1.70, 95% CI: 1.11, 2.59) as compared with the middle tertile. The cubic regression splines for the association between placental weight and cryptorchidism showed deviation from linearity among all boys (Figure 1A; P = 0.05), among white boys (Figure 1B; P = 0.01), and among black boys (Figure 1C; P = 0.01). These figures indicate that the relationship varies by race, where there is lower risk of cryptorchidism with lower and higher placental weights among whites but higher risk of cryptorchidism with lower and higher placental weights among blacks, when compared with placental weights in the 50th percentile range. No statistically significant associations between placental weight and hypospadias were evident, either in the overall model or in the race-specific models. The results remained essentially unchanged after further adjustment for gestational age for both cryptorchidism and hypospadias.
Table 2.
Associations of Placental Weight With Cryptorchidism and Hypospadias, Collaborative Perinatal Project, 1959–1965
| Anomaly and Tertile of Placental Weight, g | All Boys | White Boys | Black Boys | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ORa | 95% CI | P Value | ORb | 95% CI | P Value | ORb | 95% CI | P Value | |
| Cryptorchidism | |||||||||
| 90–399 | 1.17 | 0.90, 1.53 | 0.24 | 0.90 | 0.63, 1.29 | 0.57 | 1.70 | 1.11, 2.59 | 0.01 |
| 400–469 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| ≥470 | 0.90 | 0.68, 1.20 | 0.48 | 0.66 | 0.46, 0.95 | 0.02 | 1.46 | 0.93, 2.29 | 0.10 |
| Hypospadias | |||||||||
| 90–399 | 0.93 | 0.61, 1.43 | 0.74 | 0.77 | 0.42, 1.41 | 0.39 | 1.11 | 0.61, 2.05 | 0.73 |
| 400–469 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| ≥470 | 0.83 | 0.53, 1.30 | 0.41 | 0.85 | 0.48, 1.51 | 0.57 | 0.78 | 0.38, 1.59 | 0.49 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Adjusted for maternal age, maternal prepregnancy body mass index, smoking status, and race.
b Adjusted for maternal age, maternal prepregnancy body mass index, and smoking status.
Figure 1.
Restricted cubic regression splines for cryptorchidism according to percentile of placental weight, Collaborative Perinatal Project, 1959–1965. A) All boys; B) white boys; C) black boys. Percentiles correspond to placental weight as follows: all boys (A)—10%, 330 g; 20%, 362 g; 30%, 390 g; 40%, 410 g; 50%, 435 g; 60%, 459 g; 70%, 481 g; 80%, 515 g; 90%, 570 g; white boys (B)—10%, 340 g; 20%, 375 g; 30%, 400 g; 40%, 421 g; 50%, 445 g; 60%, 469 g; 70%, 495 g; 80%, 527 g; 90%, 580 g; black boys (C)—10%, 320 g; 20%, 355 g; 30%, 376 g; 40%, 400 g; 50%, 422 g; 60%, 448 g; 70%, 470 g; 80%, 500 g; 90%, 550 g. Gray lines, 95% confidence intervals.
Associations between placental characteristics other than placental weight and cryptorchidism are presented in Table 3, overall and by race. There were no statistically significant associations between placental characteristics and risk of cryptorchidism in either the overall model or the race-specific models.
Table 3.
Associations of Placental Characteristics With Cryptorchidism, Collaborative Perinatal Project, 1959–1965
| Placental Characteristic | All Boys | White Boys | Black Boys | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ORa | 95% CI | P Value | ORb | 95% CI | P Value | ORb | 95% CI | P Value | |
| Placental thickness, mm | |||||||||
| ≤20 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| >20 | 0.93 | 0.73, 1.17 | 0.52 | 0.82 | 0.61, 1.10 | 0.19 | 1.10 | 0.78, 1.56 | 0.59 |
| Placental infarcts | |||||||||
| None | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.08 | 0.83, 1.39 | 0.58 | 0.99 | 0.71, 1.36 | 0.93 | 1.25 | 0.83, 1.88 | 0.29 |
| Neutrophils in amnion of placental surface | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 0.94 | 0.58, 1.53 | 0.81 | 0.80 | 0.40, 1.57 | 0.51 | 1.15 | 0.58, 2.29 | 0.69 |
| Hemorrhage of maternal surface of placenta | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.29 | 0.85, 1.96 | 0.24 | 1.14 | 0.64, 2.01 | 0.66 | 1.55 | 0.83, 2.89 | 0.17 |
| Maternal surface of placenta | |||||||||
| Intact | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Lacerated | 1.06 | 0.84, 1.34 | 0.60 | 0.97 | 0.72, 1.30 | 0.83 | 1.22 | 0.86, 1.73 | 0.27 |
| Intervillous thrombosis | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.10 | 0.78, 1.53 | 0.59 | 0.99 | 0.67, 1.45 | 0.94 | 1.48 | 0.77, 2.83 | 0.24 |
| Calcification of placenta | |||||||||
| None | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Maternal surface only | 1.10 | 0.87, 1.39 | 0.42 | 1.14 | 0.83, 1.56 | 0.42 | 1.06 | 0.75, 1.50 | 0.75 |
| Throughout | 0.97 | 0.65, 1.43 | 0.86 | 1.03 | 0.62, 1.73 | 0.91 | 0.89 | 0.49, 1.64 | 0.71 |
| Macrophages in amniotic fluid | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.02 | 0.82, 1.28 | 0.84 | 0.98 | 0.72, 1.32 | 0.89 | 1.07 | 0.77, 1.48 | 0.70 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Adjusted for maternal age, maternal prepregnancy body mass index, smoking status, and race.
b Adjusted for maternal age, maternal prepregnancy body mass index, and smoking status.
Association between placental characteristics other than placental weight and the risk of hypospadias are presented in Table 4, overall and by race. Overall, boys born in pregnancies in which there was calcification on the maternal surface of the placenta were at significantly higher risk for hypospadias than boys born in pregnancies in which there was no calcification on the placenta (OR = 1.52, 95% CI: 1.05, 2.20). In the race-specific models, there were no statistically significant associations between placental characteristics and hypospadias.
Table 4.
Associations of Placental Characteristics With Hypospadias, Collaborative Perinatal Project, 1959–1965
| Placental Characteristic | All Boys | White Boys | Black Boys | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ORa | 95% CI | P Value | ORb | 95% CI | P Value | ORb | 95% CI | P Value | |
| Placental thickness, mm | |||||||||
| ≤20 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| >20 | 0.97 | 0.66, 1.42 | 0.89 | 0.86 | 0.53, 1.41 | 0.55 | 1.14 | 0.65, 1.98 | 0.65 |
| Placental infarcts | |||||||||
| None | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 0.72 | 0.45, 1.14 | 0.16 | 0.65 | 0.36, 1.18 | 0.16 | 0.84 | 0.40, 1.77 | 0.64 |
| Neutrophils in amnion of placental surface | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.06 | 0.49, 2.28 | 0.89 | 1.03 | 0.37, 2.85 | 0.96 | 1.09 | 0.33, 3.56 | 0.89 |
| Hemorrhage of maternal surface of placenta | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 0.85 | 0.37, 1.92 | 0.69 | 1.24 | 0.50, 3.12 | 0.65 | 0.33 | 0.05, 2.35 | 0.27 |
| Maternal surface of placenta | |||||||||
| Intact | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Lacerated | 0.90 | 0.63, 1.31 | 0.59 | 0.98 | 0.60, 1.58 | 0.92 | 0.80 | 0.44, 1.47 | 0.48 |
| Intervillous thrombosis | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 0.77 | 0.42, 1.43 | 0.41 | 0.70 | 0.35, 1.42 | 0.32 | 1.05 | 0.33, 3.40 | 0.93 |
| Calcification of placenta | |||||||||
| None | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Maternal surface only | 1.52 | 1.05, 2.20 | 0.03 | 1.67 | 0.98, 2.82 | 0.06 | 1.38 | 0.81, 2.36 | 0.24 |
| Throughout | 0.91 | 0.45, 1.86 | 0.80 | 0.97 | 0.36, 2.60 | 0.94 | 0.87 | 0.31, 2.49 | 0.80 |
| Macrophages in amniotic fluid | |||||||||
| Not seen | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | |||
| Present | 1.15 | 0.80, 1.65 | 0.46 | 1.38 | 0.84, 2.26 | 0.20 | 0.92 | 0.53, 1.59 | 0.77 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Adjusted for maternal age, maternal prepregnancy body mass index, smoking status, and race.
b Adjusted for maternal age, maternal prepregnancy body mass index, and smoking status.
DISCUSSION
The present study found that lower placental weight was significantly associated with risk of cryptorchidism. In race-specific models, cryptorchidism was directly associated with lower placental weight in black boys and inversely associated with higher placental weight in white boys. In the hypospadias analysis, a higher risk of hypospadias was associated with calcification on the maternal surface of the placenta.
Several prior studies have examined the association between placental weight and hypospadias (13–16), but the results have been inconsistent. In 2 Danish studies, investigators reported that lower placental weight was significantly associated with an increased risk of hypospadias (13, 14). In a small US study of 17 cases, Gatti et al. (15) found a similar association, but the results were not statistically significant. A French study of 27 cases also found that mean placental weight was lower in hypospadias cases than in noncases; however, only unadjusted results were presented (16). In contrast, a Japanese study of extremely low–birth-weight infants found no relationship between placental weight and hypospadias (24). Thus, most of the prior studies, except for the Japanese study, included only white populations. Our study, conducted in a racially diverse population, found no relationship between placental weight and hypospadias. This result does not vary dramatically from that of the large Danish study, however, as that study only found a relationship with placental weight in the lowest 20% of the data distribution (14). The relationship between low placental weight and cryptorchidism has been examined in only 1 study to date, and the relationship was found to be significant (14). Our study confirms this finding and is (to our knowledge) the first to demonstrate a similar association among black boys.
In the present study, we found that cryptorchidism was directly associated with lower placental weight in black boys and inversely associated with higher placental weight in white boys. It is possible that the differences observed in the race-specific findings may have been due to differing placental weight distributions between the white and black boys. The cubic regression splines demonstrate the differences in the placental weight distributions, in addition to showing that the odds ratio for the association with cryptorchidism decreases for black boys as placental weight increases (up to the 50th percentile) and then begins to increase thereafter; however, the relationship is somewhat opposite in white boys. The interpretation is essentially the same for both racial groups, however; lower placental weight is associated with higher risk of cryptorchidism in black boys and higher placental weight is protective in white boys.
Previous studies have suggested that both hypospadias (5, 24–29) and cryptorchidism (30–32) may be associated with impaired placental functioning. Two studies of hypospadias (24, 28) found that case children were more likely to have suffered growth restriction due to placental insufficiency than were noncases. Similar results were found in a study of cryptorchidism in which undescended testes were significantly more common among boys who had suffered growth restriction (30). Given that placental characteristics (such as placental thickness, placental calcification, placental infarcts, amnion cell metaplasia, and changes to the intervillous space) have been shown to be associated with placental insufficiency (12), the association between these characteristics and cryptorchidism/hypospadias risk was further explored in the present study. Early preterm placental calcification has previously been reported to be associated with adverse maternal and fetal outcomes, such as placental abruption, preterm birth, and low birth weight (33); however, the association between placental calcification and hypospadias risk had not been previously examined. The current study found a possible association between calcification on the maternal surface of the placenta and hypospadias risk. While the association was statistically significant among all boys, neither race-specific result was significant. Given the number of statistical comparisons, the calcification-hypospadias association could have arisen by chance alone, so the findings should be interpreted cautiously.
Other studies have suggested that cryptorchidism and hypospadias may be caused by impaired placental functioning, resulting in abnormal levels of pregnancy hormones (5, 25–27, 32). In early fetal life, hCG is produced by the placenta and stimulates steroidogenesis. Placental hCG is critical for penile, urethral, and testicular development; thus, reduced levels of hCG may be of particular importance in the etiology of cryptorchidism and hypospadias. The relationship between hCG and placental weight is difficult to examine, however, given that hCG levels in the first trimester (when placental weight cannot be measured) may be more critical than hCG levels at the time of delivery.
The strengths of this study include its relatively large sample size, inclusion of more than 1 racial group, standardized definitions of cryptorchidism and hypospadias, and ascertainment of cryptorchidism outside the delivery room. Cryptorchidism cannot be reliably diagnosed in the delivery room because a nontrivial number of boys have testes that descend spontaneously during the first year of life (34). To ensure an accurate case definition of cryptorchidism in our study, we ascertained cases diagnosed during the first 12 months of life. In the CPP, all birth defects were ascertained through 7 years of age; thus, hypospadias was ascertained over the entire 7-year period. Finally, we did not have information on the degree of hypospadias, which may have provided further insight as to the timing and severity of the placental disruption. Earlier (35) and more severe (28) placental dysfunction have both been shown to be associated with more severe hypospadias.
Our study results suggest that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.
Supplementary Material
ACKNOWLEDGMENTS
Author affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Armen A. Ghazarian, Britton Trabert, Barry I. Graubard, Katherine A. McGlynn); Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland (Armen A. Ghazarian); Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (Matthew P. Longnecker); and Ohio Perinatal Research Network, Department of Pediatrics, College of Medicine, Ohio State University and Nationwide Children’s Hospital, Columbus, Ohio (Mark A. Klebanoff).
This work was supported by the intramural research programs of the National Cancer Institute, the National Institute of Environmental Health Sciences, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Conflict of interest: none declared.
Abbreviations
- CI
confidence interval
- CPP
Collaborative Perinatal Project
- hCG
human chorionic gonadotropin
- OR
odds ratio
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