THE KURUME MEDICAL JOURNAL Vol. 39, p. 53-60, 1992

Maternal and Other Factors of Cryptorchidism A Case-control Study in

MITSURU MORI, THOMAS W. DAVIES, TAIJI TSUKAMOTO , YOSHIAKI AND KATSUHIRO FUKUDA

Department of Public Health, School of Medicine , Kurume, 830, Department of Urology, Medical College, Sapporo , 060 Japan and Department of Community Medicine, School of Clinical Medicine , University of Cambridge, Cambridge, CB2 2QQ England

Received for publication March 22, 1992

Summary: A case-control study of cryptorchidism was undertaken in Japan. A hundred and eight mothers of children with cryptorchidism and mothers of their matched controls were surveyed. After 4 pairs which consisted of one of twin siblings either in the cases or the controls were excluded, 104 paired data of singletons were analyzed. As a result, a significantly smaller propor- tion of the case mothers had suffered from vomiting during the index preg- nancy than that of the control mothers(odds ratio, or OR=0.50, 95% con- fidence interval, or CI 0.28-0.89). A significantly larger proportion of the case mothers had delivered the index child by vacuum or breech extraction, or Caesarean section than that of the control mothers(OR=2.09, 95% CI 1.01- 3.98). A significantly larger proportion of the case mothers had never breast- fed the index child than that of the control mothers(OR=3.50, 95% CI 1.20- 10.21). Significantly larger proportions of the cases had inguinal hernia (OR= 9.00, 95% CI 1.29-62.97), or congenital cardiac diseases (OR=8/0, p<0.05) than those of the controls. It was inferred that endogenous hormonal milieu of a mother, rather than exogenous hormones, might be associated with the occurrence of cryptorchidism.

Key words : case-control study-cryptorchidism-maternal factors-abnor- mal delivery-breast-feeding-congenital malformations

Introduction with subfertility(Lipshultz, 1976), but is also a well established risk factor for The incidence of cryptorchidism has testicular cancer(Mori et al. 1992). Ma- been shown in England to be 1.58% by ternal or prenatal factors associated with a survey in 1985 (John Radcliff e Hospital cryptorchidism have been investigated in Cryptorchidism Study Group, 1986). The the Occidental countries by the case-con- incidence has been on the rise there trol studies(Czeizel et al. 1981a, 1981b; (Chilvers et al. 1984; Matlai and Beral, Swerdlow et al. 1983; Depue, 1984; Beard 1985), although it has not yet been ex- et al. 1984; Davies et al. 1986; Morley plored in Japan. and Lucas, 1987; Baker et al. 1988; Cryptorchidism is not only associated Depue, 1988; Hjertkvist, 1989). We con-

Correspondence should be sent to : Mitsuru Mori, Department of Public Health, Kurume Uni- versity School of Medicine, 67 Asahi-machi, Kurume, 830 Japan.

53 54 MORI, ET AL. ducted a case-control study of cryptor- birth year without primary cancer at any chidism in Japan, where the incidence sites or congenital anomaly seen at the of testicular cancer is the lowest among Pediatric Department of the Sapporo the developed countries(Muir et al. 1987), Tenshi Hospital, another general hospital to assess the potential risk factors for in Sapporo city between 1978 and 1986. cryptorchidism which have been reported Incidentally, 230 boys were selected from in the Occidental countries. the outpatient records, and questionnaires were mailed to their mothers. A hundred and thirty one control mothers responded Materials and Methods and returned the filled questionnaire, but, 43 mothers could not be located, and An individually sex and age-matched 56 mothers did not respond to the survey case-control study of cryptorchidism was (the response rate=57.0%). All of the designed using the questionnaire, devel- control group were surveyed between 1986 oped by Davies and his coworkers (1986). and 1987. Eligible cases for the present study were We selected 108 controls from the eli- defined as all cryptorchid children who gible controls for each case. Paired data underwent orchiopexy between 1978 and of the cases and the controls were com- 1986 either at the Department of Urology pared and analyzed using the paired t of Sapporo Medical College or at the Di- test or the McNemar's test. An odds ratio vision of Urology in the Sapporo Teishin (OR)for matched data was calculated Hospital, which is a general hospital as- and it's 95% confidence interval(CI)was sociated with Sapporo Medical College. estimated with the Miettinen's test-based A hundred and two cases with cryp- method(Kleinbaum et al. 1982). torchidism were found eligible in the dis- charge records at Sapporo Medical Col- lege, and gestionnaires were mailed to Results their mothers. Eighty-two mothers re- sponded and returned the filled ques- The average age of the cases at or- tionnnaire. But, 7 mothers could not be chiopexy was 6.2 years old(the standard located, and 13 mothers did not respond deviation or S. D.=2. 6). Fifty-nine cases to the survey. Forty-one cases were de- had unilateral cryptorchidism(28 cases tected in the records at the Sapporo on the right side and 31 on the left), Teishin Hospital, and letters were sent and 49 were affected with bilateral cryp- to their mothers requesting them to have torchidism. Of the 108 controls, 33 were their children with cryptorchidism receive primarily diagnosed as common cold, 15 reexaminations at the hospital. Twenty as bronchial asthma, 12 as tonsillitis, 11 six cases and their mothers came to the as bronchopneumonia, 10 as gastroen- hospital, and received an interview by a teritis, 4 as a attendant for vaccination, nurse. However, 15 cases and their 3 as tic, 2 as dermatitis, 2 as orthostatic mothers did not visit the hospital. To- disregulation, 2 as nocturia, and the re- tally, 108 mothers(the response rate= sidual 14 as various disorders. Excluding 75.5%)of the cases with cryptorchidism 3 children of 3 twin siblings and a child responded to the present survey in 1986. of 1 twin siblings from the cases and the Eligible controls were defined as boys controls, respectively, 104 paired data of who were outpatients matched with the singletons were available for further cases on age, year at admission, and analysis. MATERNAL FACTORS OF CRYPTORCHIDISM 55

1. Maternal characteristics at the index vomiting during the index pregnancy pregnancy was significantly smaller than that of There were no differences between the the control mothers(OR=0.50, 95% CI cases and the controls in body height 0.28-0.89). (154.8cm vs. 155.5cm)and weight(49.8 kg vs. 50.0kg)of mothers before the in- 2. Perinatal and postnatal characteristics dex pregnancy. As illustrated in Table 1, As shown in Table 2, the mean age there was not statistically significant dif- of either mothers or fathers at the index ferences between the cases and the con- birth was not different for the cases and trols in proportions of maternal charac- the controls. The mean length of ges- teristics at the index pregnancy such as tation was also the same in the 2 groups. clinical signs, cigarette smoking, alcohol Mean birth weight of the cases was slight- drinking or drug usages except for the ly lower than that of the controls, but following 2 variables. That is, the pro- it was not statistically significant. The portion of the case mothers who had suf- mean duration of breast-feeding among fered from nausea during the index preg- women who had ever lactated was shorter nancy was significantly smaller than that in the case mothers than in the control of the control mothers(OR=0.53, 95% CI mothers, but the difference was not sig- 0.29-0.96). Likewise, the proportion of nificant. However, the proportion of the the case mothers who had suffered from case mothers who had never breast-fed

TABLE 1. Maternal charactereristics at the index pregnancy among the cases and the controls

Item Cases=104) (N=104)Controls Odds(Nratio 95% CI # Percentage of: Clerical work 44.2% 51.0% 0.78 0.44-1.33 Nausea 63.5 78.8 0.53 0.29-0.96 Vomiting 39.4 57.7 0.50 0.28-0.89 Threatened abortion 14.4 14.4 1.00 0.45-2.19 Hypertension 9.6 13.5 0.69 0.28-1 .63 Proteinuria 20.2 31.7 0.52 0.25-1.07 Glucosuria 0.0 1.0 (0/1) -$ Any X-ray 22.1 17.3 1.33 0.68-2.73 Any ultrasound 24.0 32.7 0.63 0.35-1.20 Smoking 17.3 17.3 1.00 0.48-2.08 Drinking alcoholic beverages 19.2 19.2 1.00 0.50-2.00 Iron tablet 18.3 26.0 0.64 0.33-1.24 Drug against nausea 5.8 8.7 0.67 0.21-1.93 Drug against abortion 15.4 11.5 1.50 0.62-3.20 Hypnotics 1.9 0.0 (2/0) -$ Analgesics 1.0 1.0 1.00 0.20-37.85 Using any contraceptive method in the 12 months prior to conception 32.7 43.3 0.59 0.32-1.09 Taking oral contraceptives in the 12 months prior to conception 0.0 4.8 (0/5) -$ # : 95% confidence intervals for odds ratios $ : Could not be calculated 56 MORI, ET AL.

TABLE 2. Perinatal and postnatal characteristics among the cases and the controls

Cases Controls Odds Item 95% CI # (N=104) (N=104) ratio Mean maternal age at birth 27.0 years 27.5 years Mean paternal age at birth 29.8 years 29.7 years Mean length of gestation 276.8 days 276.3 days Mean birth weight of the index child 3088.1g 3137.5g Mean duration of breast-feeding among women who had lactated 5.7months 6.0months Percentage of : Had never breast-fed the index child 14.4% 4.8% 3.50 1.20-10.21 First child 60.6 51.0 1.50 0.85- 2.58 (a) Vacuum extraction 12.5 8.7 1.57 0.61-3.83 (b) Breech extraction 3.8 1.0 4.00 0.19-83.44 (c) Caesarean section 11.5 6.7 1.83 0.68-5.04 Any of (a), (b) or (c) 27.9 16.3 2.09 1.10-3.98 Inguinal hernia 8.7 1.0 9.00 1.29-62.97 Congenital cardiac disorders 7.7 0.0 (8/0) -$ #, $ : See Table 1 the index child was significantly larger defect, 1 ventricular septal defect, 1 aor- than that of the control mothers(OR= tic stenosis, 1 pulmonary stenosis, and 3. 50, 95% CI 1.20-10.21). The proportion 1 tetralogy of Fallot, as compared to none of the cases who were the first child was of the controls(OR=8/0, 95% CI could slightly but insignificantly larger than not be calculated, p<0.05). Furthermore, that of the controls. 3 cases were complicated with chromoso- The proportion of mothers who had mal anomalies including a case of Klein- received obstetrical procedures, i. e. vac- felter syndrome and a case of Noonan's uum extraction, breech extraction, or syndrome. Three cases were also compli- Caesarean section for delivery of the in- cated with hydrocephalus, 2 cases with dex child was larger in the cases than in cleft palate, and 1 case with polydactyly. the controls. When those 3 methods were combined and compared, the difference 3. Characteristics of other pregnancies and became statistically significant(OR=2.09, menstruation 95% CI 1. 10-3.98). As shown in Table 3, either the mean Urogenital abnormalities other than number of pregnancies or the mean num- cryptorchidism were more common among ber of live-births was not different be- the cases. Nine cases were complicated tween the case mothers and the control with inguinal hernia, as compared to mothers. The mean age at menarche as one in the control group(OR=9.00, well as the mean age at the first live- 95% CI 1. 29-62.97), 5 cases with hydro- birth was identical in case mothers and cele, and 1 case with hypospadias. Other control mothers. Statistically insignificant congenital abnormalities were also more differences were observed between the frequent in the cases. Eight cases were case mothers and the control mothers in afflicted with congenital cardiac disorders the proportion of the mothers who had including 2 aortic atresia, 2 atrial septal experienced miscarriage, induced abor- MATERNAL FACTORS OF CRYPTORCHIDISM 57

TABLE 3. Characteristics of other pregnancies and menstruation among the cases and the controls

Cases Controls Odds Item 95% CI. (N=104) (N=104) ratio Mean number of pregnancies 3.0 3.3 Mean number of live-births 2.2 2.4 Mean age at menarche 13.3 years 13.3 years Mean age at first live-birth 25.5 years 25.5 years Percentage of : Miscarriage 22.1% 22.1% 0.95 0.52-1.94 Induced abortion 33.7 44.2 0.62 0.36-1.13 Ectopic pregnancy 0.0 4.8 -$ -$ Irregular menstruation 18.3 13.5 1.46 0.68-3.11 #, $: See Table 1 tion, ectopic pregnancy, or irregular Caesarean section were significantly menstruation at the time of the survey. larger among the case group than among the control group. These unusual deliv- eries are mostly performed because of Discussion malpresentation(Myerscough, 1977). Factors which influence the occurrence The case mothers were less likely to of malpresentation are various, but some have suffered from nausea or vomiting of them are related to placental impair- during the index pregnancy. The cause ment such as placental praevia(Braun et of nausea and vomiting in pregnancy is al. 1975; Myerscough, 1977)or low pla- not definitely known(Fairweather 1986), cental weight(Brenner et al. 1974). Con- but a rise of hormonal levels, especially sequently, it is possible that these unu- estrogens, has been thought to induce sual deliveries would be associated with nausea and vomiting during pregnancy. cryptorchidism through the impaired Accordingly, the tendency for no nausea functioning of the placenta. or no vomiting would indicate the re- Swerdlow et al. (1983) have reported latively low increase of estrogens among that there was a substantially increased mothers of the cases with cryptorchidism. risk of cryptorchidism for those who had As a matter of fact, Burton et al. (1987) undergone breech labor. On the other have reported that the mean estradiol hand, Hjertkvist et al. (1989) reported, levels of maternal serum in early preg- from the results of a case-control study nancy were lower in cases born with in Sweden, that Caesarean section was cryptorchidism than in controls, although found to be significantly more common the difference was not statistically sig- in the cryptorchid than the control group, nif icant. The lower increase of estro- and that breech labor was not associated gens, if any, would reflect anomalous with cryptorchidism. They have inferred hormonal milieu among the pregnant from the finding that cryptorchidism case mothers, as compared to the con- might be caused by hormonal influences trol mothers. during pregnancy, which could be af- The number of mothers who had de- fected by placental dysfunction, because livered the index child by means of vac- placental insufficiency has been reported uum extraction, breech extraction, or to be the most common reason for Cae- 58 MORI, ET AL.

sarean section in Sweden. which showed the significantly elevated The percentage of mothers who had risk for lower birthweight, gestational never breast-fed the index child was use of progestins, and breech labor higher among cases with cryptorchidism (Depue, 1984). But, more researches on than among controls. Because low levels inguinal hernia should be conducted by in secretion of placental steroids and/or a well designed analytical epidemiology, prolactin have been suggested to cause because of few such studies. maldevelopment of mammary glands and Depue (1984) have found multiple mal- breast-feeding failure(Johnson and formations including chromosomal anom- Everitt, 1988), it is possible that the pi- aly among cases with cryptorchidism. tuitary hypofunction of a mother or an Benson et al. (1991)showed, from a study impaired functioning of the placenta of 224 cases with cryptorchidism as com- would result in the higher proportion of paring the local population in Rochester, the case mothers who had never breast- Minnesota, that the increased risks were fed. But, further researches should be noted for inguinal hernia, hydrospadias, carried out with regard to this associ- cleft palate, clubfoot, and congenital ation, because any of the case-control heart disease among the cases. These studies conducted in the Occidental coun- congenital malformations were consis- tries have not indicated the relation of tently observed in our study except for maternal breast-feeding failure to cryp- clubfoot. torchidism. Depue (1984) have reported that in- Davies et al. (1986)have found that utero exposure to external estrogens was the mothers of the cases with cryptor- significantly associated with the elevated chidism were more likely to have been risk for cryptorchidism, but we could not subjected to a threatened abortion in get the supportive result for his find- their study. They have suggested that ing. Some other studies (Beard et al. impaired functioning of the placenta in 1984; Davies et al. 1986) have also shown early pregnancy would be related both to no significant relationship of in-utero es- a threatened abortion and defective de- trogen exposure to cryptorchidism. Low scent of testis through a reduced pro- birth weight was not associated with duction of human chorionic gonadotro- cryptorchidism in our data, although phin. other case-control studies(Czeizel et al. Baker et al. (1988)have revealed that 1981a; Swerdlow et al. 1983; Depue, 1984; cryptorchid preterm infant failed to show Beard et al. 1984; Morley and Lucas, 1987) the normal rise in plasma testosterone have noticed this relationship. in the first week, as compared to the There are possible sources of bias matched controls. They have speculated which we could not eliminate from the from the finding that inadequate stim- study. Firstly, the controls were selected ulation of testosterone release by human from outpatients of a pediatric division chorionic gonadotrophin in the fetus in a general hospital, even though most might contribute to the pathogenesis of of them were diagnosed as having only cryptorchidism in preterm infant. minor disorders. Thus, selection bias Our study as well as those by Swerdlow may be found in the control group. Fur- et al. (1983)and Depue (1984)have shown ther, because boys primarily diagnosed the high prevalence of cryptorchidism as cancers or congenital anomaly were with inguinal hernia or hydrocele, as ex- excluded from the survey, another se- pected on embryological grounds. There lection bias may exist in the study. Es- is a case-control study on inguinal hernia pecially, it is plausible that odds ratios MATERNAL FACTORS OF CRYPTORCHIDISM 59 concerning complicated congenital dis- CHILVERS,C., PIKE, M. C., FORMAN,D., FOGELMAN,K. eases might be overestimated due to and WADSWORTH,M. E. J. (1984). Apparent this exclusion. Secondly, about 25% of doubling of frequency of undescended testis mothers contacted for the case group and in England and Wales in 1962-81. Lancet ii, 330-332. around 40% of mothers contacted for the CZEIZEL,A., ERODI,E. and TOTH, J. (1981a). An control group did not respond to the sur- epidemiological study on undescended testis. vey. Accordingly, non-respondent bias J. Urol. 126, 524-527. may exist in the results. Thirdly, about CZIZEL,A., ERODI,E, and TOTH, J. (1981b). Gene- 24% of the case mothers were interviewed, tics of undescended testis. J. Urol. 126, 528- but the rest of the case mothers and all 529. the control mothers were surveyed DAVIES,T. W., WILLIAMS,D. D. R, and WHITAKER, through the mail to fill out and return. R.H. (1986). Risk factors for undescended This difference might induce informa- testis. Int. J. Epidemiol. 15, 197-201. tion bias such as recall bias and inter- DEPUE,R.H. (1984). Maternal and gestational factors affecting the risk of cryptorchidism viewer bias. and inguinal hernia. Int. J. Epidemiol. 13, 311-318. Acknowledgments : We thank Dr. H. Nanbu DEPUE,R. H. (1988). Cryptorchidism, an epi- of Sapporo Tenshi Hospital, Drs. S. Shimamura demiologic study with emphasis on the re- and K. Horino of Sapporo Teishin Hospital for lationship to central nervous system dys- allowing us to access to their patients. 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