Statistical analysis
We listed the number of infants with hypospadias in the CH group, PIH
group, and control group to estimate the prevalence of hypospadias among
pregnancies with or without hypertension. A t-test and single-factor
chi-square analysis were used for continuous variables and categorical
data,respectively, to screen out potential exposure factors for
hypospadias. These exposure factors, which showed significant
differences upon single-factor analysis, were included in the follow-up
binary logistic regression analysis for categorical variables and the
linear regression for continuous variables. The crude regression
analysis was conducted to estimate the prevalence of odds ratios (ORs)
and 95% confidence intervals (CI) for the associations of hypospadias
with the different risk factors in the single-factor analysis.
Multivariate regression analysis assessed the independent contribution
of these factors to the risk of hypospadias. The Statistical Package for
the Social Sciences software (version 25.0) was used to sort out and
statistically analyze the relevant data. A significance level of
P<0.05 was set for all the tests.
Results
A total of 42,075 pregnancies produced 42,832 male infants from January
2015 to December 2019. There were588 male infants (including three pairs
of twins) who had any other deformities except hypospadias, and we
excluded these male infants and their mothers (n=585). Finally,
41,490pregnanciesand 42,244 male infants were enrolled (Figure 1). The
prevalence of gestational hypertension and hypospadiasis shown in Table
1. In all, 97 newborns were diagnosed with hypospadias, and the overall
incidence of hypospadias was 0.23% (97/42,244). Of all the pregnant
women, 119(0.29%) had CH, 2,648(6.38%) had PIH, and 38,723(93.33%)
had no evidence of hypertensionand were therefore used as the control.
The occurrencerate of hypospadias was higher in the PIH group than in
the control group (0.944% vs. 0.186%, respectively; RR: 5.08), whereas
the occurrence rate in the chronical hypertension group was 0% (Table
1).
The results of the t-test and chi-square test revealed that patients
with PIH (25.8% vs. 6.8%), multiple births (17.5% vs. 5.5%),
hyperthyroidism (4.1% vs. 0.6%), preterm deliveries (30.9% vs.
9.0%), low-birth-weight (LBW) infants (34.0% vs. 5.1%), and SGA
infants (27.8% vs. 2.0%)hada higher incidence of hypospadias than the
control participants (P<0.01; Table 2). The influence of the
mothers’ age, CH, placenta previa, DM, hypothyroidism, hepatitis B,
obesity, amniotic fluid, and use ofin vitro fertilization (IVF)on
the prevalence of hypospadias was not significant between
groups(P>0.05).
To estimate the contribution of these factors on hypospadias, a binary
logistic regression analysis was conducted for categorical variables
(PIH, singleton births, hyperthyroidism, SGA), and a linear regression
was also carried out for continuous variables (gestational age, birth
weight; Table3). These factors still showed a significant relationship
with hypospadias in this crude model. However, after adjustment for
these potential confounders in a multivariate logistic regression
analysis, the results indicated that singleton births (OR: 1.215, 95%
CI: 0.672–2.196, P=0.520) and gestational age (OR: 1.138, 95% CI:
0.982–1.319, P=0.087) failed to maintain statistical significance,
whereas PIH (OR: 2.437, 95% CI: 1.478–4.016, P<0.01),
hyperthyroidism (OR: 4.008, 95% CI: 1.364–11.773, P=0.012), LBW (OR:
0.852, 95%CI: 0.795–0.912, P<0.01), and SGA (OR: 3.282,
95%CI: 1.644–6.549, P<0.01) wereindependent factors that
contributed to hypospadias.
Discussion
Prior studies have suggesteda certain relationship between hypertensive
disorders in pregnancy and the occurrence of hypospadias in Caucasian
populations [11, 12]. However, there is still a lack of large-scale
clinical research related to this condition in China. Our study was
based on a retrospective cohort study of 41,490 maternal patients and
their 42,244newborns, and it found that the occurrence rate of
hypospadias also had a significant correlation with PIH inChina. In this
study, PIH caused a significant increase in the incidence of hypospadias
in male newborns that reached 0.944%, which was about five times as
highas the rate in the normotensive pregnancies in the control group
(0.186%). Moreover, the statistical analysis showed that the risk of
hypospadias caused by PIH was still more than three times as high after
multi-factor correction.Interestingly, no newborn with hypospadias was
identified in the group with CH in this study, which may have been
influenced by the difference in the etiology of these two conditions. CH
and PIH share common symptoms of high blood pressure, butthe former is a
type of vascular disease that is mostly related with atherosclerosis,
psychological factors, or genetic factors, while PIH is typically
associated with gestational status and may be caused by placental
dysfunction. This study may help explain the potential pathogenesis of
hypospadias related with HIP.
The key time window for male reproductive organ development is from
8–14 weeks of gestation during early pregnancy. There is evidence
[8] that the morphogenesis of the male reproductive organs depends
on a series of hormonal stimulations in which placental-derived hormones
play a key role. At first, the human chorionic gonadotropin hormone
secreted by the placenta in the early embryo stimulates the
differentiation of testicular stromal cells. By the eighth week of
pregnancy, testicular stromal cells begin secreting testosterone, which
is essential for the normal development of the penis and testes.
Therefore, placental dysfunction in early pregnancy could be a possible
pathogenic factor for hypospadias. Placental dysfunction was common in
patients with PIH [9], which indicated that PIH was relevant to the
pathogenesis of hypospadias. In many pregnancies with PIH, especially
preeclampsia, early placental function is seriously affected.
Hypertension caused by placental spiral, insufficient arterial invasion,
luminal contraction and stenosis, or inadequate placental blood flow
perfusion may lead to important changes in placental function and
consequently affect fetal growth and development [9, 10]. Although
PIH is usually diagnosed after 20 weeksof gestation (after the key time
window of hypospadias development), the condition may beginlong before
20 weeks, which means that PIH may impact urologic development
substantially earlier than it is diagnosed. It is still unknown whether
hypospadias occurs secondary to PIH or whether both are outcomes of a
common pathogeny. Further genetic or pathologic studies should reveal
the potential pathogenesis.
The proportions of hypospadias in LBW and SGA neonates were
significantly higher than those in normal-weight neonates. LBW is
usuallyrelated with premature delivery, which is a common complication
in patients who have hypertensive disorders in pregnancy. A multivariate
regression analysis indicated thatgestational age showed no significant
relationship with hypospadias after adjustment for confounding factors.
However, a decreasing birth weight still increased the incidence of
hypospadias in the multivariate regression analysis. In addition, SGA
was determined to be an independent risk factor for hypospadias
regardless of gestational age. This finding suggested that chronic
intrauterine distress might predict the risk of hypospadias in the male
fetus despite the gestational age. The birth weight for gestational age
could also reflect the condition of fetal growth in the uterus at every
stage of gestation; the most intuitive manifestation of fetal growth
restriction is that the fetal weight, body length, and biparietal
diameter during pregnancy arelower than the normal average [15]. The
rate of hypospadias after birth was as high as 1.9% in the group with
limited fetal growth during pregnancy[15]. Therefore, fetal weight
assessment, body length, and biparietal diameter monitoring during
pregnancy can play a vital role in predicting the risk of hypospadias.
Our findingsfrom this study may contribute to further information about
this condition and a better understanding of how it develops.
The presence ofhyperthyroidism during pregnancy also showed a
significantlyincreased risk of hypospadias in newborns in our study. The
relationship between neonatal malformations and hyperthyroidism that is
treated during pregnancy is still controversial. Most scholars believe
that the drugs used to treat hyperthyroidism are more likely to be
teratogenic; for example, propylthiouracil is recommended to treat
hyperthyroidism during pregnancy [13, 14]. Additionally, the timing
of the onset of hyperthyroidism and beginning its associatedmedication
may also affect the pathogenesis of hypospadias. Our study showed that
the 95% CIsspanned a wide range from 1.364–11.773, which may have
decreased the confidence level. Studies with further classification of
thyroid diseases and the medications that pregnant women take for
themcouldbetter explain their relationship with hypospadias with more
certainty.
IVF did not increase the risk of hypospadias in newborns, and this
result is consistent with those of previous studies [16]. The risk
of hypospadias in the offspring of older women was significantly
increased according to the statistics of California Birth Defects
Monitoring[17]. However, this present study did not reach a similar
conclusion. The statistical results showed that there was no significant
difference in maternal age between the two groups.
One limitation of our study was that we did include any information
about family history, hormonal medications, exposure to toxic and
hazardous substances, or the history of previous abortions. During the
process of data collection, we also found that the information we
already had might not be correct due to a consideration for the
patients’ personal privacy or inadequate medical history collecting.
Therefore, to avoid inaccuracies, we did not include these data.
Additionally, the classification of hypertensive disorder in pregnancy
might need more refinement. Further work may require optimized
classifications and a more comprehensive design to provide deep insight
into the complex etiology of hypospadias.
Conclusion
Our findings suggested that maternal PIH was an important independent
risk factor for hypospadias in Chinese newborns, while CH showed no
relationship with hypospadias in the offspring of mothers with PIH. In
addition, LBW and SGA (which indicaterestricted growth of the fetus) and
hyperthyroidism of the mother werealso significantly associated with
hypospadias.