Intrauterine Exposure to Mild Analgesics During Pregnancy and the Occurrence of Cryptorchidism and Hypospadia in the Offspring

The Generation R Study

Claudia A. Snijder; Andreas Kortenkamp; Eric A.P. Steegers; Vincent W.V. Jaddoe; Albert Hofman; Ulla Hass; Alex Burdorf


Hum Reprod. 2012;27(4):1191-1201. 

In This Article

Abstract and Introduction


BACKGROUND Recently, over-the-counter mild analgesic use during pregnancy has been suggested to influence the risk of reproductive disorders in the offspring. We examined the influence of maternal exposure to mild analgesics during pregnancy on the occurrence of cryptorchidism and hypospadia in their offspring.
METHODS Associations between maternal exposure to mild analgesics during pregnancy and cryptorchidism or hypospadia in the offspring were studied in 3184 women participating in a large population-based prospective birth cohort study from early pregnancy onwards in the Netherlands (2002–2006), the Generation R Study. Cryptorchidism and hypospadia were identified during routine screening assessments performed in child health care centres by trained physicians. The use of mild analgesics was assessed in three prenatal questionnaires in pregnancy, resulting in four periods of use, namely, periconception period, first 14 weeks of gestation, 14–22 weeks of gestation and 20–32 weeks of gestation. Logistic regression analyses were used to study the associations between maternal exposure to mild analgesics and cryptorchidism and hypospadia.
RESULTS The cumulative prevalence over 30 months of follow up was 2.1% for cryptorchidism and 0.7% for hypospadia. Use of mild analgesics in the second period of pregnancy (14–22 weeks) increased the risk of congenital cryptorchidism [adjusted odds ratio (OR) 2.12; 95% confidence interval (CI) 1.17–3.83], primarily due to the use of acetaminophen (paracetamol) (adjusted OR 1.89; 95% CI 1.01–3.51). Among mothers of cryptorchid sons, 33.8% reported (23 of 68) the use of mild analgesics during pregnancy, compared with 31.8% (7 of 22) of mothers with a boy with hypospadia and 29.9% (926 of 3094) of mothers with healthy boys.
CONCLUSIONS Our results suggest that intrauterine exposure to mild analgesics, primarily paracetamol, during the period in pregnancy when male sexual differentiation takes place, increases the risk of cryptorchidism.


Congenital anomalies are a significant cause of stillbirth and infant mortality and are also important contributors to childhood morbidity (Dolk et al., 2010). Although cryptorchidism (undescended testis) is one of the most common abnormalities in newborn boys worldwide, the aetiology in boys without chromosomal abnormalities is largely unknown (Pierik et al., 2005; Chacko and Barthold, 2009). Reproductive disorders, including cryptorchidism, hypospadia and poor semen quality are hypothesized to constitute a testicular dysgenesis syndrome, in which environmental and genetic factors play a role (Skakkebaek et al., 2001; Main et al., 2009).

Use of medication, such as diethylstilbestrol and valproic acid therapy, during pregnancy increases the risk of congenital malformations, including cryptorchidism and hypospadia (Palmlund et al., 1993; Palmer et al., 2009; Jentink et al., 2010). Recently, some evidence was presented that over-the-counter mild analgesic use may also increase the risk of cryptorchidism in the offspring (Kristensen et al., 2010). In the Netherlands, ~40% of the population uses over-the-counter self-medication such as acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs (NSAIDS) which are also used by pregnant women (Werler et al., 2005; Statistics Netherlands, 2011).

Experimental rat models have shown that normal androgen action during a critical male programming window (gestational day 15.5–17.5) is crucial for the programming of the testis decent (Welsh et al., 2008). Factors that diminish androgen action during that time may have detrimental consequences for male sexual differentiation (Skakkebaek et al., 2001). Exposure of pregnant rats to phthalate esters during gestational days 15–17 resulted in hypospadia, cryptorchidism, testicular injury and nipple retention in male offspring, and this was attributed to reductions in testosterone synthesis (Foster, 2006). A recent study by Kristensen et al. (2010) showed that paracetamol, even at low plasma concentrations such as 1 μM, is a potent inhibitor of testosterone production, reducing anogenital distance and testosterone production in rats. Furthermore, cyclooxygenase (COX) inhibitors, such as acetaminophen, ibuprofen and acetylsalicyclic acid have shown endocrine disrupting properties in rainbow trout, affecting steroid hormone synthesis (Gravel and Vijayan, 2006).

These experimental observations have found echos in human observational studies. As early as 1996, Berkowitz and Lapinski (1996) reported that the use of analgesics during pregnancy was a risk factor for cryptorchidism. A recent study by Jensen et al. (2010) among 47 400 live born children in the Danish National Birth Cohort showed that exposure to acetaminophen in both the first and second trimester increased the risk of cryptorchidism. Kristensen et al. (2010) were able to substantiate these observations among a different cohort of Danish pregnant women, and observed that combined use of acetaminophen with other analgesics further increased the risk of cryptorchidism. However, similar associations were not observed among Finnish mothers and their boys, possibly because this disorder is comparatively rare in Finland (Kristensen et al., 2010). Further research is therefore urgently needed to corroborate or refute these findings.

The aim of this study was to investigate whether the use of mild analgesics during pregnancy by mothers was associated with an increased occurrence of cryptorchidism and/or hypospadia in their offspring. We conducted this study within the Generation R Study, a large prospective birth cohort study from early pregnancy onwards examining determinants of growth, development and health from fetal life until young adulthood (Jaddoe et al., 2010).


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