TY - JOUR
T1 - Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons
T2 - a cohort study of 1027 mother-child pairs
AU - Lind, Dorte Vesterholm
AU - Main, Katharina Maria
AU - Kyhl, Henriette Boye
AU - Kristensen, David Møbjerg
AU - Toppari, Jorma
AU - Andersen, Helle Raun
AU - Skovsager Andersen, Marianne
AU - Skakkebæk, Niels Erik
AU - Jensen, Tina Kold
N1 - © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2017/1/1
Y1 - 2017/1/1
N2 - STUDY QUESTION Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD) - the distance from the anus to the genitals - in the offspring? SUMMARY ANSWER Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls. WHAT IS KNOWN ALREADY Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD. STUDY DESIGN, SIZE, DURATION A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score. MAIN RESULTS AND THE ROLE OF CHANCE A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found. LIMITATIONS REASONS FOR CAUTION Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use.
AB - STUDY QUESTION Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD) - the distance from the anus to the genitals - in the offspring? SUMMARY ANSWER Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls. WHAT IS KNOWN ALREADY Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD. STUDY DESIGN, SIZE, DURATION A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score. MAIN RESULTS AND THE ROLE OF CHANCE A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found. LIMITATIONS REASONS FOR CAUTION Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use.
KW - Journal Article
U2 - 10.1093/humrep/dew285
DO - 10.1093/humrep/dew285
M3 - Journal article
C2 - 27852690
SN - 0268-1161
VL - 32
SP - 223
EP - 231
JO - Human Reproduction
JF - Human Reproduction
IS - 1
ER -
