Analgesic medications (painkillers) even when taken at the recommended dosages, could possibly still have a negative impact on an unborn child if taken during a woman’s pregnancy.
For expecting moms, this may be somewhat uncomfortable news. During the different stages of pregnancy, various minor discomforts, like headaches or backache are commonly experienced. The odd paracetamol, even at the low dosages often recommended by doctors, provides some relief, but could that even be harmful to an unborn baby?
This question has already been researched in animal studies and medication usage during pregnancy has been highlighted as something to be cautious about, even though scientific proof is yet to conclusively demonstrate any major defects and developmental problems in an unborn foetus.
New research, however, is examining the potentially adverse fertility influences these medications may have in humans and findings seemingly show that there is reason to question their safety and the possibility of adverse effects that can occur at such critical development stages of life as a result of their use.
Analgesics (pain relievers) and safety during pregnancy
For the most part, medication use during pregnancy is not a well-established area in terms of researched efficacy (safety) – mostly because actual human subjects are not feasible research participants due to the high-risk trials would impose on expectant mothers and their unborn children.
As a result, certain medications are deemed ‘safe’ at specific low dosages (therapeutic doses) during different gestational periods, while many others are classified as more high risk with serious complication factors for both mother and unborn child.
But, this places many women in a slightly confusing spot. Are painkillers really safe, or aren’t they? Since (human) research is limited and adverse effects not conclusively clear, just how concerned should women be about use of painkillers during their pregnancy? It would seem that researchers are still questioning this too and starting to make some inroads when it comes to producing answers…
Types of painkillers and their associated risks in pregnancy
There are two primary categories of analgesics – systemic non-opioid analgesics and opioid analgesics. Typical over-the-counter drug variations such as aspirin, acetaminophen (paracetamol) and NSAIDs (non-steroidal anti-inflammatories) are classed as the former. While the latter category typically includes prescription varieties and can include codeine, oxycodone, hydrocodone, morphine or meperidine.
Such medications, regardless of their class, are not always entirely avoidable for women during pregnancy. Medical professionals also do not typically completely discourage pregnant women from their use either as enduring physical pain may have adverse effects too. Many women legitimately require opioids for symptom management, but this must be carefully controlled and managed by a medical doctor in order to avoid problems such as premature birth or even drug withdrawal complications (affecting both mother and unborn baby). Major and minor birth defects are also regarded as serious risk factors, as is drug addiction.
The risk of birth defects is of significant concern, and for good reason. Many defects are difficult to treat or ‘cure’ at all. The general guidelines urge all expecting women to engage in detailed consultation with their medical doctor before ‘popping any pills’, and to adhere to the prescribed lower dosages, this applies to any varieties of a herbal nature too. It’s important to assess the symptoms experienced with caution and then weigh risks against benefits when it comes to general medication as a form of treatment.
Nevertheless, with relatively high percentages of women using non-prescription medications, which are easily obtained over-the-counter, it may be worth a second thought when it comes to safety. ‘Relatively-safe-to-use’ and ‘completely-safe’ are not the same thing – major malformation may not be high on the list of things to think about when it comes to maternal paracetamol usage, but it must surely be reasonable to assume that such a drug has ‘some effect’ - other than simply alleviating symptoms of mild pain and fever? This is what researchers have been investigating, and here’s what studies have shown…
For minor pain and fever-related ailments, acetaminophen (paracetamol) is widely used all around the world and is considered the safest analgesic for relief of mild to moderate symptoms – at any stage of pregnancy. In fact, for pregnant women there are few, if any, other alternatives.
The general guidelines for ‘safe usage’ promote usage at the lowest dosages and for the shortest period of time possible. The priority is to safeguard the unborn baby and minimise risk with as little drug exposure as is possible.
That said, it is believed that compounds in acetaminophen and NSAID medications are able to cross the placenta during pregnancy and thus impact foetal circulation. In this way, adverse effects on development can occur.
According to a study published in the Scandinavian Journal of Pain, the adverse effects on an unborn baby associated with the use of acetaminophen during pregnancy (particularly in the first trimester) include the development of asthmatic conditions, allergies, autism spectrum disorder, lower IQ (intelligence quotient), neurodevelopmental issues (relating to communication and gross motor development), impaired attention, behavioural issues and poor male reproductive concerns. (1)
Compromised neurodevelopment and risk factors due to gestational acetaminophen use has been researched in both large and small prospective studies, linking prenatal exposure to the development of ADHD (attention deficit / hyperactivity disorder) and ADHD-like behaviours in children.
Associations have not seemingly produced conclusive results and thus, gestational use isn’t yet entirely frowned upon, but general practice does tend to err on the side of caution. (2)
The impact on language development is another example which has been recently studied as an adverse effect following acetaminophen use during pregnancy. One of the most recent studies determined that language development in the offspring of women who used the drug could be compromised at 30 months. (3)
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is found in common brands like Arthrofen, Brufen, Ebufac, Fenbid and Nurofen. It is not generally recommended for use during pregnancy, but an odd low dose has been known to feature in many pregnancies without major implications. It should not be used at all during the third trimester.
The injurious effects of acetaminophen or ibuprofen are associated with a predisposition to oxidative stress in the body. This occurs when the body is unable to detoxify or counteract the presence of harmful substances with neutralising antioxidants, causing an imbalance in the production of free radicals. Oxidative stress causes damage to the body’s cells, proteins and even our DNA.
Could the fertility of future generations be put at risk?
A research team from the University of Edinburgh (United Kingdom) and Copenhagen University Hospital (Denmark) published a new study in the April 2018 edition of the journal, Environmental Health Perspectives detailing their findings regarding the fertility of generations in the future. (4)
Their study, funded by the Medical Research Council (MRC), Wellcome Trust and the British Society of Paediatric Endocrinology and Diabetes, focussed on the commonly used medications paracetamol (acetaminophen) and ibuprofen, aiming to determine if these drugs could have any effect on an unborn baby’s fertility later in life, or perhaps even further down the line when he/she had a child of their own. The research team aimed to assess whether these medications could potentially impact DNA by leaving epigenetic marks (i.e. inherited changes in gene expression) when used during pregnancy.
Senior author, Dr Rod Mitchell hasn’t yet urged a major shift in general recommendation practice when it comes to painkiller use, and still reiterates the same precautionary advice – “We would encourage women to think carefully before taking painkillers in pregnancy and to follow existing guidelines — taking the lowest possible dose for the shortest time possible.”
The team’s findings, however, do highlight the potentially adverse effects of these medications, which perhaps further research will be able to help solidify even more down the line. For now, it is reasonably clear to this team of researchers that exposure to paracetamol and ibuprofen triggers cell mechanisms that impact the structure of DNA, resulting in epigenetic marks. This means that potential problems, like fertility difficulties could then be inherited (i.e. passed down through generations).
The idea that DNA structure alternations can occur didn’t stem from nowhere. Previous animal studies (in rats) have highlighted this before. These experimental studies have shown reduced levels of testosterone production in the foetal testis of rodents. Further study using human foetal testis tissues exposed to acetaminophen which were xenografted in mice also showed reduced plasma testosterone levels.
Biological cells, called germ cells / GCs (functioning as embryonic precursors of gametes - sex or reproductive cells) were shown to experience some adverse impact due to exposure to the two drugs. Female gametes are essentially ova / egg cells and male gametes refer to sperm. In the animal studies, it was noted that germ cells in female offspring were considerably reduced as a result of exposure. Drug exposure was shown to have an impact on prostaglandins (physiologically active lipid molecules / compounds). These molecules influence the healthy function of the ovaries in females and testes in males, which means that any alteration would have a domino effect on fertility in subsequent generations.
With this in mind, the research team aimed to carefully assess the impact therapeutically recommended dosages could have of human fertility for both unborn boys and girls later in life.
How was the study conducted and what were the findings?
The research team conducted their study using in vitro (cells analysed outside of their usual biological environment) and xenograft (tissues taken from a donor and grafted to another recipient) methods, working with both human tissues and rat models. The rat participants served as a physiological model for comparison with the more laboratory orientated methods (in vivo cultured tissues).
The team made use of cultured human foetal ovary and teste tissues (obtained during the first-trimester) which were exposed to acetaminophen or ibuprofen medications over a 7-day period. The team also used human foetal testes tissues (obtained during the second-trimester) which were exposed to acetaminophen (for between 1 and 7 days) or ibuprofen (for 7 days) in a culture dish, and xenografted to rat models.
The host rodents (36 of them) were castrated 2 weeks before the xenografting process and given Carprofen (an NSAID widely used in veterinary practice) in drinking water. The team prepared the testes tissue by separating each sample into between 4 and 6 pieces. This was then subcutaneously grafted beneath the dorsal skin of each rodent recipient (side or midline body portions). These grafts were maintained for a 7-day period. From there the hosts (rodents) were exposed to acetaminophen for 1 day and then 7 days (acetaminophen and ibuprofen). Acetaminophen dosages were 20mg/kg three times a day. Ibuprofen dosages were 10mg/kg three times a day. To mimic the in-utero (IU) environment of a human pregnancy, each host was injected with hCG (human chorionic gonadotropin) every 72 hours. Grafts were later retrieved once the process was complete for immunohistochemistry analysis (sophisticated imaging study) in order to quantify the germ cell numbers.
The team did not use human foetal ovarian tissues for xenograft analysis as previous attempts had not achieved favourable viability.
To assess the prostaglandin pathway, the team then went on the assess the effects of the drugs on NTera2 cells (human testicular embryonic carcinoma stem cell line). These cells were selected as the isolation and culture of human foetal germ cells is currently not feasible. NTera2 cells are however, similar to foetal germ cells, making them useful for analysis. Exposure was done using acetaminophen, ibuprofen and an EP2 (prostaglandin E2 receptor).
The team noted in their laboratory analysis that the short period of drug exposure did indeed have an impact on the germ cells. First trimester female ovarian tissues exposed to acetaminophen produced 43% fewer egg cells. With exposure to ibuprofen, this cell number virtually halved (49%).
The key take out from this finding is that female foetuses produce all of their lifetime eggs while still in the womb. “… If they are born with a reduced number it could lead to an early menopause,” says Dr Mitchell.
Testicular tissues exposed to both drugs showed a reduction of sperm producing cells by about a quarter.
When the researchers xenografted human tissues to 36 castrated rodent recipients during the animal study portion of the research, sperm producing cells in testes tissue declined by 17% with just one day’s worth of drug exposure. This reduced even more following one week’s worth of medication exposure with declines of 43% (acetaminophen) and 53% (ibuprofen) respectively.
The three exposure methods (acetaminophen, ibuprofen and EP2) used to assess the prostaglandin pathway did reduce the cell numbers within a 48-hour period. This further suggested that DNA alteration (impacting the expression of epigenetic regulatory genes in the NTera2 cells) was entirely possible due to drug exposure.
What conclusions have the research team drawn?
Taken at therapeutically recommended dosages during pregnancy, acetaminophen and ibuprofen are capable of reducing germ cell numbers in both human foetal ovaries and testes significantly. The team managed to demonstrate this in both the cultured (using first trimester samples) and xenograft (using second trimester samples) methods. These analgesics are capable of altering the epigenetic genes in NTera2 cells as well. Altered DNA could be induced by exposing the drugs to NTera2 cells. These methods were selected since analysis is not feasible using actual human pregnant female participants.
This study effectively reinforces what has already been previously noted when using pregnant rodents with regards to the future fertility of next-generation females. This study demonstrates that both male and female fertility can be impacted with maternal use of either of the two drugs. The concentration dosages used were consistent with recommended human usage. The mechanism for reduction for both males and females appears to be mediated by prostaglandin pathways.
The research team feel that the consistent findings from their most recent study and previous analysis in rodents supports a need for further investigation. There is still much to be learned through follow-up research in relation to reduced fertility during adulthood.
The team do acknowledge that the gene expression changes noted in their study were not entirely consistent, making potential consequences a somewhat grey area, which further research could help to clarify. One reason for this is that the methods used can only mimic certain aspects of normal human foetal development. None of the methods used can precisely recreate in vivo human conditions. Another recognised limitation is that dose-response analysis was somewhat inadequate as a result of a lack of human foetal tissue samples. NTera2 cells are also essentially tumour cells and do not represent a true foetal germ cell line, however, they are believed to originate from foetal germ cells.
That said, the research team believe that their findings show consistency with previous research in rodents and add to a growing body of study analysis that highlights potential adverse effects impairing normal human development using therapeutic dosages during pregnancy. The team recommend that prospective studies analyse these effects even further using these particular medications (since they are widely used by a high percentage of pregnant women around the world) to explore the reproductive outcomes of these chemical exposures on future generations.
1. The Journal of the European Psychiatric Association. October 2017. Prenatal exposure to acetaminophen and children's language development at 30 months: http://www.europsy-journal.com/article/S0924-9338(17)32989-9/abstract [Accessed 18.04.2018]
2. US National Library of Medicine - National Institutes of Health. March 2016.Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring: https://www.ncbi.nlm.nih.gov/pubmed/27046315 [Accessed 18.04.2018]
3. The Journal of the European Psychiatric Association. October 2017. Prenatal exposure to acetaminophen and children's language development at 30 months: http://www.europsy-journal.com/article/S0924-9338(17)32989-9/abstract [Accessed 18.04.2018]
4. Environmental Health Perspectives. April 2018. Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems: https://ehp.niehs.nih.gov/ehp2307/ [Accessed 18.04.2018]