Paracetamol and pregnancy: is it compatible?

The National Birth Defects Prevention Study (NBDPS), which examined data from 16,110 children in the United States exposed to paracetamol in utero, found no increased risk of congenital malformations with paracetamol use. Among women using paracetamol specifically for febrile illnesses (fever), a reduced risk of various cranial and facial malformations and of gastroschisis (a congenital abdominal wall defect in which the baby's intestines are located outside the body [4]) was observed. In these situations of fever during pregnancy, paracetamol may be protective as fever increases the risk of these malformations [5]. 

Similarly, in a study of more than 26,000 children exposed to paracetamol during the first trimester of pregnancy, researchers did not observe an increased prevalence of congenital anomalies compared with more than 61,000 children not exposed to paracetamol. No association was found between congenital anomalies and the duration of use during the first trimester. However, they did observe a more than 2-fold increased risk of developing "median cysts, fistulas, sinuses" (congenital anomalies of the ear, face and neck) [6].

During pregnancy, changes occur in paracetamol metabolism, which may make pregnant women and their foetus more vulnerable to toxic effects. A fraction of paracetamol is converted into a toxic metabolite (N-acetyl-p-benzoquinone imine), and under normal health conditions outside of pregnancy, this metabolite is rapidly detoxified from the body. The results of a study modelling the action of paracetamol suggest that formation of this toxic metabolite is higher in pregnant women than in non-pregnant women, particularly during the first trimester [7]. 
These results should be interpreted with caution, as this study is based on a model and was not conducted directly in pregnant women.

Paracetamol can be toxic to the liver and, as it appears to cross the placenta freely, therapeutic and certainly toxic doses could affect not only maternal liver cells but also those of the foetus. It should be noted that during foetal development, the liver transiently functions as the main haematopoietic organ (blood cell formation) [8]. 

An experimental study, in which researchers transplanted fragments of human foetal testicular tissue into 64 mice, showed that prolonged use of paracetamol (for 1 week) may reduce testosterone production in the human foetal testis [9]. 

A growing body of clinical evidence (drawn from case studies observing the effects of paracetamol use in certain individuals and associated clinical manifestations) suggests that a probable action of paracetamol in inhibiting prostaglandin signalling (hormones of the immune system) during the third trimester may lead to constriction of the ductus arteriosus, a condition that could result in foetal loss or potentially fatal heart failure in the newborn [22].

A combination of clinical studies and experimental work on animal models and cell lines has suggested that exposure to paracetamol during pregnancy may reduce the number of foetal haematopoietic stem cells (the cells that give rise to white and red blood cells and platelets), alter steroid hormone synthesis in the placenta, and induce placental damage [23].

Animal studies have shown that paracetamol directly disrupts hormone-dependent processes, including the inhibition of androgen production, increased oestrogen production and disruption of immune function. These disruptions have been linked to mechanisms involved in the development of neurodevelopmental and reproductive disorders [10]. 

An observational study from 2010 involving 47,400 boys showed that excessive paracetamol use by the mother for more than 4 weeks during pregnancy within the time window of testicular descent (weeks 8 to 14 of pregnancy) was moderately associated with a 1.38-fold increased risk of cryptorchidism (undescended testicles) [11].

Foetal exposure in animal models has been shown experimentally to cause disorders of the male urogenital tract by reducing the action of androgens [12].

An observational study of pregnant women examined prenatal paracetamol exposure and reproductive outcomes in females. 54% of these women reported having taken paracetamol at least once during their pregnancy. It found that markers of female pubertal development (e.g. pubic hair, acne development) were reached progressively earlier as the number of weeks of prenatal paracetamol exposure increased, with this effect being greater as the dose of paracetamol taken increased [13].

A study on a human foetal ovarian tissue culture showed that paracetamol exposure reduces reproductive cells in the ovaries by 40% and by nearly 30% in the testes. These results are similar for ibuprofen use [14].

A study in mice published in 2016 showed that female mouse pups exposed throughout pregnancy to doses of paracetamol commonly measured in pregnant women in the United States and Europe were born with fewer ovarian follicles. From middle age, adult female mice born with fewer follicles experienced difficulties reproducing and developed premature ovarian insufficiency [15]. 

Four independent research teams consistently found that prenatal exposure to paracetamol may reduce reproductive health and fertility in females. These teams used different rat and mouse models with paracetamol exposure at doses equivalent to or close to the maximum recommended human dose from 13 days after conception until birth. The combined data show that this exposure results in a reduced number of follicles in the adult ovaries and subsequent infertility due to ovarian insufficiency [10].

A population-based study of 754 pregnant women at gestational weeks 8 to 13 examined the relationship between paracetamol use and language development in children [16].

59.2% of women enrolled between weeks 8 and 13 reported having taken paracetamol between conception and enrolment in the study. Paracetamol was detectable in all urine samples, and the amount of urinary paracetamol was correlated with the number of doses taken during pregnancy. Both the number of tablets and the urinary concentration were associated with greater language delay in girls but not in boys. The risk was six times higher for mothers who reported taking more than 6 paracetamol tablets compared to those who had taken none. 

In one study, mothers reported their paracetamol use at weeks 17 and 30 of pregnancy and at 6 months after delivery. They used data from 48,631 children whose mothers returned the follow-up questionnaire at age 3. This sample included 2,919 same-sex sibling pairs, which were used to adjust for family and genetic factors (helping to limit bias by including children from the same sibling group) [17].

The sibling control analysis observed that children exposed to prenatal paracetamol for more than 28 days had poorer gross motor development, communication, and a higher activity level. Children exposed before birth to short-term paracetamol use, 1 to 27 days, also showed poorer gross motor outcomes, but the effects were smaller than with long-term use.

A 2021 study assessed the association between levels of paracetamol metabolites in umbilical cord plasma (direct evidence of foetal exposure, allowing the observed data to be stated with greater certainty) and attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders diagnosed by a physician during childhood [18]. Metabolite concentrations in umbilical cord plasma for the highest intake compared to lower intakes were associated with a more than 2-fold greater likelihood of an ADHD diagnosis and up to a 3-fold greater likelihood of an ASD diagnosis. This association is dose-dependent on the amount of paracetamol taken. 

Another study indicated that children exposed to acetaminophen during the prenatal period were 19% and 21% more likely to later exhibit borderline or clinical symptoms of autism spectrum disorder and attention deficit/hyperactivity disorder compared to unexposed children [19].  

Other studies have also highlighted a link with symptoms of hyperactivity and impulsivity, with the effects being stronger the higher the paracetamol consumption [20], [21].

In one study, the authors sought to quantify the association between spontaneous miscarriage and the types and doses of non-steroidal anti-inflammatory drugs in a population of pregnant women [24]. They obtained data from the Quebec Pregnancy Registry for 4,705 women who had experienced a spontaneous miscarriage. For each case, they randomly selected 10 controls from the other women in the registry, matched by the date of spontaneous miscarriage and gestational age.

The use of non-steroidal anti-inflammatory drugs other than aspirin during pregnancy was significantly associated with the risk of spontaneous miscarriage, with a 2.4-fold increase in risk. More specifically, the use of ibuprofen was associated with a more than 2-fold increased risk of spontaneous miscarriage. This effect was independent of the dose of ibuprofen taken.

Non-steroidal anti-inflammatory drugs are contraindicated in the third trimester, as observational studies show an increased risk of impaired uteroplacental blood flow and a higher incidence of oligohydramnios (i.e. insufficient amniotic fluid) [25], persistent pulmonary hypertension of the newborn [26], renal toxicity [25], and premature closure of the ductus arteriosus [27].