Letter: P

Pivmecillinam is a penicillin antibiotic indicated for the treatment of cystitis, chronic or recurrent bacteriuria, and urinary tract infections.

The limited data available do not provide compelling evidence of an increased risk of congenital malformations, miscarriage, intrauterine death, low birth weight, preterm delivery, or neonatal complications following exposure to pivmecillinam. Where possible associations with adverse outcomes have been suggested, findings are considered likely influenced by the effects of maternal infection during pregnancy.

The extensive body of data relating to maternal use of penicillin antibiotics as a class does not indicate an increased risk of adverse fetal outcomes, although not all pregnancy outcomes have been studied in sufficient detail to fully exclude an increased risk. However, due to the potential adverse consequences of untreated maternal infection during pregnancy, the use of penicillin antibiotics, including those with limited or no pregnancy safety data, may be considered where clinically necessary.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines. It is important to ensure adequate treatment of infections in order to avoid adverse maternal and fetal effects from uncontrolled infection or pyrexia.

The Royal College of Obstetricians and Gynaecologists (RCOG) advises routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without pre-labour rupture of membranes (PROM). Benzylpenicillin should be used preferentially, but a cephalosporin should be used in women with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to women who cannot tolerate erythromycin.

Exposure to pivmecillinam at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Phenoxymethylpenicillin is a penicillin antibiotic indicated for the treatment of pneumonia, bronchitis, bacterial pharyngitis, otitis media, and skin and soft tissue infections.

The limited data do not suggest an increased risk of congenital malformations, miscarriage, intrauterine death, low birth weight (LBW), preterm delivery, or neonatal complications following prenatal exposure to phenoxymethylpenicillin. Where possible associations with adverse outcomes have been suggested, findings are considered likely influenced by the effects of maternal infection during pregnancy.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines. It is important to ensure adequate treatment of infection in order to avoid adverse maternal and fetal effects from uncontrolled infection or pyrexia.

The Royal College of Obstetricians and Gynaecologists (RCOG) advises routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without pre-labour rupture of membranes (PROM). Benzylpenicillin should be used preferentially, but a cephalosporin should be used in women with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to women who cannot tolerate erythromycin.

Exposure to phenoxymethylpenicillin at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Perampanel is licensed as an adjunctive treatment for partial-onset seizures with or without secondarily generalised seizures, and primary generalised tonic-clonic seizures in people with idiopathic generalised epilepsy.

It is important that epilepsy remains well-controlled during pregnancy.

There is limited evidence regarding the safety of perampanel use in pregnancy, with data provided by a small number of uncontrolled studies which collectively describe the outcomes of 99 exposed pregnancies, mainly exposed in early pregnancy only. As such, the available evidence regarding perampanel exposure in later pregnancy is highly limited.

Although the available data do not demonstrate increased risks of adverse pregnancy or fetal outcomes following perampanel use in early pregnancy, these data are highly limited and higher quality studies are required before a more accurate safety assessment can be provided. Additionally, no studies have investigated the risk of longer-term childhood outcomes such as neurodevelopmental impairment.

A case of presumed perampanel withdrawal and two cases of low Apgar scores have been described. Use of any centrally acting drug throughout pregnancy or near delivery may be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome. These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should be planned in a unit with neonatal intensive care facilities.

Although not predicted from the recognised pharmacology of perampanel, it is unknown whether use prior to conception or during pregnancy may impact upon maternal folate status. UK guidelines state that women who take any anti-seizure medication should be prescribed high-dose folic acid (5mg).

More research is required to define the pregnancy safety profile of perampanel. Pregnant women and women of childbearing potential should be made aware of the limited data for most pregnancy outcomes, and highly limited data regarding exposure in late pregnancy. Perampanel should only be used during pregnancy if there is no suitable alternative anti-seizure medication with a more favourable pregnancy safety profile. In view of the limited human pregnancy data, close monitoring of mother and fetus should be considered following perampanel use in pregnancy. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Paracetamol is an antipyretic analgesic indicated for the treatment of mild-to-moderate pain and pyrexia. For the purpose of this monograph, ‘therapeutic’ use of oral paracetamol is regarded as 500-1000mg up to four times a day, with a maximum dose of 4g within a 24-hour period. Where this dose is exceeded or other factors such as prolonged use or low maternal weight are present, an assessment for paracetamol overdose may need to be considered. Please refer to our monograph ‘Paracetamol overdose in pregnancy’ for further information.

Animal studies have indicated that a rise in maternal core body temperature of 1.5°C may be associated with teratogenicity and there are limited human data that suggest that maternal fever, specifically a rise in temperature of 2°C, in the first trimester of pregnancy may increase the risk of neural tube defects (NTDs) in the offspring, however data are conflicting. Severe or chronic pain, if inadequately treated, may also impact on maternofetal outcome through alteration of both maternal cardiovascular function and uteroplacental perfusion. Adverse effects on maternal and fetal outcome due to the underlying maternal condition for which paracetamol is used should therefore be considered when interpreting pregnancy safety data.

Several studies which have investigated overall congenital malformation rates following in utero exposure found no increase in risk. No increase in risk has been reported for miscarriage, small for gestational age/low birth weight infants or preterm delivery.

A large number of studies have investigated neurodevelopmental outcomes following in utero exposure to paracetamol, with conflicting results. Read our joint official position statement for more information about the risk of autism following paracetamol use in pregnancy. Three meta-analyses have analysed the prevalence of ADHD. Although these meta-analyses identified an increased likelihood of ADHD in children exposed to paracetamol in utero, when one of the meta-analyses accounted for unmeasured confounding, no statistically significant difference in the rates of ADHD in paracetamol-exposed and unexposed cohorts was found. Additionally, evidence of familial confounding has been described. Therefore, residual confounding cannot be excluded. Due to significant methodological limitations of these studies, the conclusions that can be drawn are limited and a causal association remains unproven.

Frequent paracetamol use during late pregnancy (20-32 weeks) has been associated with an increased incidence of wheezing or childhood asthma in some studies but not others.

Exposure to paracetamol at any stage of pregnancy is not regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Pyridoxine (vitamin B6) is an essential vitamin. It is converted to pyridoxal-5’-phosphate which is the co-enzyme for a variety of metabolic transformations. Pyridoxine is used at varying doses in the treatment of nausea and vomiting of pregnancy (NVP), isoniazid-induced peripheral neuritis, idiopathic sideroblastic anaemia and vitamin B6 deficiency states.

The majority of human pregnancy data relate to use of pyridoxine in combination with doxylamine in the treatment of NVP. Risk of infant congenital malformation following in utero exposure to products containing this combination of drugs have been widely studied, with no robust evidence of an increased risk. No increased risk of miscarriage has been observed following gestational pyridoxine exposure. There is no robust evidence of associations with small for gestational age infants, preterm delivery, intrauterine death or neonatal complications, although data are too limited to fully exclude an increased risk.

In women with a healthy and varied diet, the use of additional vitamin B6 supplements in pregnancy is not usually required. Where a deficiency state exists, or in the treatment of maternal illness, the use of pyridoxine may be considered if clinically appropriate.

Exposure to pyridoxine at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.