Letter: I

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancy-specific liver condition with onset most commonly in the third trimester.

Maternal signs and symptoms of ICP include pruritus and raised serum bile acids; abnormal liver function (ALT/AST) is also a common feature. The pruritus can cause sleep disturbance and can adversely affect quality of life, but ICP is otherwise not detrimental to maternal health. ICP is, however, associated with serious risks to the fetus, including stillbirth, rates of which are thought to be particularly elevated with maternal serum bile acid concentrations >100 µmol/L. Other adverse outcomes associated with ICP include neonatal respiratory distress secondary to meconium aspiration, preterm delivery (spontaneous and iatrogenic) and the potential for fetal and neonatal bleeding disorders. Fetal monitoring has not been shown to predict or to reduce the risk of adverse perinatal outcomes in pregnancies affected by ICP, but may be offered to provide reassurance. Regular monitoring of maternal serum bile acid levels and liver function is routine; serum bile acid levels may predict the risk of stillbirth and the requirement for delivery. All women with ICP should be offered consultant-led care and delivery at a hospital unit.

Symptomatic treatments to reduce the sensation of itch include topical emollients (with or without menthol) and sedating antihistamines. The most widely used pharmacological treatment to reduce bile acid concentrations in ICP is ursodeoxycholic acid (UDCA). Rifampicin is also occasionally used on a case-by-case basis as an adjunct to UDCA if bile acid levels are extremely high.

ICP is associated with an increased risk of vitamin K deficiency due to reduced enterohepatic recirculation of bile acids and resultant malabsorption of fats and fat-soluble vitamins. Although there are no randomised controlled clinical trials that support or refute the use of vitamin K, the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines recommend maternal and neonatal vitamin K supplementation.

Exposure to the medications included in this monograph 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.

Iodine 131 (I-131) is a radioactive iodine nuclide that emits beta particles and a small amount of gamma particles. It is widely used in nuclear medicine imaging studies of the thyroid gland and in the management of hyperthyroidism and thyroid cancer.

I-131 therapy potentially exposes the fetus to ionising radiation and is therefore contraindicated in pregnancy. Given that the fetal thyroid begins functioning at approximately 8 to 10 weeks post-conception (gestational weeks 10 to 12), a delay between I-131 treatment and pregnancy is usually suggested to avoid radioactive iodine accumulation in the fetal thyroid. UK guidelines currently recommend that women avoid pregnancy for at least six months following treatment.

The available human pregnancy exposure data consist mainly of uncontrolled studies which describe pregnancy outcomes following pre-conception exposure, with only a small number of uncontrolled studies and case reports describing the outcomes of pregnancies where I-131 exposure occurred during pregnancy.

There is currently no conclusive evidence that exposure to I-131 either prior to conception or during pregnancy is associated with the occurrence of fetal congenital malformation, miscarriage, impaired fetal growth, preterm delivery or stillbirth. However, the available data is limited and of relatively poor quality; as such, it is recommended that pregnancy is avoided after I-131 treatment.

There have been a number of case reports of congenital hypothyroidism following I-131 treatment of maternal thyrotoxicosis or thyroid cancer. The absolute risk of congenital hypothyroidism in the offspring following I-131 exposure during pregnancy remains unquantified. Neurodevelopmental impairment with congenital hypothyroidism has also been reported in a small number of infants exposed to I-131 in utero, however, this may have been influenced by delays in the diagnosis of congenital/neonatal hypothyroidism and/or in the administration of neonatal thyroxine supplementation. Monitoring of the neonatal thyroid function is advised for all cases of in utero I-131 exposure.

Rates of thyroid carcinoma were not significantly increased amongst the offspring of women exposed to I-131 during the Chernobyl disaster when compared to an unexposed cohort. No cases of thyroid cancer have been reported in offspring of women treated with I-131 prior to conception or during pregnancy. 

Monitoring of neonatal thyroid function is advisable where inadvertent exposure to I-131 therapy has occurred during pregnancy. Other risk factors may also be present in individual cases which 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.

Oral retinoids and their metabolites are associated with a significant teratogenic risk and should only be prescribed and dispensed to women under the Pregnancy Prevention Program (PPP).

Isotretinoin is a retinoid (13-cis-retinoic acid) used orally or topically in the treatment of severe acne which has not responded to standard forms of therapy. Oral isotretinoin is a confirmed major teratogen associated with major structural and neurodevelopmental anomalies (isotretinoin embryopathy). Use during pregnancy is contraindicated. A negative pregnancy test and confirmation that effective contraception (preferably two forms) is used prior to, during, and for at least one month after the last dose is required before isotretinoin is provided to women of childbearing potential.

Malformations associated with isotretinoin embryopathy include central nervous system abnormalities (hydrocephalus, cerebellar abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), renal, thymus gland abnormality and parathyroid gland abnormalities. 

The absolute risk of congenital malformation following oral isotretinoin therapy is currently unclear. Overall malformation rates in live-born infants from prospectively reported pregnancies range from 5% to 20%, but risk estimation is hampered by the small sample sizes due to the rarity of the exposure, and the fact that rates of elective pregnancy termination are high following gestational isotretinoin exposure, potentially leading to an underestimation of malformation rates. The only (small) study to have attempted to quantify structural malformation risk in different exposure periods found no statistically significant difference in rates of malformation between infants exposed before two weeks gestation and those exposed in the period from 2-9 weeks gestation, with data also suggesting that even brief exposure (less than one week’s duration) may carry a high risk. No minimum dose or duration of treatment has therefore been specified as without risk for congenital malformation. Because of the long half-life of the drug, women are advised to avoid conception for at least one month following discontinuation of therapy. The currently available data are too limited to facilitate an evidence-based assessment of the risk of infant congenital malformation following conception within this period.

Neurodevelopmental delay of varying severity has been reported following exposure to isotretinoin in utero, both in association with congenital anomalies and in exposed infants without structural malformation. The period of risk for impaired neurodevelopment is undetermined and may hypothetically extend throughout gestation, as central nervous system development continues to term. Spontaneous abortion rates appear to be increased above those commonly reported in observational studies, with estimates from more recent prospective datasets in the range of up to 30%. An increased incidence of ectopic pregnancy has also been reported.  

A detailed fetal anomaly scan is recommended following all first trimester exposures to isotretinoin. Women should be made aware of the limitations of this investigation and that impaired neurodevelopment may occur in the absence of structural anomalies. When counselling women regarding the teratogenic risk of isotretinoin, possible synergistic effects of other exposures and the effects of prolonged exposure, high dose regimes or inter-individual variation in isotretinoin metabolism should be considered. 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. 

There are inadequate data to assess fetal risk following exposure during pregnancy to topical isotretinoin. Use during pregnancy cannot therefore be recommended, however, women who are inadvertently exposed during or within the month prior to pregnancy should be reassured that systemic absorption of the drug is generally low and that existing studies show no evidence of a teratogenic risk for topical retinoids as a group. The risk of isotretinoin embryopathy remains unquantified where exposure to supratherapeutic doses of topical isotretinoin occurs, or risk factors which increase absorption of the drug are present. 

Discussion with UKTIS is recommended in all cases.

SUMMARY: Insecticides are chemical compounds that are used in public health to kill vectors of disease such as mosquitoes, in agriculture to kill pests that damage crops, domestically to eradicate household and garden pests, and medically to eradicate body lice. Commonly used classes of insecticide include carbamates, organophosphates, pyrethrins/pyrethroids, and neonicotinoids.

There are a wealth of data describing pregnancy outcomes following gestational exposure to insecticides in general, but data relating to exposure to specific insecticides are generally scarce. Although associations with various adverse pregnancy outcomes and negative effects on infant/child neurodevelopment have been described following (usually chronic) insecticide exposure, findings of studies are generally inconsistent, and data are often confounded by multiple exposures and sociodemographic factors. Studies are further limited by potential misclassification of exposure as this is often assumed due to job title or place of residence. Few conclusions can therefore be drawn and there are no data specifically relating to acute exposure. Pregnant women should be advised to avoid exposure to insecticides. Where exposure cannot be avoided, personal protective equipment (PPE) should be employed as per the manufacturer’s instructions.

Low-level exposure to insecticides at any stage in pregnancy would not be regarded as medical grounds for termination of pregnancy. The need for additional fetal monitoring should be determined on a case-by-case basis, taking into account factors such as whether exposure was acute or chronic, whether personal protective equipment was employed, and the stage of pregnancy. Where high level exposure and/or symptoms of maternal toxicity have occurred, please contact UKTIS for a case-specific assessment of the risk of fetal harm. Maternal toxicity should be treated as for the non-pregnant patient and where a specific antidote is clinically indicated this should not be withheld on account of 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.

Interferon beta is an immunomodulating therapy used in people with multiple sclerosis.

Although highly limited and potentially confounded for certain specific outcomes, the available data do not suggest an increased risk of congenital malformation, miscarriage, low infant birth weight or impaired neurodevelopment following maternal interferon beta use in pregnancy. Due to a lack of any controlled data the risk of intrauterine death is currently unquantifiable.

Following confirmation of pregnancy, it is recommended that an individualised clinical review is carried out by a neurologist. In some cases, pregnancy is associated with spontaneous remission of multiple sclerosis and discontinuation of interferon beta therapy may therefore be an option for some women. In cases where continued treatment with interferon beta is required it should not be withheld on account of pregnancy.

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

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used to treat acute and chronic pain, and in the management of arthritis.

Use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, persistent pulmonary hypertension of the newborn (PPHN), oligohydramnios, premature closure of the ductus arteriosus (DA), structural cardiovascular defects and a number of other congenital anomalies, including orofacial clefts. However, the available data are limited, confounded and often conflicting; further research is therefore required to define the risk of these outcomes more accurately.

Twenty studies collectively including more than 20,000 ibuprofen-exposed pregnancies have investigated the risk of adverse fetal effects following in utero exposure. These studies have provided conflicting evidence, with a small number of individual studies describing increased risks of miscarriage, overall and specific malformations, and low birth weight. However, it is possible that confounding has affected the interpretation of these data. Further studies using additional datasets are required before robust conclusions can be drawn concerning the fetal effects of maternal ibuprofen use in pregnancy.

There is no robust evidence of an association with intrauterine death/stillbirth, preterm delivery or neurodevelopmental impairment. No controlled studies investigating malignancy risks were located.

Exposure to NSAIDs after 30 weeks of gestation has been associated with an increased risk of premature closure of the DA and oligohydramnios. These effects are thought to be mediated by the inhibitory effect of NSAIDs on prostaglandin production. There have been case reports of premature closure of the DA occurring after ibuprofen use in pregnancy. There are also conflicting findings regarding the risks of PPHN following antenatal use of NSAIDs. Further evidence is required before this possible association can be confirmed. Where published data concerning the fetal effects of gestational exposure are unavailable or limited, a possible class effect for these associations should be considered for all NSAIDs.

All NSAIDs should, where possible, be avoided during the third trimester. In circumstances where the maternal clinical condition requires treatment with ibuprofen during the third trimester, discussion with a Fetal Medicine Unit regarding antenatal monitoring for oligohydramnios and ductus arteriosus patency is recommended. Where use of ibuprofen is being considered at any stage of pregnancy, the available pregnancy data should be discussed with the patient to support informed decision-making regarding the risks and benefits of treatment.

Please refer to the NSAID overview monograph for more information. 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.

Imatinib is a tyrosine kinase inhibitor used in the treatment of haematological malignancies (specifically Philadelphia chromosome positive chronic myeloid leukaemia (CML) or acute lymphoblastic leukaemia (ALL)), Kit (CD117) positive gastrointestinal stromal tumours and other malignancies. Imatinib inhibits signalling and proliferation of cells driven by dysregulated platelet-derived growth factor receptor (PDGFR) and ABL kinase activity.

Inadequately treated haematological malignancies in pregnancy may be associated with increased risks for miscarriage, thromboembolism, fetal growth restriction, preterm birth (and associated sequelae) and perinatal mortality, in addition to severe maternal illness and, potentially, death.

Data regarding imatinib use in human pregnancy are limited to retrospective case reports and case series describing approximately 290 pregnancies, 196 of which were exposed in the first trimester. No controlled epidemiological studies have assessed the risk of congenital malformation, miscarriage, intrauterine death, low birth weight, preterm delivery, neonatal complications or adverse neurodevelopmental outcomes following in utero imatinib exposure.

Both animal studies and human case reports have described malformations in fetuses exposed to imatinib during organogenesis. Certain specific anomalies (combinations of exomphalos, renal agenesis, scoliosis and hemivertebrae) have been reported in four infants in the published literature and in one infant reported retrospectively to UKTIS. Although duplicate reporting of the same malformed child is possible, and investigation for a genetic cause was not undertaken for any of these cases, further investigation is warranted to determine if these reports signal a pattern of malformation attributable to in utero imatinib exposure.

Cases of miscarriage, stillbirth, preterm delivery, intrauterine growth restriction/low birth weight and neonatal complications following in utero imatinib exposure have been described in the literature. Due to the lack of controlled studies and the potential for these outcomes to be influenced by the underlying conditions for which imatinib is used to treat, it is not currently possible to assess the direct impact imatinib use in pregnancy may have on these outcomes.

The potential teratogenicity of imatinib and other tyrosine kinase inhibitors requires that their use in pregnancy be carefully considered against the need to prevent deterioration of the maternal disease. Patients wishing to interrupt therapy to become pregnant should also be informed of the risk of relapse, even where complete molecular remission was achieved, and of the possibility of a suboptimal response on restarting therapy. Imatinib should only be used during the first trimester of pregnancy where benefits of treatment clearly outweigh the potential risk of congenital malformation and where these risks and benefits have been fully discussed with the patient.

Due to the lack of data, additional fetal monitoring for structural malformation and growth may be warranted on a case-by-case basis. 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.

Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced by recombinant DNA technology. It is administered in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease and ulcerative colitis where other systemic therapies are ineffective or unsuitable.

The available human pregnancy exposure and outcome data are mainly provided by uncontrolled studies which together describe more than 2,400 infliximab-exposed pregnancies, with more than 1,200 exposed in at least the first trimester. Although the total number of exposed pregnancies is quite large, the available data for specific pregnancy outcomes can be limited and evidence from controlled studies is often lacking.

There is currently no convincing evidence of an association between infliximab and an overall increased risk of congenital malformation, or any specific malformation or pattern of malformations. The available evidence also does not suggest increased risks of miscarriage, intrauterine death, preterm delivery or neurodevelopmental impairment. Although some studies have suggested associations between infliximab exposure and impaired fetal growth, the available data are conflicting and likely confounded by the underlying maternal condition.

Use of immunosuppressant antibodies that actively cross the placenta during pregnancy could result in immunosuppression in the newborn and increase the risk of infection. Rare cases of fatal infection following BCG vaccination after in utero infliximab exposure have been described in the literature. General guidance has been provided from a number of authorities around avoiding/deferring live vaccine use in infants exposed to infliximab in utero. These recommendations vary depending on both the circumstances of infliximab exposure and infant infection risk. UKTIS recommend a case-specific risk assessment approach when considering the use of live vaccines following in utero infliximab exposure. Discussion with UKTIS is recommended in all cases where use of a live vaccine is being considered in an infant <12 months of age where there has been in utero exposure to infliximab.

Pregnant women treated with infliximab are likely to have additional fetal growth monitoring due to their underlying medical condition; no additional fetal monitoring is required as a result of infliximab exposure specifically. 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.

Insect repellents are agents applied to the skin, clothing and/or bed nets to deter biting insects such as mosquitos and ticks. They are important in the prevention of mosquito-borne infections such as malaria, Zika virus, dengue fever and yellow fever, and tick-borne infections including Lyme disease and tick-borne encephalitis.

Pregnant women should be advised against travel to areas where there is a risk of mosquito-borne infection, and should be aware that rates of Lyme disease transmission vary locally and globally. Ticks are most commonly found in forest fringes, forest glades, riverside meadows and marshland, and forest plantations with brushwood and shrubbery.

When exposure to environments where insect bites may lead to serious illness is unavoidable, non-pharmacological preventative measures are important. These include staying indoors at the times of day when mosquitos are most active, using bed nets impregnated with insecticide to avoid mosquito bites, and minimising skin exposure when outdoors by wearing long sleeves and trousers (including tucking trousers into socks where there is a risk of mosquito/tick exposure). Insect repellent should be applied to clothing and exposed skin according to the manufacturer’s instructions, and washed off once returning indoors. Ticks should be removed from the skin intact as soon as possible to reduce the risk of transmission of tick-borne disease.

The use of diethyl-m-toluamide (DEET) 20-50% is recommended first-line for all pregnant women, at any stage of pregnancy, travelling to a malarial area. The benefits of using DEET in these circumstances are likely to outweigh any risk of harm. There are, however, limited data on the use of DEET in human pregnancy, especially in the first trimester. One case-control study has reported an association between use of insect repellent (not specifically DEET) in pregnancy and hypospadias in male infants, however more data are required to accurately assess the risks. A single study found no adverse effects on fetal growth and postnatal development in the offspring of women who used DEET 20% in the second and third trimesters of pregnancy.

P menthane-3,8-diol (PMD) and picaridin (icaridin) ≥20% are possible alternatives to DEET containing products, although PMD should not be used where there is a risk of malaria as it may not afford an appropriate level of protection. There are no data relating to exposure to these agents in human pregnancy, however animal studies have not demonstrated any features of maternal or developmental toxicity.

Exposure to insect repellents, according to the manufacturer’s instructions, at any stage of 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.

Note: Where travel to a malarial area during pregnancy is unavoidable, additional prophylaxis will be necessary. Please consult the Malaria Prophylaxis monograph or contact UKTIS on 0344 892 0909 for more information.

Iron is an essential mineral and is necessary for the formation of red blood cells. Iron requirements increase during pregnancy and the use of iron supplements is common, particularly in the second and third trimesters. What constitutes an iron overdose may vary, as for most drugs the risk of toxicity is calculated on a mg/kg bodyweight basis, however for the purpose of this document iron overdose is defined as ingestion of iron in excess of the recommended daily dose, or where maternal symptoms or serum iron concentration indicate toxicity.

Published data and data collected by UKTIS on iron overdose in pregnancy are limited to case reports and small case series amounting to <100 exposed pregnancies, with the majority of exposures occurring after the first trimester. The very limited data from around 20 cases of first trimester iron overdose do not provide any signal of structural teratogenesis but are too limited to perform an accurate assessment of risk of malformation. 

Maternal toxicity is likely to be a major predictor of fetal outcome. There are currently no published guidelines on the treatment of iron overdose in pregnancy. Iron overdose can be fatal, therefore treatment of the mother should be as for the non-pregnant patient. Desferrioxamine, when indicated, should not be withheld on account of the pregnancy. For current UK guidelines regarding treatment of iron overdose please refer to TOXBASE. There are no epidemiological studies reporting on rates of outcomes such as spontaneous abortion, stillbirth, neonatal problems, low birth weight or preterm delivery following maternal iron overdose with or without desferrioxamine treatment in pregnancy, but the limited data available suggest that timely and adequate treatment of maternal toxicity as for the non-pregnant patient mitigates against the risk of these adverse outcomes. Effects on longer term infant neurodevelopment have not been studied and many reports relate to infant outcome shortly after birth.

When iron overdose is associated with maternal toxicity, enhanced fetal monitoring may be warranted. The absence of maternal toxicity, however, does not exclude the possibility of adverse events and obstetric follow up should be determined on a case-by case basis.

All episodes of overdose, whether intentional or apparently accidental, should be fully documented in the maternity record. Referral to a perinatal psychiatrist should be considered in all cases of intentional iron overdose.

Discussion with UKTIS is recommended for all cases.

Please note, this document relates only to iron overdose in pregnancy and not therapeutic use of iron supplements.