Glucocorticoids: Safe During Pregnancy?

Glucocorticoids are steroid hormones that play a crucial role in pregnancy and fetal development. They are responsible for implantation and fetal adrenal development, and adequate endogenous glucocorticoid reserve is essential during labour.

Glucocorticoids are generally considered safe to use during pregnancy and breastfeeding, but there are some risks associated with their use. For example, fetal exposure to excessive levels of glucocorticoids can impact fetal growth and potentially cause long-term health issues such as glucose intolerance, diabetes, hypertension and cerebrovascular disease.

The decision of how and when to instigate glucocorticoid therapy during pregnancy is challenging due to the potential for acute and chronic adverse effects on both the mother and fetus.

Glucocorticoids are also used to treat rheumatic diseases during pregnancy, and there is some evidence that they may be associated with an increased risk of cleft lip and palate in the offspring, although data are conflicting. There is little evidence to suggest that glucocorticoids cause preterm birth, low birth weight, or preeclampsia.

Overall, glucocorticoids are an important tool in reproductive medicine, but their use during pregnancy and breastfeeding requires careful consideration and monitoring to balance the benefits against the potential risks.

Glucocorticoids and the placenta

Glucocorticoids are steroid hormones produced by the adrenal cortex, which play a key role in the body's stress response. They are also critical for embryogenesis and fetal development.

Glucocorticoids regulate many of the processes required for successful embryo implantation, as well as for the subsequent growth and development of the fetus and placenta. In utero, the endometrium, placenta, and embryo/fetus are each exposed to physiological glucocorticoids arising from either maternal or fetal adrenal glands.

The placenta is a critical determinant of fetal growth, and glucocorticoids affect growth and development of the fetus indirectly by affecting placental development and function. Glucocorticoids have been shown to stimulate syncytiotrophoblast differentiation and maturation. Glucocorticoids also alter the production and metabolism of hormones by the placenta, such as prostaglandins, placental lactogen, leptin, corticotrophin-releasing hormone (CRH), estrogens, progesterone, and other progestagens.

Maternal glucocorticoid administration is used mainly in the management of women at risk of preterm labor and in the antenatal treatment of fetuses at risk of congenital adrenal hyperplasia. However, increased exposure of the fetus to glucocorticoids in mid- to late pregnancy may result in adverse outcomes including intrauterine growth restriction (IUGR), postnatal hypertension, postnatal cardiovascular disease, and postnatal glucose intolerance.

Adverse pregnancy and birth outcomes

Concerns about the safety of glucocorticoids in pregnancy arose in the 1950s following reports of oral clefts in the offspring of pregnant mice treated with glucocorticoids. Since then, epidemiological studies have investigated the association between glucocorticoid exposure and oral clefts in humans, although results have been inconsistent. Some studies have reported a statistically significant association between glucocorticoid exposure and oral clefts, while others have found no significant association. It is important to note that the majority of these studies did not adjust for underlying maternal disease or disease severity, which may confound the results.

In addition to oral clefts, there have been concerns about the potential association between glucocorticoid exposure during pregnancy and other adverse outcomes such as preterm birth, low birth weight, preeclampsia, and gestational diabetes mellitus. However, the evidence to date suggests that there is little support for a direct causal relationship between glucocorticoid use during pregnancy and these adverse outcomes. For example, in the case of preterm birth and low birth weight, it appears that disease severity, rather than glucocorticoid exposure, is responsible for the reported associations. Similarly, the risk of preeclampsia may be confounded by disease severity, as the only study that adjusted for disease and proxy measures of disease severity did not find a significant association between glucocorticoid use and preeclampsia.

Regarding gestational diabetes mellitus, there is limited research on the potential association with glucocorticoid exposure during pregnancy. The existing studies have methodological limitations, such as small sample sizes and a lack of adjustment for maternal conditions, which make it difficult to draw definitive conclusions.

Overall, while there may be a small increased risk of cleft lip with or without cleft palate associated with glucocorticoid exposure during pregnancy, the evidence is conflicting, and the contribution of maternal disease is unclear. There is currently insufficient evidence to support a direct causal link between glucocorticoid use during pregnancy and other adverse outcomes such as preterm birth, low birth weight, preeclampsia, or gestational diabetes mellitus. Well-designed studies that account for potential confounding factors, such as disease severity and glucocorticoid dosage, are needed to better understand the potential risks associated with glucocorticoid exposure during pregnancy.

Corticosteroids and pregnancy complications

Corticosteroids are a type of medication offered to pregnant women who are at risk of giving birth prematurely. They can increase the chance of the baby surviving and reduce the risk of health problems. They are most beneficial to the baby if given between 24 hours and 1 week before birth.

Pregnancy Complications

Corticosteroids are given to pregnant women to reduce the risk of complications arising from premature birth. Premature babies may have a range of health problems, which tend to be more serious the earlier they are born. These include problems with breathing and bleeding into the brain.

Side Effects and Risks

A single course of corticosteroids is considered safe for the mother. However, there may be some minor side effects, such as pain at the injection site. For those with pre-existing or gestational diabetes, steroids can affect blood sugar control. Treatment with steroids between 22 and 35 weeks of pregnancy is likely to be safe and beneficial for the baby, with no long-term harm observed. However, there is some evidence that steroids may impact the mental wellbeing of babies born at full term (after 37 weeks) who were given steroids between 22 and 37 weeks.

If the mother is more than 35 weeks pregnant when given steroids, there is a chance the baby may have low blood sugar levels after birth. This can be harmful if left untreated, and the baby may need to be admitted to a neonatal unit.

Multiple Courses of Corticosteroids

If the mother has had a course of steroids and does not give birth within the next 7 days, a second course may have beneficial effects on the baby's breathing if they are still expected to be born prematurely. However, evidence to support this is limited, and there is also evidence that a repeat course may result in the baby being smaller than usual at birth.

When Corticosteroids Are Not Necessary

Corticosteroids are not necessary if the mother is unlikely to give birth within 7 days. Even if there is a higher risk of premature birth, steroids will not be given unless birth is expected within the next 7 days.

Glucocorticoid therapy for rheumatic diseases

Glucocorticoid therapy is used to treat symptoms of autoimmune conditions, as standard immunosuppressive drugs and biologic agents are regarded as riskier in pregnancy or as having unknown effects on fetal development. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus.

The initial dose, dose reduction and long-term dosing depend on the underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient. Except for treatment with glucocorticoids in early rheumatoid arthritis as a disease-modifying antirheumatic drug, in which dosages of 5 to 10 mg prednisone equivalent during 1 to 2 years are used, for prolonged treatment the glucocorticoid dosage should be kept to a minimum, and a glucocorticoid taper should be attempted in the case of remission or low disease activity.

The choice of administration route depends on the indication for glucocorticoids. The most commonly used routes are oral and intra-articular. Oral glucocorticoids are often used in combination with other immunosuppressive drugs and biologic agents. Intra-articular glucocorticoid injection can be considered in persisting nonbacterial arthritis of a joint.

The risks of glucocorticoid therapy are dependent on the dose and duration of treatment. The most commonly self-reported adverse events by patients who are prescribed with longer-term glucocorticoid use are weight gain, skin bruising, sleeping problems and mood problems. The more serious adverse reactions are osteoporosis, osteonecrosis, hyperglycaemia, increased risk of infection, and adverse effects on the immune system.

Glucocorticoid use in pregnancy: a review

Glucocorticoids are steroid hormones that play a crucial role in pregnancy and fetal development. They are produced by the adrenal cortex in response to stress or illness, and they coordinate many functions, including inflammatory and immune responses, metabolic homeostasis, cognitive function, reproduction, and development.

Role in fetal development

Glucocorticoids enable implantation and, in early pregnancy, they are responsible for fetal adrenal development and the repression of adrenal androgen synthesis, which enables female genital development. They are also essential for fetal organ development, particularly lung maturation.

Maternal glucocorticoids

Maternal glucocorticoids play a role in milk secretion and lactation. They bind to the glucocorticoid receptor (GR) and mineralocorticoid receptor to activate or repress transcription of target genes.

Potential adverse effects

While glucocorticoids are critical for fetal development, overexpression can be harmful. Excessive fetal exposure to glucocorticoids can impact fetal growth and potentially program the fetus for lifelong diseases such as glucose intolerance, diabetes, hypertension, and cerebrovascular disease.

Treatment strategies

There are several pathological conditions that require steroid treatment or replacement during pregnancy, and optimizing therapy is crucial. The potential for acute and chronic adverse effects on both the mother and fetus makes decisions about when and how to administer steroid therapy challenging.

Pregnancy outcomes

Pregnancy outcomes associated with glucocorticoid use include cleft lip and palate, preterm birth, low birth weight, preeclampsia, and gestational diabetes mellitus. However, the evidence regarding these outcomes is limited and inconsistent, and further research is needed to establish causal relationships.

Dosing considerations

It is generally recommended that prednisone doses be kept below 20 mg/day during pregnancy, but higher doses are acceptable for aggressive disease management. Adjustments to dosing may be necessary across the trimesters, particularly in the third trimester, when a 20-40% increase is often required. Emergency steroid cover during active labor is also crucial for women with adrenal insufficiency.

Breastfeeding considerations

There is limited data on the impact of steroid treatment during lactation, but at physiological replacement doses, it is unlikely that sufficient glucocorticoids would be transferred to cause significant harm to breastfed children. Current guidance does not recommend any changes in breastfeeding behavior for women taking glucocorticoid therapy.

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