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Chelsey J. Forbess Smith. Author information Copyright and License information Disclaimer. Corresponding author. Copyright notice. See other articles in PMC that cite the published article. Synopsis The evidence to date regarding corticosteroid exposure in pregnancy and select pregnancy and birth outcomes is limited and inconsistent. Keywords: Pregnancy, corticosteroids, adverse pregnancy and birth outcomes, review. Introduction Corticosteroids are administered in pregnancy for their immunosuppressive and anti-inflammatory effects 1 They are used to treat symptoms of autoimmune conditions, as many standard immunosuppressive drugs and biologic agents are regarded as riskier in pregnancy or as having unknown effects on fetal development.
Corticosteroids and the placenta Cortisol, a naturally occurring glucocorticoid in humans, is critical for embryogenesis. Oral clefts Clefts of the lip and palate affect approximately 1. Table 1 Studies of oral or systemic corticosteroids and the risk of oral clefts organized chronologically.
Open in a separate window. Preterm birth and low birth Following reports that corticosteroids were teratogenic in mice, researchers reported that prednisone use in pregnancy was associated with low birth weight in the full term offspring of both humans and mice. Table 2 Studies of oral or systemic corticosteroids and the risk of preterm birth, low birth weight, or IUGR organized chronologically.
Low birth weight A few studies have reported birth weight or intrauterine growth restriction IUGR as an outcome. Preterm birth Studies have examined the use of prednisone or prednisolone in pregnant women with SLE and the odds of preterm birth.
Preeclampsia Preeclampsia, a pregnancy disorder characterized by high blood pressure and proteinuria, is a serious pregnancy complication associated with both maternal and fetal morbidity and mortality. Gestational Diabetes OR: 4. Gestational diabetes mellitus The risk of gestational diabetes mellitus from corticosteroid use has received little attention to date Table 3.
Footnotes Disclosure: the authors report no conflicts of interest or financial disclosures. References 1. McGee DC. Steroid use during pregnancy. J Perinat Neonatal Nurs. Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol. Obstet Gynecol Surv. The management of rheumatic diseases in pregnancy. Scand Jouranl Rheumatol.
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A nationwide cohort study. Arthritis Rheum. Inflamm Bowel Dis. Matern Child Health J. Efficacy and Safet y of Inhaled Cort icosteroids. Clinical Pharmacokinetics of Prednisone and Prednisolone. Clin Pharmacokinet. J Am Acad Dermatol. Effects of fluticasone propionate, triamcinolone acetonide, prednisone, and placebo on the hypothalamic-pituitary-adrenal axis.
J Allergy Clin Immunol. Safety and efficacy of fluticasone propionate in the topical treatment of skin diseases. Skin Pharmacol Physiol. Cleft lip and palate. The genetics of isolated orofacial clefts: From genotypes to subphenotypes. Oral Dis. Philadelphia: Saunders; Hum Mol Genet. Epub ahead of print. Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids.
Corticosteroids during pregnancy and oral clefts: A case- control study. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet. Maternal corticosteroid use and orofacial clefts. Am J Obstet Gynecol. Corticosteroid use during pregnancy and risk of orofacial clefts.
C Can Med Assoc J. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Use of corticosteroids in early pregnancy is not associated with risk of oral clefts and other congenital malformations in offspring. Am J Ther. Oral clefts and life style factors - A case-cohort study based on prospective Danish data.
Eur J Epidemiol. Risk of oral clefts in relation to prepregnancy weight change and interpregnancy interval. Am J Epidemiol. Lateef A, Petri M. Managing lupus patients during pregnancy. Best Pract Res Clin Rheumatol. Am J Gastroenterol. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: Results of a national prospective study. Pregnancy outcome after first trimester exposure to corticosteroids: A prospective controlled study.
Reprod Toxicol. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. PLoS One. Am J Perinatol. Arthritis Care Res. Reece EA. The fetal and maternal consequences of gestational diabetes mellitus. J Matern Fetal Neonatal Med. J Perinat Med. Intrapartum corticosteroid use significantly increases the risk of gestational diabetes in women with inflammatory bowel disease. J Crohns Colitis. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.
Socio-economic factors including sub-optimal maternal nutrition, variable access to clean water and quality housing, and variable hospital infection control practices may also contribute to both the lack of efficacy and increase in suspected maternal infection. Similarly, the use of these agents in high-resource settings with improved antibiotic coverage and aseptic practice may camouflage an increased susceptibility to infection.
What is clear, however, is that new research into the use of ANS that considers pregnancy-specific factors and medical resources are needed. In addition to efficacy and safety per se, healthcare providers need to have adequate information to appropriately administer ANS therapy, an additional challenge in low- and middle-resource settings.
Potential concerns regarding appropriate use of ANS therapy are highlighted by a study of midwives and physicians in Latin America, which reported substantial differences in ANS administration practice, including in the use of repeated courses of steroids Aleman et al. Similarly, the authors of a recent Chinese study concluded that ANS were often under-prescribed to women at risk of preterm birth and inappropriately prescribed to women after 35—36 weeks of pregnancy Wang et al.
ANS are of benefit if delivery occurs between 24 h and 7 days after treatment administration Roberts and Dalziel, Delivery outside of this timeframe is associated with increased risk of adverse outcomes McLaughlin et al. However, the optimal timing for administration of antenatal corticosteroids is hampered by the imprecise identification of women at risk of preterm delivery and the likely remaining latency.
The majority of preterm births are spontaneous i. Conditions such as pre-eclampsia and intrauterine growth restriction that may necessitate medically indicated preterm delivery are variable in presentation and progression. Evidence supports prolonging a preterm gestation until the benefits of delivery clearly outweigh the risks, thus delivery may be delayed for some time after initial diagnosis Stock et al.
The recommendations are to give ANS at the first signs of impending delivery or potential indication for medically indicated PTB. Given the clear advantages of ANS to babies born preterm, it is understandable that a treat-all approach is often taken, but this is at the expense of optimally-timed ANS administration.
The magnitude of the problem of timing ANS administration is demonstrated in a recent population study from Canada, which reported that as uptake of appropriate ANS increased over time, so did inappropriate administration Razaz et al. Despite well-developed maternity care systems and guidelines for administration for steroids, more than half of women who received steroids in delivered at 35 weeks of gestation or greater Razaz et al.
Difficulty in predicting preterm delivery results in unnecessary steroid exposure to babies who eventually deliver at term. It also leads to uncertainty regarding the best course of management if delivery does not occurs within 7 days, but high risk of preterm delivery persists. The administration of multiple courses of antenatal corticosteroids remains a matter of contention.
On the one hand, a number of clinical and experimental studies have reported fetal growth restriction and alterations in organ notably brain development and childhood behaviour in association with repeated ANS administration French et al. Two observations support the argument for administering repeated doses of ANS: i the beneficial effects of ANS therapy on preterm respiratory function appear to be lost approximately 7 days after completion of the initial treatment; and ii delivery more than 7 days after a single course of treatment is associated with an increased risk of perinatal death and maternal infection McLaughlin et al.
A number of large, well-controlled studies have now been repeated to determine the efficacy and safety of repeated ANS administration. Several excellent structured reviews, including that by Crowther and colleagues for the Cochrane Collaboration, provide an in-depth composite picture of the outcomes. The repeated administration of corticosteroids is associated with a small but significant decrease in RDS and a reduction in serious adverse infant outcomes Crowther et al.
One of the central issues relating to the repeated administration of ANS is that the dose for repeated courses of antenatal steroids has not been empirically optimized. Some trials have simply repeated the initial treatment used by Liggins and Howie in Liggins and Howie, whereas others have used modified treatment schedules. This hospital-based study investigated the use of a single, weekly dose of The study reported reduced respiratory distress, and reduced severe lung injury with repeated doses of corticosteroids.
Interestingly, the significant reductions in weight, length and head circumference at birth in babies exposed to repeated corticosteroid treatment were not maintained at discharge Crowther et al. Of note is the authors' observation that there was no difference in perinatal mortality between the repeated steroid and placebo groups, and that the causes of death were p.
This finding is a significant departure from the original trial conducted by Liggins and Howie, which demonstrated a significant reduction in perinatal mortality between a single ANS course infants and those receiving placebo control 3. Assuming that repeated ANS administration does indeed convey a benefit to the preterm infant, the reasons for the similarity in risk of death between groups are unclear.
Advances in neonatal care over the past four decades especially with regards ventilation and surfactant therapy contribute to increased survival and blunt any benefit from repeated corticosteroid therapy. Whether or not this finding of equivalence would be replicated in a patient population drawn from mid and low-resource settings is of interest, given the high preterm birth and mortality burden in the developing world. In a 2-year follow-up to the ACTORDS study, the authors concluded that aside from an increase in treatment for attention problems, there were no statistically significant differences in body size, blood pressure or health service utilization between children exposed to repeated ANS and those exposed to placebo Crowther et al.
There is a strong body of epidemiological data demonstrating an association between low birthweight, accelerated neonatal growth and chronic diseases including type-2 diabetes, obesity, cardiovascular disease, hypertension and depression van Deutekom et al. Whilst noting the need for further, long-term follow-up, the authors concluded that the equivalence of 2-year survival free of major neurosensory disability supports consideration of administering a weekly treatment with a single dose of betamethasone in women who remain at risk of very preterm delivery 7 or more days after their initial corticosteroid treatment.
Additional reassurance is provided by data from a 6—8 year follow-up, suggesting no association between repeat antenatal corticosteroid exposure and cardio-metabolic disease risk in early school age McKinlay et al. However, an alternative view is that these rigorous clinical studies in fact support the adoption of a more conservative position.
In light of ongoing concerns regarding administration of multiple courses of ANS discussed below, a demonstrated equivalence in perinatal morbidity and overall childhood wellbeing argues in favour of not administering repeated doses of ANS to women at continued risk of preterm delivery. The multiple courses of antenatal corticosteroids for preterm birth study MACS evaluated the effect of repeated courses of ANS given at two weekly intervals in high-risk women who had failed to deliver 14—21 days after initial treatment Murphy et al.
The study involved women drawn, importantly, from a number of countries with differing levels of economic development and large differences in perinatal mortality rates. There was no difference in a composite primary outcome perinatal mortality and morbidities associated with prematurity including severe respiratory distress syndrome, neurological injury, haemorrhage and necrotising enterocolitis between the corticosteroid and placebo groups.
However, there were small but significant reductions in weight, length and head circumference at birth in infants exposed to repeated courses of antenatal corticosteroids. A pre-discharge study assessing the effect of repeated ANS exposure on auditory brainstem response in preterm infants found no difference in brain maturity or auditory function but did identify significant reductions in birthweight, length, and head circumference in association with repeated antenatal corticosteroid exposure Church et al.
The subsequent 5-year follow-up to the MACS study concluded that there were no significant differences in the risk of neurodevelopmental disability or death Asztalos et al. These conflicting data suggest that, if there are indeed changes in fetal neurodevelopment as a result of repeated antenatal corticosteroid exposure, then any adverse effects may be partially dependent on the gestational age at which the infant was born and also the post-natal age that neurosensory function is assessed.
Additionally, sex-dependent effects of antenatal corticosteroid exposure were observed in juvenile baboons Rodriguez et al. Long-term follow-up studies of children at risk of congenital adrenal hyperplasia and treated with dexamethasone in early pregnancy have suggested variable effects on brain function. Meyer-Bahlburg performed a questionnaire survey of children exposed prenatally to dexamethasone including 48 with congenital adrenal hyperplasia and unexposed children including with congenital adrenal hyperplasia between 1 month to 12 years of age Meyer-Bahlburg et al.
They found no significant effect of dexamethasone treatment on nine different social or developmental scales. These results conflict with those of a prospective follow-up study, of 40 children treated prenatally with dexamethasone and aged 7—17 years, which included neuropsychological testing as well as validated child and parental questionnaires Hirvikoski et al. These studies suggest possible negative cognitive and behavioural effects resulting from steroids in early pregnancy.
Although further long-term studies are needed, the potential long-term effects on brain function should be considered when weighing up the risks and benefits of early pregnancy steroid use. The intrauterine environment plays a key role in regulating fetal growth and development; data, predominantly from rodent studies, also suggest that it can also program health throughout life.
Corticosteroids are key mediators in this process, and excess exposure to antenatal corticosteroids is associated with adverse pregnancy outcomes, including reduced birthweight, and a host of persistent changes in hypothalamic—pituitary—adrenal HPA axis programming that manifest as elevated stress responses, hypertension and changes in glucose metabolism, behaviour and motivation Reynolds, ; Moisiadis and Matthews, Precisely how excess exposure to antenatal corticosteroids might affect pathological changes on the fetus remains unclear; however, several excellent reviews have recently highlighted the potential roles of the fetal HPA axis and the placenta Braun et al.
Impaired HPA axis function is associated with changes in behaviour and neurodevelopment along with an increased risk of chronic cardiovascular and metabolic diseases. Antenatal steroid exposure appears to differentially affect basal cortisol activity in neonates based on fetal sex, post-natal age at which studies are undertaken, and whether the infant was delivered preterm or at term Moisiadis and Matthews, Interestingly, a year follow-up of adults exposed to a single course of antenatal corticosteroids concluded that treatment did not adversely impact cardiovascular function but might cause insulin resistance Dalziel et al.
There are limited human data available on the long-term effects of repeated antenatal corticosteroid exposure on HPA axis function, although studies in sheep suggest that changes in HPA function associated with repeated antenatal corticosteroid exposure persist into adulthood Moisiadis and Matthews, Antenatal corticosteroids may also unbalance maturational effects in certain systems by selective stimulation of GR. In contrast, synthetic corticosteroids selectively activate GR.
In general, mineralocorticoid target tissues co-express 11 Beta-HSD-2, which converts cortisol to inactive cortisone to prevent unwanted stimulation of MR by cortisol Chapman et al. However, some of the functions of endogenous corticosteroids that mediate maturation of the developing fetus are signalled through MR not GR. There is thus the potential that dexamethasone or betamethasone may perturb maturation in extra pulmonary systems by only stimulating GR Rog-Zielinska et al.
Relative to late pregnancy, surprisingly little is known about the effects of GC exposure on the developing fetus in early pregnancy. Using a sheep model of pregnancy, Dodic and colleagues reported that transient 2 day exposure to dexamethasone at Day 27 of pregnancy resulted in hypertension, left ventricular hypertrophy, and reduced cardiac function in adult offspring Dodic et al. The same group demonstrated changes in nephrogenesis in adult sheep exposed to corticosteroids in early pregnancy Wintour et al.
Antenatal dexamethasone exposure in early pregnancy has been demonstrated to alter HPA axis function and maturation in fetal lambs Braun et al. If we are to understand how we might refine the use of antenatal corticosteroids then we must attempt to clarify how the maternal and fetal responses to such treatment might be modified by preterm birth-associated factors.
Factors including gestational age, maternal diet, the presence of intrauterine infection, and fetal sex have each been implicated as potential modulators of corticosteroid effects Fig. The scope for refining the use of ANS is highlighted by the observation that, under current obstetric protocols, a 60 kg women carrying a 33 week fetus would be given the exact same the same dose of ANS as a kg woman carrying a 24 week fetus in an attempt to improve neonatal outcomes.
Factors that may influence the effectiveness of antenatal corticosteroids in reducing morbidity and mortality associated with prematurity. T here are good data to suggest that GR density in target organs is critical in determining the level of response, or resistance, to corticosteroid stimulation. Accordingly, the ontology of GR receptor expression in the developing fetal lung should also be taken into account in future studies investigating gestation-specific antenatal steroid dosing.
Nuclear localization of labelled dexamethasone was also dependent on the cytoplasmic receptor. The lung is the human fetal tissue with the highest GR concentration and the GR is expressed from as early as 12 weeks gestation through to term. GR expression was also detected in the human fetal liver, kidney, heart, intestine, muscle and skin Ballard and Ballard, , GR mRNA expression was detected in the fetal rat brain from embryonic day Interestingly, Ballard and Ballard concluded that with regards the developing lung p.
This observation is supported by the findings of Labbe et al. More recently, Rajatapati and colleagues surveyed GR expression in human fetal lung samples collected at 16 pseudoglandular phase , Using immunohistochemistry, they identified nuclear GR reactivity in all samples analysed and, interestingly, that the GR mRNA concentration did not significantly differ with gestational age Rajatapiti et al. Maternal nutrition is one factor that may warrant consideration in any future optimization of antenatal corticosteroid dosing regimens, both in low-resource settings with maternal nutrient restriction and in the increasingly obese developed world.
Overweight or obese women are at an increased risk of gestational diabetes, potentially resulting a hyperglycaemic, hyperinsulaemic fetus. In sheep, maternal nutrient restriction did not impact lung growth but did result in small increases relative to animals maintained on normal diets in lung GR mRNA expression at 80 and days gestation in singleton lambs Gnanalingham et al.
Interestingly, studies in sheep have suggested that maternal undernutrition is associated with substantial changes in GR methylation and increased hypothalamic GR mRNA and protein expression in both male and female offspring Begum et al.
In baboons, maternal nutrient restriction resulted in sex-dependent changes in GR mRNA, but not protein, expression. How sub-optimal maternal nutrition might impact the fetal maturational effects mediated by corticosteroids remains poorly understood. However, the accumulating body of evidence suggests that maternal diet can influence the corticosteroid signalling machinery. Whether or not infection might alter fetal and maternal responses to antenatal corticosteroid therapy is another important consideration.
Intrauterine infection and inflammation are strongly associated with preterm birth, especially those deliveries occurring at or below 32 weeks of gestation Goldenberg et al. Histologic chorioamnionitis is the hallmark of intrauterine infection most commonly identified in early gestation deliveries Lahra and Jeffery, Intrauterine infection is frequently polymicrobial and access of organisms to the fetal environment has been suggested to occur following a discrete breach in the chorioamniotic membranes Jones et al.
Ureaplasma species are commonly isolated from the gestational tissues in preterm birth Goldenberg et al. In the sheep model of pregnancy, chronic Ureaplasma infection increased surfactant production and had a surfactant-independent additive effect on lung compliance following a single course of antenatal betamethasone Moss et al. Similar additive improvements in fetal ovine lung compliance in the absence of increased surfactant production were identified following the co-administration of maternal betamethasone with intraamniotic lipopolysaccharides from Escherichia coli Newnham et al.
Differential effects of infection and ANS on pulmonary growth factors may play a role in these observed differences. Fetal sex is known to influence the risk of adverse outcomes in response antenatal corticosteroid therapy. The underlying mechanisms remain poorly understood, although sex-specific differences in the placenta have been hypothesized as being important in determining fetal responses to antenatal insults and prematurity Clifton, Female premature infants respond more effectively to antenatal betamethasone exposure than their male counterparts, with lower rates of respiratory distress syndrome Papageorgiou et al.
This observation from clinical studies has been replicated in a sheep model of prematurity; a retrospective analysis of fetuses that received 0. The observed difference in corticosteroid responsiveness between male and female fetuses does not appear to derive from differences in lung structural development or surfactant production between the sexes Ishak et al. Studies of the fetal programming of hypertension in sheep have shown that betamethasone exposure has a sex-dependent effect on endothelin-1 responsiveness Lee et al.
Zuloaga et al. In baboons, repeated antenatal betamethasone exposure reduces motivation in both male and female offspring; interestingly, reductions in reversal task performance were more pronounced in female offspring compared with males Rodriguez et al. The use of antenatal steroids has prevented the loss of thousands of pregnancies, and prevented significant morbidity in many more. However, it is also clear that ANS are not innocuous, and may have significant and long lasting effects on health.
Maternal and fetal factors, as well as the healthcare setting, can influence the risk benefit ratio for ANS. There is surprisingly little data available to inform drug dosing and timing for early pregnancy complications such as recurrent miscarriage and congenital adrenal hyperplasia. Even in obstetric medicine, which possesses the strongest empirical evidence base for ANS administration, there are still only two ANS dosing regimens, neither of which have been significantly refined to determine the optimal dose or treatment interval since their clinical introduction.
In the era of personalized medicine, we must move away from a one-size fits all approach. There is a need to trial new formulations to maximize benefits and minimize unwanted side effects, provide better delivery systems and dosage, and tailor treatment to individual circumstances, ensuring delivery of the right ANS, to the right pregnancy and at the right time. In this way, we can realize the full potential of this life saving, and morbidity sparing treatment.
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Search dates: March 1 to November 7, , and June 19 to July 3, Already a member or subscriber? Log in. Family Medicine Residency. Address correspondence to David S. Reprints are not available from the authors. Coco A. How often do physicians address other medical problems while providing prenatal care?
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BMC Pregnancy Childbirth. Franke H, Franke JD, et al. Osteopathic manipulative treatment for low back and pelvic girdle pain during and after pregnancy. J Bodyw Mov Ther. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
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Read the Issue. Sign Up Now. Previous: Type 2 Diabetes Mellitus in Children. Next: Treatment of Knee Osteoarthritis. Nov 1, Issue. Author disclosure: No relevant financial affiliations. B 7 , 8 , 10 Pregnant women with more than , colony-forming units of one bacterial species on urine culture should be treated with antibiotics to prevent pyelonephritis.
A 32 Initial choices for treating musculoskeletal back pain in pregnancy include exercise and physical therapy, but additional therapy with acetaminophen, warm baths, acupuncture, support devices, or epidural steroids may be needed. C 36 , 37 Pregnant women with new-onset headaches or a new type of headache should be further evaluated to distinguish urgent or emergent causes e. Image used with permission from VisualDx. Read the full article. Get immediate access, anytime, anywhere.
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General: dyspnea, hypoxemia. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Total infant doses are expected to be about 0. High doses for long periods of time could produce infant growth and development problems, interfere with infant endogenous corticosteroid production, and occasionally cause temporary loss of milk supply. Use caution; this drug should be used only if clearly needed Excreted into human milk: Yes Comments: -If this drug is necessary, the lowest dose should be prescribed; avoiding breastfeeding for 4 hours after a dose should minimize exposure to the infant.
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances. See references See Also References for pregnancy information Cerner Multum, Inc. Deltasone prednisone. Prelone prednisoLONE. Pediapred prednisoLONE sodium phosphate. References for breastfeeding information "Product Information. Toxicology Data Network.