Infant and Maternal Levels of Lithium May Be Strongly Correlated at Delivery; New Guidelines Proposed

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

Nov. 29, 2005 — There is a strong correlation between infant levels and maternal levels of lithium at the time of delivery, according to the results of a study published in the November issue of the American Journal of Psychiatry. The investigators provide guidelines for managing peripartum lithium.

"Lithium has been used during pregnancy for more than four decades, but quantification of fetal lithium exposure and clinical correlations of such exposure are limited," write D. Jeffrey Newport, MD, MS, MDiv, from the Harvard Medical School in Boston, Massachusetts, and colleagues. "The literature includes numerous reports of neonatal complications in association with lithium treatment during late pregnancy, including cardiac dysfunction, diabetes insipidus, hypothyroidism, low muscle tone, lethargy, hepatic abnormalities, and respiratory difficulties."

The objectives of this study were to quantify the rate of lithium placental passage, to determine any association between plasma concentration of lithium at delivery and adverse perinatal events, and to determine whether lithium concentrations can be reduced by briefly suspending therapy proximate to delivery.

In 10 women, lithium was assayed in maternal blood and umbilical cord blood at delivery, and obstetrical outcome data were collected prospectively. These data were pooled with those from 32 cases in which maternal lithium was administered throughout delivery, identified from MEDLINE and PsycINFO searches.

Across a wide range of maternal concentrations (0.2 - 2.6 mEq/L), the ratio of lithium concentrations in umbilical cord blood to maternal blood was uniform (mean, 1.05 ± 0.13). Infants with higher lithium concentrations (>0.64 mEq/L) at delivery had significantly lower Apgar scores, longer hospital stays, and higher rates of central nervous system (CNS) and neuromuscular complications. Withholding lithium therapy for 24 to 48 hours before delivery reduced maternal lithium concentrations by 0.28 mEq per L.

"Lithium completely equilibrates across the placenta," the authors write. "Higher lithium concentrations at delivery are associated with more perinatal complications, and lithium concentrations can be reduced by brief suspension of therapy proximate to delivery."

To improve neonatal well-being when lithium use is indicated in late pregnancy, the authors propose the following guidelines:

• Maintain a target lithium concentration at the minimum effective level (sometimes lower than the ideal cited of 0.8 to 1.0 mEq/L).
  Periodically monitor lithium concentrations during pregnancy, especially during late gestation when marked changes in glomerular filtration rate can alter lithium clearance.
  During pregnancy, avoid treatments that increase the potential for lithium toxicity, but if such measures are needed, more frequent lithium monitoring and dose reduction are indicated.
  When pregnancy is complicated by preeclampsia, polyhydramnios, or other conditions predisposing the mother or her child to lithium toxicity, lower the maternal lithium dose. Oligohydramnios or other abnormality in amniotic fluid volume could also increase the likelihood of lithium-associated fetal nephrotoxicity.
  Suspend lithium treatment 24 to 48 hours before a scheduled cesarean section or induction or at the onset of labor in the event of spontaneous delivery.
  Check the maternal lithium concentration when the mother presents to the hospital for delivery.
  Administer oral and/or intravenous fluids throughout labor and delivery, and check maternal lithium concentration if there are clinical signs of toxicity.
  
• As sproximate to delivery."

To improve neonatal well-being when lithium use is indicated in late pregnancy, the authors propose the following guidelines:

• Maintain a target lithium concentration at the minimum effective level (sometimes lower than the ideal cited of 0.8 to 1.0 mEq/L).
   
• Periodically monitor lithium concentrations during pregnancy, especially during late gestation when marked changes in glomerular filtration rate can alter lithium clearance.
   
• During pregnancy, avoid treatments that increase the potential for lithium toxicity, but if such measures are needed, more frequent lithium monitoring and dose reduction are indicated.
   
• When pregnancy is complicated by preeclampsia, polyhydramnios, or other conditions predisposing the mother or her child to lithium toxicity, lower the maternal lithium dose. Oligohydramnios or other abnormality in amniotic fluid volume could also increase the likelihood of lithium-associated fetal nephrotoxicity.
   
• Suspend lithium treatment 24 to 48 hours before a scheduled cesarean section or induction or at the onset of labor in the event of spontaneous delivery.
   
• Check the maternal lithium concentration when the mother presents to the hospital for delivery.
   
• Administer oral and/or intravenous fluids throughout labor and delivery, and check maternal lithium concentration if there are clinical signs of toxicity.
   
• As soon as the mother is medically stabilized after delivery, reinstitute lithium therapy at the preconception dose, because the maternal glomerular filtration rate rapidly returns to pregravid levels after delivery.

Study limitations include the small number of participants, limited statistical power to elucidate the association between clinical outcome and lithium concentration, limited generalizability of the results because of a homogeneous population, and inclusion of case data from earlier reports, some of which were incomplete.

"Given the considerable morbidity of untreated bipolar disorder and the significant risk of perinatal relapse in the absence of continued pharmacotherapy, prolonged discontinuation of treatment is seldom a viable option," the authors write. "Despite documented concerns about effects of lithium in reproduction, this medication remains the preferred alternative during gestation for many women with bipolar disorder. When lithium is used during late pregnancy, infant and maternal well-being can be maximized by maintaining maternal concentrations at the minimal effective level, suspending lithium therapy 24 - 48 hours before delivery to reduce neonatal concentrations further, and avoiding inadvertent or iatrogenic lithium toxicity during gestation."The National Institutes of Health have disclosed that it supported this study.

Am J Psych. 2005;162:2162-2170

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the rate of lithium placental passage and whether brief suspension of lithium therapy prior to delivery will reduce maternal lithium concentrations.
  
• Describe the association between infant plasma concentration of lithium at delivery and adverse perinatal events.

Clinical Context

Lithium has been the main pharmacotherapy for bipolar disorder since the 1950s. Recommendations regarding the use of lithium in late pregnancy vary. Compared with other mood stabilizers, lithium appears to have a positive safety profile. According to Yonkers and colleagues in the April 2004 issue of the American Journal of Psychiatry, there are no guidelines for monitoring lithium during pregnancy besides monitoring for cardiac teratogenicity. Reduction or discontinuation of lithium in pregnancy has been recommended to prevent possible neonatal complications, including cardiac dysfunction, diabetes insipidus, hypothyroidism, low muscle tone, lethargy, hepatic abnormalities, and respiratory difficulties. It is not known whether neonatal complications are due to lithium levels immediately prior to delivery or are unrelated to lithium concentration.

However, 50% to 60% of women with bipolar disorder relapse during pregnancy if pharmacotherapy is discontinued, especially if lithium is abruptly discontinued. Postpartum psychosis is more common in women with bipolar disorder. Reinstitution of lithium therapy prior to delivery might prevent postpartum relapse of bipolar disorder.

This is a study using pooled data from subjects followed up prospectively and previous studies to evaluate (1) the rate of lithium placental passage, (2) association between infant lithium concentration at delivery and adverse perinatal events, and (3) whether lithium concentrations can be decreased by discontinuation of lithium immediately prior to delivery.

Study Highlights

• 10 pregnant women with bipolar disorder I or II, defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, were recruited at Women's Mental Health Program, where protocol recommends suspension of lithium 1 to 2 days prior to scheduled delivery or at onset of labor. Maternal and umbilical cord blood samples were tested for lithium during gestation and at delivery. The ratio of lithium concentrations in infants to lithium concentrations in mothers was calculated to indicate lithium placental passage. A search of MEDLINE and PsycINFO databases identified 32 additional fetal-maternal pairs exposed to lithium at delivery.
   
• Lithium concentrations were known for 27 fetal-maternal pairs: 9 of the 10 Women's Mental Health Program pairs and 18 of the 32 previously reported pairs. The mean infant-mother lithium ratio at delivery was uniform (1.05; SD, 0.13) across a range of maternal concentrations from 0.20 to 2.60 mEq/L (mean, 0.71; SD, 0.59). The infant lithium concentrations ranged from 0.20 to 2.80 mEq/L (mean, 0.72; SD, 0.57).
   
• Although the Women's Mental Health Program group had lower lithium concentrations for infants (0.49 vs 0.84 mEq/L) and mothers (0.49 vs 0.82 mEq/L) than the previously reported group, the lithium ratios were similar (1.01 vs 1.06).
   
• Lithium concentrations and neonatal outcomes were known for all 10 infants in Women's Mental Health Program and for 14 of 32 reported dyads. Based on the median lithium concentration of 0.64 mEq/L, these 24 infants were assigned to low lithium group (range, 0.20 - 0.58 mEq/L) or high lithium group (range, 0.70 - >4 mEq/L); 8 of the Women's Mental Health Program infants were in the low lithium group. The low lithium and high lithium groups had similar mean infant-mother lithium ratios at delivery.
   
• The CNS complication rate (lethargy and "depression") was significantly greater in the high lithium group (90%) vs the low lithium group (18%; risk ratio, 40.5; 95% confidence interval [CI], 3.09 - 530.29; P < .002). The neuromuscular complication rate (hypotonia, "flaccidity," diminished deep tendon reflexes, poor suck or Moro reflex) was significantly greater in the high lithium group (100%) vs the low lithium group (25%; P < .002). Hospital stay was longer for the high lithium group (mean, 10.1 days; 95% CI, 5.0 - 15.3) vs the low lithium group (4.3 days; 95% CI, 1.2 - 7.3; P < .03). The 1-minute Apgar score was lower in the high lithium group (4.3; 95% CI, 2.2 - 6.6) vs the low lithium group (7; 95% CI, 5.9 - 8.1; P < .03).
   
• Higher rates were reported in the high lithium group for preterm delivery (33% vs 0%; P < .05), low birth weight (40% vs 0%; P < .05), and respiratory complications, including apnea, cyanosis, labored breathing, and need for intubation (67% vs 17%; P < .03).
   
• The rates were not significantly different between high and low lithium groups for cardiovascular (bradycardia, cardiomegaly, systolic murmur), hepatic (hepatomegaly and jaundice), renal (polyuria and diabetes insipidus), and thyroid (goiter) complications.
   
• 5 of 9 women in the Women's Mental Health Program had subtherapeutic lithium concentrations of less than 0.5 mEq/L at delivery. Maternal lithium concentrations at delivery were lower than during pregnancy (mean difference, 0.28 mEq/L; 95% CI, 0.08 - 0.49; P < .02), with the last lithium dose received at a mean of 20.6 hours (SD, 19.2) previously. Only 1 of 10 women was symptomatic perinatally with a depressive episode with psychotic features 2 weeks prior to delivery and prior to suspension of lithium.
   
• Limitations included small number and homogeneity of subjects and inclusion of previously reported data.

Pearls for Practice

• Lithium equilibrates across the placenta with a uniform ratio of lithium concentration in umbilical cord blood to maternal blood across a wide range of maternal concentrations. Suspending lithium for 24 to 48 hours prior to delivery reduces maternal lithium concentration.
   
• Higher lithium concentrations at delivery are associated with more perinatal complications, including CNS and neuromuscular findings, longer hospital stay, and lower one-minute Apgar score.

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