Pregnant with bipolar? What you should know about lithium during pregnancy

Lithium carbonate has been used in the US to treat bipolar disorder since 1970. However, the use of lithium in psychiatry goes back to the 1800s, although only briefly, only to resurface in 1949 as a treatment for manic episodes (1).

It has a long track record and remains the gold standard in treating bipolar disorder (2).

A quick look at lithium’s history (and its fascinating connection to uric acid)

In the mid-19th century, lithium was used to treat high uric acid conditions such as gout after discovering that uric acid crystals deposited on cartilage would dissolve if placed in a lithium solution. Eventually, side effects of lithium overuse were recognized, including dizziness, nausea, giddiness, and depression, and lithium as a pharmaceutical agent seemed to disappear from the radar for a bit (3).

Then, in 1949, a psychiatrist named John Cade hypothesized that elevated uric acid could be a factor in the manic episodes experienced by his patients. The lithium treatment worked so well that patients confined to a hospital for years were suddenly healthy enough to be discharged, a massive breakthrough in psychiatric medicine (3).

Even more amazingly, recent clinical and genetic research supports the early hypothesis that uric acid has a connection to mental illness, particularly mania (4).

Research has shown that uric acid levels are elevated in bipolar patients and significantly higher in those experiencing a manic or mixed episode (4, 5, 6).

During pregnancy, abnormal uric acid levels have been associated with abnormal fetal growth and neonatal complications. Maternal uric acid levels that are out of range, both very high and low, have been linked to a small for gestational age at birth (<10th percentile); conversely, elevated uric acid has been linked to large for gestational age at birth (>90th percentile) (7).

Uric acid that is usually high or low may increase the risk of high blood pressure during pregnancy (8).

A study of 205 women with preeclampsia and eclampsia found that high uric acid (≥393 μmol/L) resulted in a significantly increased risk of preterm birth, intrauterine growth restriction, neonatal death, and lower Apgar scores (9).

Now, on to lithium when you’re pregnant with bipolar—what does the evidence tell us?

Let’s look at the findings of a critical review article from 2018, available here.

Large studies have shown that for those pregnant with bipolar, there is an increased risk of fetal malformations, particularly when lithium is taken during the first trimester.

Lithium easily crosses the placenta, and fetal blood levels match maternal levels (10). At the same time, while studies have yielded inconsistent results regarding the risk of bipolar flare-ups during pregnancy, the postpartum period carries a high risk of symptom relapse, particularly in those not taking prophylactic medication during pregnancy.

While only a minority of bipolar patients take medication for bipolar disorder during pregnancy, the vast majority of these take lithium. Thus, it is crucial the patient be advised of the risks and benefits of lithium therapy during pregnancy before trying to conceive.

Additionally, the patient’s care team must weigh the benefits of lithium therapy against the risks to the developing fetus, considering individual risk factors affecting the likelihood of relapse of bipolar symptoms during pregnancy and postpartum.

Interestingly, countries have vastly different guidelines regarding the use of lithium during pregnancy.

However, guidelines on lithium therapy typically discourage breastfeeding in those taking the medication because of lithium excretion in the breast milk, elevated lithium levels in the breastfed infant, and the negative impact of nighttime wakings and feedings on the symptoms of bipolar disorder in the nursing mother.

The authors of the review conclude that when lithium is considered the best option during pregnancy, the following steps should be taken:

Frequent monitoring of the patient’s blood lithium levels (more frequently than is done outside of pregnancy, “with monthly monitoring of lithium blood levels until 34 weeks and weekly monitoring after that until delivery (11)”
Fetal anatomy scan at 16 or 20 weeks of gestation with high-resolution ultrasound
During delivery and the 24-hour period following delivery, maternal blood lithium levels and maternal fluid levels need to be monitored
Lithium blood levels, TSH, and free T4 should be measured in umbilical cord blood
NSAIDs and nephrotoxic medications should be avoided
When assessing anesthetics during delivery, interactions with lithium should be considered. For example, “lithium potentiates succinylcholine and pancuronium and can be expected to potentiate other depolarising and non-depolarizing muscle relaxants (12)
Regional anesthesia is considered safe in patients taking lithium (12)

For those pregnant with bipolar, it is essential to understand that physiological changes of pregnancy affect lithium levels and lithium clearance:

“Excretion of lithium is almost exclusively renal, hence, blood plasma levels mainly depend on intravascular volume and glomerular filtration rate (GFR). As pregnancy progresses, total body water, plasma volume and GFR are increased with GFR rising from as early as 6 weeks gestation up to 50% over non-pregnant women by the end of the first trimester. Clinical studies have shown lithium blood levels to decrease significantly during pregnancy. An average decrease of 24% in the first trimester, 36% in second trimester and 21% in third trimester was described. Creatinine blood levels showed a similar longitudinal pattern, showing that indeed changes in lithium blood level reflect changes in renal physiology (13).”

Importantly, if you’re pregnant with bipolar, you may have a higher risk of adverse pregnancy outcomes, regardless of treatment with lithium or other mood-stabilizing medication.

Pregnant people with bipolar disorder are at higher risk than their non-bipolar counterparts of antepartum hemorrhage, C-section, and placental abnormalities (14, 15).

The mechanism behind this heightened risk is not completely clear; however, it is thought that being pregnant with bipolar increases psychosocial stress and cortisol levels, affecting pregnancy outcomes and fetal development (15).

Additionally, it’s essential to consider that elevated uric acid is also linked to adverse pregnancy outcomes, as discussed above. Bipolar patients have been reported to have higher-than-normal levels of uric acid. Because altered uric acid can indicate oxidative stress, this could also be a factor in the increased risk of pregnancy complications in those pregnant with bipolar.

Further, a 2012 population-based cohort study found that unmedicated and medicated bipolar during pregnancy was associated with increased rates of infant microcephaly, small birth weight, and neonatal hypoglycemia (15).

**However, some research shows that if you’re pregnant with bipolar, lithium may not increase the risk of pregnancy complications.**

A 2018 meta-analysis of 727 lithium-exposed pregnancies found that lithium use during pregnancy was not associated with pregnancy complications, including preeclampsia, gestational diabetes, fetal distress, cesarean section, or postpartum hemorrhage (16).

Two more studies support these results, showing that the rates of obstetric complications were not higher for bipolar women who continued lithium during pregnancy compared to women who discontinued lithium before pregnancy or early in the first trimester (17,18).

However, in one of those studies, though pregnancy complications were not significantly affected by lithium use, lithium use throughout the first trimester was associated with significantly increased rates of ultrasound abnormality, predominantly fetal abdominal circumference >90th percentile. Despite this phenomenon, no congenital abnormalities were reported in infants exposed to lithium (17).

So, is lithium a teratogen?

Several malformations are associated with the pharmacological use of lithium during pregnancy. However, the exact reason for the increase in malformations isn’t known.

“It might be related to lithium’s inhibition of the glycogen synthase kinase-3β (GSK3β). GSK3β expression is of importance for the Wnt signaling pathway, which is of influence on cardiac and vascular development in the embryo (13).”

Lithium use during pregnancy is linked to increased cardiovascular malformations in the baby, including Ebstein anomaly, a rare congenital heart defect that generally has a 1 in 20,000 chance of occurring.

For women pregnant with bipolar who take lithium throughout the pregnancy, the risk of Ebstein may rise by 400%, as observed in data from the 1974 Register of Lithium Babies (19).

A 2008 study based on data from 2908 women in the Swedish Medical Birth Register found an association between lithium use and congenital malformations, including cardiac defects. In this study, 74 women used lithium during pregnancy, and the rate of cardiac defects was 5.1% (CI: 1.4% – 12.5%) (20).

A 2017 cohort study of 1,325,563 pregnancies found that cardiac malformations, including Ebstein anomaly, were present in 2.41% of infants exposed to lithium and 1.15% of infants not exposed to lithium. The risk of cardiac defects due to lithium exposure was dose-dependent—a daily dose <600mg lithium resulted in a risk ratio of 1.11 (CI: 0.46 to 2.64), and when the daily dose increased to 601-900mg, the risk ratio increased to 1.60 (CI: 0.67 to 3.80). A daily lithium dose exceeding 900 mg raised the risk ratio to 3.22 (CI: 1.47 to 7.02) (21).

However, we must be incredibly careful interpreting these statistics, as the confidence intervals of the two lowest doses (<600mg and 601-900mg) both include 1, indicating no statistical significance, and the confidence interval of the highest dose (>900mg) is very wide (CI: 1.47 to 7.02).

Additionally, a large meta-analysis of six multinational cohort studies found a link between lithium use during pregnancy and major malformations in the infant, as well as a significant increase in neonatal readmission. In this study, fetal exposure to lithium in the first trimester was associated with a higher risk of malformations at birth compared to infants born to mothers with a mood disorder (bipolar or major depressive disorder) not taking lithium or other mood-stabilizing medication (pooled prevalence 7.4% vs. 4.3%) (22).

Cardiac malformations were increased in the lithium group, but the results were not statistically significant (2.1% vs. 1.6%). Interestingly, there were no cases of Ebstein anomaly within these cohorts (22).

Other research has provided contrasting results regarding the teratogenic effects of lithium. A 2012 Lancet review on lithium toxicity during pregnancy concluded that:

“The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy (23).”

A 2016 registry-based case-control study found an association between Ebstein anomaly and maternal mental health. However, this relationship was independent of lithium use, and the authors noted that “changing or stopping medications may not be preventative (24).”

Lithium and neonatal outcomes

Exposure to lithium in utero is associated with an increased risk of neonatal complications, such as higher rates of central nervous system and neuromuscular complications, lower Apgar scores, and increased neonatal hospital admissions.

Newport et al. (2005) observed that increased lithium exposure at delivery correlated with worse neonatal outcomes, and briefly withholding lithium during 24-48 hours before delivery may be an option to improve neonatal outcomes (25).

Various case reports have observed more severe complications associated with lithium exposure. This includes jaundice (26), nephrogenic diabetes insipidus (27), and lithium toxicity in the infant, marked by symptoms such as lethargy, respiratory problems, hypotonia, poor oral feeding ability, cyanosis, and thyroid abnormalities (28).

What are the long-term effects of lithium on the developing child?

Minimal literature is available on the potential long-term effects of in-utero lithium exposure on developmental and cognitive skills.

A 1992 prospective multicenter study found that babies exposed to lithium in the first trimester reached developmental milestones such as lifting the head, crawling, walking, and talking in a similar period to controls not exposed to lithium. However, the article did not show specific data (29).

A 2012 study on 15 children exposed to lithium in utero showed normal neurological function and motor and behavioral skills. Lithium-exposed children scored lower on intelligence testing utilizing Block patterns than their counterparts, but this difference was insignificant (30).

Finally, a more recent study showed no difference in childhood IQ for children exposed to lithium in utero compared to non-exposed children born to a mother with a mood disorder as well as controls (31).

Is lithium safe to use in the postpartum period?

For those pregnant with bipolar who cease lithium therapy during pregnancy, lithium treatment immediately after delivery may be an effective prophylactic strategy to prevent bipolar relapse as well as postpartum psychosis.

The postpartum period can be wonderful…but also mentally, emotionally, and physically exhausting. These factors may affect those with mental illness more severely than those without. Therefore, the authors note:

“Women with a history of bipolar disorder or postpartum psychosis are at extremely high risk of relapse postpartum…Numbers are very small, but in all studies on prophylactic treatment with lithium postpartum, women with bipolar disorder had significantly lower rates of postpartum relapse compared to medication-free women (13).”

Additionally, according to Berkman et al. (2016), lithium is highly effective at preventing postpartum psychosis, and thus, it is the preferred prophylactic drug (32).

The authors of the review suggest the following strategy when using lithium prophylaxis postpartum (13):

Begin lithium treatment the first evening after delivery, dosing to get a target blood level of 0.8–1.0 mmol/L.
Consider a higher lithium target level (for example, 0.8 mmol/L) in the first month of postpartum, as this is a high-risk time for relapse. The authors note that the benefits during this initial period outweigh the potential risks.
Monitor lithium blood levels twice a week for two weeks following delivery.
If tapering off lithium is desired, wait until three months postpartum to begin this process.

Other considerations for those pregnant with bipolar

Nutrition is an essential piece for both pregnancy and bipolar disorder. Additionally, for bipolar, specific nutrition strategies can be remarkably therapeutic.

For instance, gluten is a protein in wheat products that can trigger psychiatric symptoms even in those without celiac disease. However, the prevalence of bipolar disorder is significantly higher in those with celiac disease. You can read more about eating for bipolar disorder here.

Balancing the diet with abundant antioxidant-rich foods may also be helpful, partly because this helps counteract the elevated oxidative stress often present in bipolar disorder (read more about that here) but also because antioxidant-rich foods help support metabolic health.

Metabolic health is a priority for those with bipolar disorder, given that metabolic conditions such as insulin resistance and type II diabetes are frequently found in bipolar patients.

Interestingly, high uric acid has also been associated with physiologic states linked to metabolic dysfunction, such as chronically elevated blood glucose and thyroid imbalances. Eating in a way that helps support balanced blood sugar is a helpful strategy for those pregnant with bipolar.

In the next part of this series, I’ll discuss thyroid function during pregnancy and for those with bipolar.

Are you pregnant with bipolar and need support?

Bipolar disorder is a diagnosis that is professionally and personally important to me. If you or someone you love is living with this diagnosis and needs support, please schedule a free 15-minute consultation call.

We can discuss the aspects of the diagnosis most impactful to you, what your care team needs to be aware of, and if nutritional therapy is a good fit.

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