Can Low-Dose Naltrexone (LDN) use in a woman of childbearing age with a history of infertility and underlying conditions such as endometriosis or autoimmune disorders cause an enlarged yolk sac during pregnancy?

Low-Dose Naltrexone (LDN) and Enlarged Yolk Sac: No Established Association

There is no evidence linking Low-Dose Naltrexone (LDN) use in infertility treatment or pregnancy to enlarged yolk sac, and the available data on naltrexone use during pregnancy shows reassuring fetal outcomes without reported structural anomalies.

Current Evidence on Naltrexone in Pregnancy

The available literature addresses standard-dose naltrexone (not specifically LDN) for opioid use disorder (OUD) and alcohol use disorder (AUD) treatment during pregnancy, but provides relevant safety data:

Fetal Structural Outcomes

• No birth defects or fetal anomalies have been reported in prospective studies of naltrexone-exposed pregnancies, including a 2020 study of 230 pregnant women where no cases of birth anomalies occurred in the naltrexone group 1
• A 2024 case series of 7 pregnant individuals treated with naltrexone reported no fetal anomalies 2
• Earlier case reports from 2001 involving 10 deliveries showed unremarkable neonatal features with good Apgar scores, birthweight, and head circumference, with normal fetal development observed on ultrasound 3

Placental Transfer and Fetal Exposure

• Naltrexone crosses the placenta with concordant maternal and fetal blood levels 1
• The drug clears rapidly from maternal circulation (undetectable if discontinued >60 hours before delivery) 1
• No neonatal opioid withdrawal syndrome occurs in infants exposed to naltrexone through delivery 1, 2

Critical Knowledge Gaps

Lack of LDN-Specific Data

The evidence base has significant limitations for your specific question:

• No published studies specifically examine LDN (typically 1.5-4.5 mg daily) for infertility treatment or autoimmune conditions during pregnancy
• All available pregnancy data involves standard naltrexone dosing (50 mg oral daily or 380 mg monthly injectable) for substance use disorders 1, 2
• No studies have evaluated yolk sac measurements as an outcome in naltrexone-exposed pregnancies

Guideline Perspective on Naltrexone Safety

• The Society for Maternal-Fetal Medicine, ACOG, and American Society of Addiction Medicine joint 2019 workshop report states that "data are insufficient" regarding naltrexone use during pregnancy 4
• A 2021 review concluded that naltrexone "does not appear to be associated with substantial risks of congenital malformations" but emphasized that further research is warranted 5

Enlarged Yolk Sac: Alternative Etiologies to Consider

Since there is no evidence linking naltrexone to yolk sac abnormalities, evaluate other causes:

Common Associations with Enlarged Yolk Sac

• Aneuploidy and chromosomal abnormalities (most common pathologic cause)
• Early pregnancy loss risk (yolk sac >6 mm associated with poor prognosis)
• Maternal factors: Advanced maternal age, poorly controlled diabetes
• Idiopathic findings that may resolve or represent normal variation

Clinical Approach

• Document precise yolk sac diameter and gestational age at measurement
• Correlate with crown-rump length and fetal cardiac activity
• Consider genetic counseling if yolk sac >6 mm with other concerning features
• Serial ultrasound follow-up to assess pregnancy viability

Risk-Benefit Considerations for LDN Continuation

If a patient is taking LDN for infertility or autoimmune conditions and becomes pregnant:

• The theoretical risk of continuing LDN is unknown due to absence of data 4
• The risk of stopping LDN depends on the underlying condition being treated and whether alternative therapies exist
• For autoimmune conditions like endometriosis, weigh the lack of safety data against disease control needs
• First trimester exposure should be minimized when possible, as this is the period of organogenesis 6, 7

Practical Clinical Recommendation

Given the absence of any evidence linking naltrexone to yolk sac abnormalities and the reassuring structural outcomes in available pregnancy studies, an enlarged yolk sac in a patient taking LDN should be evaluated using standard obstetric protocols without attributing causation to the medication. However, due to insufficient safety data for LDN specifically, discuss discontinuation during organogenesis (first trimester) unless maternal benefits clearly outweigh unknown fetal risks 4, 5.

Common Pitfalls to Avoid

• Do not assume causation between LDN and any ultrasound finding without supporting evidence
• Do not continue LDN without informed consent acknowledging the lack of pregnancy safety data
• Do not overlook standard causes of enlarged yolk sac while focusing on medication exposure
• Do not extrapolate standard-dose naltrexone data directly to low-dose formulations without acknowledging this limitation