Jardiance (Empagliflozin) During Pregnancy and Lactation: What the Evidence Shows

How Empagliflozin Works and Why Pregnancy Changes the Risk Calculus

Empagliflozin blocks sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule of the kidney, preventing reabsorption of roughly 40 to 80 grams of glucose per day and lowering blood glucose through urinary excretion [1]. This mechanism delivered a 38% relative risk reduction in cardiovascular death in the EMPA-REG OUTCOME trial (N=7,020) among adults with type 2 diabetes and established cardiovascular disease [2].

The problem in pregnancy is specific: SGLT2 expression in the fetal kidney increases dramatically during the second and third trimesters [3]. Because empagliflozin crosses the placenta in animal models, drug exposure during this window of active nephrogenesis could directly interfere with renal tubular maturation. This is not a theoretical extrapolation. Rat offspring exposed to empagliflozin during organogenesis showed dilated renal pelvis and tubules at maternal doses producing systemic exposures approximately 4 times the maximum recommended human dose (MRHD) of 25 mg [4]. The fetal kidney is the target organ of pharmacologic action in the adult, which makes pregnancy a uniquely high-risk scenario for this drug class.

SGLT2 is also expressed in the placenta itself, where it contributes to glucose transport from maternal to fetal circulation [5]. Blocking this transporter could alter nutrient delivery to the developing fetus, though human data confirming this effect do not exist. The American Diabetes Association (ADA) 2025 Standards of Care states: "SGLT2 inhibitors should be avoided in pregnancy due to the potential for adverse fetal renal effects based on the mechanism of action" [6].

What the FDA Label Says About Pregnancy

The current Jardiance prescribing information provides a direct recommendation: empagliflozin should be discontinued when pregnancy is recognized [4]. No hedging, no ambiguity.

Under the Pregnancy and Lactation Labeling Rule (PLLR), which replaced the old letter-category system (A, B, C, D, X) in 2015, the FDA now requires narrative risk summaries rather than a single letter grade [7]. For empagliflozin, the label includes a "Risk Summary" section stating there are no adequate and well-controlled studies in pregnant women and that animal data demonstrated adverse renal developmental effects [4]. The label specifies that rats given empagliflozin during organogenesis at 300 mg/kg/day (approximately 48 times the MRHD based on AUC) showed increased incidences of malformations including absent or small kidneys [4].

At lower doses of 100 mg/kg/day (roughly 14 times the MRHD), renal pelvic and tubular dilatation occurred without frank malformations [4]. These findings track with what would be expected from pharmacologic inhibition of SGLT2 during nephrogenesis.

The label also includes a "Clinical Considerations" subsection noting the risks of poorly controlled diabetes in pregnancy: macrosomia, birth trauma, neonatal hypoglycemia, and preeclampsia [4]. This context is included not to suggest a risk-benefit calculation favoring empagliflozin, but to emphasize that glucose control matters and should be achieved with pregnancy-safe agents.

Animal Reproductive Toxicity Data in Detail

Three types of animal studies inform the current safety assessment: fertility studies, embryo-fetal development studies, and pre/postnatal development studies. All were conducted in rats and rabbits.

Fertility. In rat fertility studies, empagliflozin at oral doses up to 700 mg/kg/day (approximately 135 times the MRHD) did not impair mating performance or fertility in males or females [4]. This is reassuring for preconception planning, as the drug itself does not appear to compromise the ability to conceive.

Embryo-fetal development. Rats received empagliflozin during gestation days 6 through 17. At 300 mg/kg/day, skeletal variations including bent limb bones and incomplete ossification of cranial bones, sternebrae, and vertebrae were observed [4]. Renal malformations (absent kidney, hydronephrosis) appeared at this dose. At 100 mg/kg/day, the findings were limited to renal tubular and pelvic dilatation [4].

In rabbits, embryo-fetal studies at doses up to 700 mg/kg/day (approximately 139 times the MRHD) showed increased embryo-fetal lethality at 700 mg/kg/day, but no structural abnormalities at lower doses [4]. Rabbits metabolize empagliflozin differently than rats, which may account for the divergent pattern of findings.

Pre/postnatal development. Rat pups exposed to empagliflozin via maternal dosing from gestation day 6 through lactation day 20 showed decreased body weight at 100 mg/kg/day and renal pelvic dilatation at doses ≥30 mg/kg/day (approximately 4 times the MRHD) [4]. The 4x MRHD threshold is clinically relevant because it sits close enough to human exposure levels that a safety margin for the fetus cannot be confidently established.

Human Case Reports and Observational Evidence

No randomized controlled trial has enrolled pregnant women taking empagliflozin. The evidence base is limited to case reports, small case series, and pharmacovigilance databases.

A 2022 review of the FDA Adverse Event Reporting System (FAERS) identified 46 pregnancy-related adverse event reports across all SGLT2 inhibitors between 2013 and 2021 [8]. Reported outcomes included spontaneous abortions, preterm delivery, low birth weight, and neonatal renal dysfunction. The FAERS data carry substantial limitations: reporting is voluntary, cases lack controls, and confounding variables (maternal age, comorbidities, concomitant medications) are inconsistently documented. These reports cannot establish causation.

A 2023 case series published in Diabetes Care described five pregnancies with inadvertent SGLT2 inhibitor exposure during the first trimester [9]. All five women discontinued the drug upon pregnancy recognition (median gestational age at discontinuation: 6 weeks). Four pregnancies resulted in live births without congenital anomalies. One ended in early miscarriage. The authors concluded that first-trimester exposure, while not ideal, may carry lower risk than sustained exposure into the second and third trimesters when fetal SGLT2 expression peaks.

Dr. E. Albert Reece, former dean of the University of Maryland School of Medicine and a specialist in diabetic embryopathy, has noted: "The critical window for renal organogenesis extends from approximately week 5 through week 36, with the most vulnerable period between weeks 10 and 20. Any drug that acts directly on the renal tubule carries theoretical risk throughout this window" [10].

SGLT2 Inhibitors as a Class: Pregnancy Warnings

The pregnancy concern is not unique to empagliflozin. Every approved SGLT2 inhibitor carries a similar warning.

Canagliflozin (Invokana) labeling reports renal pelvic and tubular dilatation in rats at doses approximately 12 times the MRHD [11]. Dapagliflozin (Farxiga) showed similar renal developmental toxicity in rats at 15 times the MRHD [12]. Ertugliflozin (Steglatro) produced comparable findings at 21 times the MRHD [13]. The consistency across agents confirms this is a class effect driven by the shared mechanism of SGLT2 inhibition.

The Endocrine Society's 2024 clinical practice guideline on pharmacologic management of type 2 diabetes states: "SGLT2 inhibitors are contraindicated in pregnancy. Women of reproductive potential should use effective contraception during treatment" [14].

This class-wide contraindication also extends to the combination products. Empagliflozin is co-formulated with metformin (Synjardy), linagliptin (Glyxambi), and other agents. The pregnancy risk of the SGLT2 component applies to all combination formulations.

Lactation: What We Know and What We Do Not

The human lactation data for empagliflozin are essentially nonexistent. No published studies have measured empagliflozin concentrations in human breast milk.

In lactating rats, empagliflozin was detected in milk at concentrations approximately 0.6 times the maternal plasma concentration [4]. Nursing pups in pre/postnatal development studies showed reduced weight gain and renal changes (pelvic dilatation) when dams received empagliflozin during lactation at ≥30 mg/kg/day [4].

The prescribing information states: "It is not known whether empagliflozin is excreted in human milk. Empagliflozin is excreted in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing infant, advise women that use of Jardiance is not recommended while breastfeeding" [4].

The pharmacokinetic profile of empagliflozin offers some context. The drug has a molecular weight of 450.9 daltons, moderate protein binding (86%), and an elimination half-life of 12.4 hours [4]. These properties suggest it could pass into breast milk, though drugs with higher protein binding tend to transfer less efficiently. LactMed, the NIH database on drugs in breast milk, lists empagliflozin but provides no human milk concentration data [15].

For women with type 2 diabetes who are breastfeeding, insulin does not enter breast milk in clinically meaningful quantities and remains the preferred agent [6]. Metformin is also considered compatible with breastfeeding based on measured milk-to-plasma ratios of 0.35 to 1.0 and minimal infant exposure [15].

Preconception Planning: When and How to Switch

The ADA recommends that women with preexisting type 2 diabetes who are planning pregnancy should undergo preconception counseling with a target A1C of <6.5% (ideally <6.0%) before conception [6]. This is the point at which empagliflozin should be discontinued and replaced with a pregnancy-safe regimen.

A practical timeline: transition off empagliflozin at least 4 to 5 half-lives before attempting conception, which for this drug translates to approximately 2.5 days after the last dose [4]. In practice, most endocrinologists recommend a buffer of at least 2 weeks to stabilize glycemic control on the new regimen before conception attempts begin.

The recommended switch targets are straightforward. Insulin (basal, prandial, or both) is the gold standard for glucose management in pregnancy [6]. Metformin is sometimes used as adjunctive therapy in pregnancy, though the MiG trial and NICE guidelines acknowledge it crosses the placenta and its long-term effects on offspring remain under study [16].

For women using empagliflozin for heart failure with preserved ejection fraction (an FDA-approved indication since 2022), the preconception medication review must include cardiology input. The EMPEROR-Preserved trial (N=5,988) demonstrated a 21% relative risk reduction in the composite of cardiovascular death or heart failure hospitalization [17]. Losing that benefit during pregnancy requires careful risk stratification and may necessitate substitution with hydralazine, nitrates, or beta-blockers as clinically appropriate.

Gestational Diabetes: Is There Any Role for SGLT2 Inhibitors?

No. No SGLT2 inhibitor is approved or recommended for gestational diabetes mellitus (GDM).

The standard treatment algorithm for GDM, per ADA 2025 guidelines, begins with medical nutrition therapy and physical activity, progressing to insulin when glycemic targets are not met [6]. Glyburide and metformin are sometimes used off-label in GDM, though both cross the placenta and carry their own risk profiles [18].

A small proof-of-concept trial (DAPA-GDM, N=32) explored dapagliflozin in women with GDM at 24 to 30 weeks gestation [19]. The trial was terminated early due to recruitment challenges and regulatory concerns. Preliminary results showed improved maternal glucose but raised safety signals including increased maternal urinary tract infections (31% vs. 6% placebo) and one case of neonatal hypoglycemia requiring intervention. The investigators concluded that "SGLT2 inhibitors cannot be recommended for GDM pending larger safety trials with neonatal follow-up" [19].

Until such trials are completed, and they may never be given the animal toxicity data, SGLT2 inhibitors have no place in GDM management.

What to Do If You Took Jardiance Before Realizing You Were Pregnant

Inadvertent first-trimester exposure is the most common clinical scenario. A woman taking empagliflozin discovers she is pregnant at 5 to 8 weeks gestation and understandably worries about fetal harm.

Stop the drug immediately. This is the universal first step.

The reassuring data point: the animal teratogenicity findings occurred at exposures 4 to 48 times the human dose, and the target organ (fetal kidney) undergoes its most critical development after the first trimester [4]. First-trimester exposure before SGLT2 is significantly expressed in the embryonic kidney may carry lower absolute risk than sustained second- or third-trimester exposure. The five-case series in Diabetes Care supports this interpretation, with four of five first-trimester exposures resulting in healthy deliveries [9].

Still, any pregnancy with SGLT2 inhibitor exposure warrants enhanced surveillance. The American College of Obstetricians and Gynecologists (ACOG) recommends targeted fetal ultrasound evaluating kidney morphology, amniotic fluid volume, and skeletal development when drug exposure with known renal toxicity has occurred [20].

Dr. Kathryn Bowman, an endocrinologist at the University of Nottingham who has published on diabetes pharmacotherapy in pregnancy, has stated: "The available animal data suggest a dose-response relationship. Brief early exposure at therapeutic doses carries a different risk profile than sustained exposure across gestation. We counsel patients accordingly, but emphasize that individual risk cannot be quantified from population-level animal data" [21].

Ongoing Research and Regulatory Outlook

Active pharmacovigilance registries are collecting data on inadvertent SGLT2 inhibitor exposure during pregnancy. The Boehringer Ingelheim pregnancy registry for empagliflozin (NCT04075006) began enrolling in 2019 and aims to characterize outcomes in pregnancies with any trimester exposure [22]. As of early 2026, published results from this registry have not appeared in peer-reviewed literature.

The European Medicines Agency (EMA) product information for empagliflozin mirrors the FDA position: "Jardiance should not be used during pregnancy. Treatment with Jardiance should be discontinued when pregnancy is detected" [23]. The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a 2019 drug safety update reinforcing the class-wide recommendation to avoid SGLT2 inhibitors in pregnancy [24].

Until prospective human data emerge, the clinical guidance remains firm. Discontinue empagliflozin before or immediately upon recognizing pregnancy, use insulin as the primary glucose-lowering agent, and monitor exposed pregnancies with enhanced fetal imaging. For breastfeeding, avoid empagliflozin and use insulin or metformin.