7 Hydroxyprogesterone Side Effects You Should Know About

DISCLAIMER: After this article was published, Makena's manufacturer agreed to pull the medication from the market due to effectiveness concerns. Makena, and its generic equivalents, will no longer be available in the U.S.

Hydroxyprogesterone (Makena) is an injectable prescription hormone medication. While it’s not always a routine treatment, it’s sometimes used for women who are pregnant. For expecting women who have delivered a preterm baby in the past, it might help lower the risk of going into labor too early again.

This progestin medication is injected by a trained healthcare provider. It can be given either as an intramuscular (IM) injection into the buttocks, or as a subcutaneous (under-the-skin) injection in the upper arm. At other doses, generic hydroxyprogesterone can also treat non-pregnancy related conditions too, like regulating irregular periods and treating uterine cancer.

But, like all medications, hydroxyprogesterone can cause side effects. Some are mild and manageable, while others can be more serious. Below, we’ll discuss seven hydroxyprogesterone side effects you should know about.

1. Injection site reactions

Injection site reactions can happen with hydroxyprogesterone. Symptoms of an injection site reaction can include pain and swelling at the injection site, itching, and bruising. A small hard bump under the skin can also occur. Injection site reactions are usually mild and resolve within a few days.

To lower your risk of injection site reactions, your provider should rotate the location of your injection site every dose. They can do this by switching arms or areas on the glutes. It’s also best to avoid injecting into any areas where the skin is tender, bruised, or scaly.

If you do experience injection site discomfort, you can try applying an ice pack to the injection site. Over-the-counter (OTC) pain relievers, like acetaminophen (Tylenol), may also help. If you’re pregnant, remember to check with your healthcare provider before taking any medications. Some pain relievers may not be safe to take during pregnancy.

If injection site reactions worsen or last longer than a few days, speak with your healthcare provider.

2. Hives

Hives — a type of elevated, itchy rash — are another possible side effect of hydroxyprogesterone. Hives can be mild, but they can also be a sign that a more severe allergic reaction is happening. Allergic reactions, including life-threatening problems such as airway swelling or anaphylaxis, are possible after receiving hydroxyprogesterone.

If you notice severe hives, swelling of the lips or tongue, or difficulty breathing after receiving your dose of hydroxyprogesterone, seek medical attention right away. A milder rash still warrants a prompt call to your healthcare provider.

3. Nausea and diarrhea

Nausea and diarrhea are also common hydroxyprogesterone side effects. 

To help keep nausea or diarrhea at bay, try eating smaller meals throughout the day and eating bland foods. Avoid spicy, fried, or high-fiber foods. Staying hydrated with water and electrolyte drinks is also helpful if you’re experiencing nausea or diarrhea. 

If your nausea or diarrhea doesn't improve, talk with your healthcare provider. If you're pregnant, ask your healthcare provider about how best to manage nausea and diarrhea — some nausea and antidiarrheal medications may not be safe to take while pregnant.

4. Changes in glucose levels

Hydroxyprogesterone could raise your blood glucose (sugar) levels, also known as hyperglycemia. If you have diabetes or gestational diabetes, hydroxyprogesterone may make it harder for you to control your blood glucose. 

If you’re receiving hydroxyprogesterone, try to watch for symptoms of hyperglycemia. Examples include:

• Headache

• Dry mouth

• Increased thirst

• Blurry vision

• Shortness of breath

• Frequent urination

• Nausea or vomiting

• Feeling weak or tired

• Fruity smelling breath

Symptoms of hyperglycemia can become more severe as blood glucose levels get higher. You can check your blood glucose level with a glucometer. If you’re experiencing hyperglycemia, talk with your provider about how best to manage your glucose while taking hydroxyprogesterone.

Also let your healthcare provider know if you have diabetes or any problems with your blood glucose levels before you start taking hydroxyprogesterone. You might need to monitor your blood glucose levels more closely while receiving this medication.

5. Fluid retention

Hydroxyprogesterone can cause your body to hold on to extra fluid, especially in your legs, ankles, and feet. This fluid build-up is also known as fluid retention. It’s more likely to happen if you have certain underlying conditions, like heart failure or kidney disease.

This is usually a gradual change. But if you notice rapid weight gain or swelling, or have sudden difficulty breathing, it’s a good idea to seek swift medical attention.

6. Preeclampsia

Fluid retention can also be a sign of preeclampsia, or high blood pressure that develops during pregnancy. Preeclampsia that isn’t treated can put you and your baby’s health at risk. It may also raise the risk of health problems in the future.

Possible signs or symptoms of preeclampsia can include:

• Sudden swelling in the hands and face

• Severe headache

• Changes or loss of vision

• Severe pain in the upper part of the belly

• Vomiting that begins later in pregnancy

• Difficulty breathing

If you're pregnant and receiving hydroxyprogesterone, contact your provider right away if you notice any symptoms of preeclampsia.

7. Miscarriage or stillbirth

Although rare, hydroxyprogesterone may raise your risk of having a miscarriage (pregnancy loss before 20 weeks of pregnancy) or stillbirth (fetal death during or after the 20th week of pregnancy).

In a clinical study, miscarriage or stillbirth happened more often in pregnant women who received hydroxyprogesterone compared to women who didn’t. However, this risk is still considered to be low.

When should I contact a healthcare provider about hydroxyprogesterone side effects?

Hydroxyprogesterone is generally well-tolerated and causes few side effects. But some side effects can become serious. 

You should contact your healthcare provider if you experience any side effects that are bothering you or don’t go away on their own. This could include:

• Nausea, vomiting, or diarrhea that doesn’t go away

• High blood sugar levels 

• Fluid build-up with severe headache or changes in visions

• High blood pressure, especially if pregnant

If you experience trouble breathing, severe hives, or signs of facial swelling, you should go to the nearest emergency room. These may be clues of a more serious allergic reaction.

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Written by:

Sonja Jacobsen, PharmD, BCPS, BCOP

Sonja Jacobsen, PharmD, BCPS, BCOP,  is a clinical oncology pharmacy specialist currently practicing in Seattle. She has been practicing as a pharmacist since 2015 and is licensed to practice in Washington state and North Carolina.

Edited by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

Reviewed by:

Tegan Smedley, PharmD, APh

Tegan Smedley, PharmD, APh, has 10 years of experience as a pharmacist. She has worked in a variety of settings, including retail, hospital, and ambulatory care.

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