Tocolysis Drugs for Preterm Labor

Are these valuable tools for prolongation of pregnancy being threatened?

Recently, issues regarding the safety of a number of medications utilized to stop preterm labor (tocolytics) and therefore prolong pregnancy have been addressed by the news media. We, at The Triplet Connection, are concerned about the impact of this less-than-favorable reporting, both for patients and their physicians. Physicians on our Scientific Advisory Board are extremely concerned. Let me explain why.

The most common complication of multiple gestation is preterm labor. It occurs in approximately 12% of singleton pregnancies, 50 % of twin pregnancies, 70% of triplet pregnancies and 90% of quadruplet pregnancies. In most practices preterm labor accounts for the most common reason why early delivery occurs in a high-order multiple gestation. In fact, up to 75% of all perinatal deaths are attributed to prematurity. Therefore, whenever we review the potential complications associated with tocolytic medications, it is very important to realize the consequences of not utilizing these important medications that allow pregnancy prolongation.

Treatment of preterm labor involves bed rest, hydration, and most often treatment with tocolytic drugs (medications that reduce contractions). There are several drugs available to the Ob/Gyn physician or Perinatologist to use to treat preterm labor. These would include magnesium sulfate, which is an intravenous medication that is the most effective medication to treat preterm labor in high order multiple gestations. Terbutaline can be utilized as well, either subcutaneously (beneath the skin) or orally. Terbutaline can generally be utilized subcutaneously for a longer period of time, using a smaller amount, when preterm labor begins early in pregnancy. Nifedipine is a drug that lowers blood pressure, but it has an effect on the smooth muscle of the uterus causing relaxation and decreasing contractions. Finally, non-steroidal anti-inflammatory agents (NSAID's) including Indomethacin, Motrin and Toradol are sometimes used to help control preterm labor.

Two of the most commonly used tocolytic drugs have recently been criticized. Magnesium sulfate has been challenged by two physicians in an editorial published last year in the American Journal of Obstetrics and Gynecology. Terbutaline has recently been criticized by a lawyer in Baltimore who is creating medical legal concerns regarding its use. In the view of doctors on The Triplet Connection Scientific Advisory Board, these criticisms are unfounded.

A recent Current Commentary article published in October 2006 in Obstetrics & Gynecology entitled Magnesium Sulfate Tocolysis - Time to Quit, criticized the use of magnesium sulfate tocolysis. It is currently estimated that 120,000 women with preterm labor are treated each year with this medication. The authors cited the medication to be ineffective and dangerous to mothers and babies.

Dr. John Elliott, a most respected members of The Triplet Connection Scientific Advisory Board (and also one of the most experienced and successful physicians caring for higher-order multiple gestations in the world), feels that the studies quoted were poorly done, and that "the problem with the use of magnesium sulfate is that the dosage being given is often inadequate to achieve the desired result, which is stopping preterm labor and halting cervical dilation." He states, "Magnesium sulfate, as it is used in most hospitals in the U.S., is not given in an adequate dose to treat preterm labor. Therefore, when labor continues and the patient delivers, the drug is blamed as being ineffective rather than to understand that it is the dosage that is ineffective and giving a higher dosage to the mother will be effective in stopping the preterm labor."

Criticism in the aforementioned article extends to the effects of the drug on the babies, and again "selective data are utilized to suggest that magnesium sulfate may cause harm to babies whose mothers receive the drug for tocolysis." Dr. Elliott says, "the authors ignore other large studies which suggest that magnesium sulfate not only is not harmful, but may actually be beneficial to the babies in reducing the incidence of neurologic damage and cerebral palsy."

This article reported that magnesium sulfate tocolysis might be "associated with an excess of 1,900 to 4,800 fetal and neonatal deaths annually in the United States." They suggested that 7% of infant mortality might be caused by magnesium sulfate. "This figure seems to be extremely overestimated, but still pales in comparison to the 75% of perinatal mortality caused by prematurity," says Dr. J. Stephen Jones, a well respected, exerienced Minnesota perinatologist and longtime member of The Triplet Connection Scientific Advisory Board.

I (Janet Bleyl) was appalled to recently learn of a Baltimore law firm that has been advertising on television and other media to attract women who had ever used terbutaline for preterm labor to respond for possible litigation. If they had utilized terbutaline during pregnancy and had a child who later had any kind of birth defect, brain damage, autism, development delay, speech defects, movement disorders, etc., they were asked to become part of a possible impending lawsuit.

"This attorney is relying on one article that seems to associate terbutaline with autism," says Dr. Elliott: "The scientific quality of this article is very questionable, and to my knowledge there has never been a substantial scientific link showing that terbutaline causes autism."

Dr. Steven Jones defends the use of terbutaline therapy, particularly infusion pump therapy: "The safe use of terbutaline infusion pump therapy to prolong pregnancies was first reported in 1988, with a total of 43 studies being reported to date. Forty-one of those 43 studies have shown efficacy in prolonging pregnancy. In 2001, Dr. Elliott reported the successful use of continuous subcutaneous terbutaline infusion therapy in a series of 104 triplet pregnancies. Pregnancy prolongation of 5.4 weeks in the terbutaline infusion group was found, compared to 2.8 weeks with oral therapy in triplet patients experiencing recurrent preterm labor. Triplet delivery at less than 35 weeks occurred in 19.7% of the patients on the continuous infusion pump, verses 37.5% in those treated with oral therapy.

As for associated safety for mothers, two very large studies have reported the safety of continuous subcutaneous terbutaline therapy. One study, from the University of Mississippi Medical Center in 1995, reported on 8,709 women prescribed this therapy for preterm labor. Less than 0.6% of patients experienced cardiopulmonary problems, and less than 1/3 of 1% developed pulmonary congestion. Another report by Dr. Elliott, published in the American Journal of Obstetrics & Gynecology in 2004, looked specifically at a large group of pregnant women with recurrent preterm labor managed with home health care. Nine thousand three hundred fifty-nine patient records were reviewed with transient medication side effects (side effects lasting for a very short time) reported by 15.5%, and serious adverse events identified by only 12 of the 9,359 patients. There was no reported maternal mortality."

According to Dr. Elliott, "It is unfortunate that the threat of a lawsuit has caused physicians to refuse to use terbutaline as part of the treatment plan for a patient in preterm labor. It is truly unfortunate that unscrupulous lawyers are willing to file lawsuits against physicians who utilize a drug in an effort to prevent prematurity, which is a known cause of poor fetal outcome." Too often the response from physicians is, 'I don't want to be sued, so I won't use the medication.'"

"In my opinion there is absolutely no reason to change our therapeutic use of terbutaline either orally or by terbutaline pump, and there is no need to discontinue using magnesium sulfate (if anything, we should use more of it to achieve the desired effects of stopping preterm labor). It is my opinion that physicians choosing to not utilize these medications will ultimately end up with earlier deliveries and potentially worse outcomes for our patients who are trying to carry a triplet, quadruplet, quintuplet or higher pregnancy. There really is no good reason to change our pattern of therapy unless it is to be more aggressive with these medications, not less aggressive."

Dr. Elliott says this situation is very similar to that involving Bendectin many years ago with the numerous suits for birth defects that were never proven, and the company finally stopped making the dug because it lost so much money defending the suits. "Not a single one of the lawsuits was ever won by a plaintiff, and yet we no longer have Bendectin to use to treat pregnant women with hyperemesis gravidarum."

Dr. Jones concludes: "The continuous terbutaline infusion pump and oral terbutaline therapy can be utilized safely in singleton pregnancies and also with higher order multiples. The pregnancy prolongation time seen with successful tocolysis impacts the lives of babies and families. Parents should be knowledgeable regarding safety concerns, but the tragedy of preterm birth must be a high priority in the decision to utilize medication to stop preterm labor."