premie

It was a happy accident that magnesium was discovered to reduce the risk of seizures in women with preeclampsia with severe features; and it was wonderful because it replaced so many barbaric interventions, like suboccipital trephining. After the discovery of insulin and other important medical breakthroughs in the 1920s and 1930s, physicians became inspired to apply the scientific method to medical problems. Many were eager to abandon some of the seemingly barbaric practices that had defined medicine of the last century.

By the 1950s, Obstetrics had been on a great run for the previous 100 years. Maternal mortality had dropped from about 1% per pregnancy (8-9% lifetime risk) to under 0.05% per pregnancy, a 20-fold decrease. Neonatal care was improving. Surgery was becoming dramatically safer. Many problems which had been a low priority in the minds of obstetricians now had the luxury of being tackled. One of these was preterm labor.

The first editions of Williams’ Obstetrics treat premature labor as a subset of miscarriage with just a few pages of discussion. Though syphilis was largely blamed, there was no antibiotic treatment. Williams opined that narcotics and bedrest might have some impact, but only in the very earliest stages of preterm labor. No real hope or treatments were offered.

Joseph DeLee’s 1943 edition of Principles and Practice of Obstetrics offers less than one page about premature labor, and reports that E. Shute was using high doses of Vitamin E for treatment (an interesting read), while others were advocating the use of “corpus luteum extract.” Vitamin E (and C) are still the subject of some investigation for prevention of preterm labor, but neither has shown benefit. Corpus luteum extract, better known as progesterone, has, of course, become a mainstay of the prevention of recurrent preterm labor, but has not been shown to have an effect once labor starts.

The 1965 edition of DeLee’s text (Greenhill’s Obstetrics), which includes the latest information about electronic fetal heart monitoring, doesn’t dedicate any space at all to premature labor. By 1965, we had sent a spacecraft to the moon (the Soviets at least), but we had no treatment to offer women with premature labor. This was soon about to change, however.

In 1967, Fuchs et al. reported that IV ethanol was an effective treatment for premature labor. Zlatnick and Fuchs reported in 1972 that among women dilated less than 3 cm, ethanol cut the rate of premature delivery within 72 hours in half. The poorly controlled study of 42 women was typical of medical literature of the time; the ability of ethanol to stop or delay delivery has since been thoroughly repudiated. Nevertheless, for obstetricians desperate for some intervention, it was a godsend. Ethanol became widely popular in the decade following Fuchs’ 1967 paper. But the side effects of intoxicating pregnant women for days at a time were horrendous. Doctors were searching for something – anything – that might be better.

Note what happened: a de facto standard of care was created for ethanol. Prior to 1967, no interventions were routinely utilized for premature labor; but by the mid-1970s, it was standard of care to intervene. Obstetricians at the time were unaware that their intervention was no better than placebo. They didn’t feel that they could just stop using it due to its horrible side-effects, though they desperately wanted to. So the atmosphere was ripe for a replacement.

Beta-adrenergic drugs such as ritodrine, salbumatol, and orciprenaline were being investigated in the mid-1970s, as well as aspirin and indomethacin, for the treatment of preterm labor, but investigators were hesitant because the results were mixed. For example, Castrén et al. in 1975 conducted a double blind study where patients were given either placebo, nyldrin (a beta-mimetic), isoxuprine, or alcohol. They found no difference between placebo and alcohol or the other drugs in terms of on-going pregnancy at 7 days. In fact, 73% of women were still pregnant at one week with placebo versus 56% of women with ethanol.

Studies of the time regarding tocolytics suffered from several methodological flaws.

  • Observed outcomes varied widely and were mostly unimportant. The outcomes that matter for trials of tocolytic efficacy should involve neonatal outcomes, since the ultimate goal is to improve neonatal mortality and morbidity. Early studies looked at things like the number of uterine contractions in a certain time period, on-going pregnancy at 24 or 48 hours or at 1 week or 37 weeks of gestation. Almost none tracked neonatal outcomes. It is not necessarily a desirable goal to prolong a 32 weeks gestation that is suffering from infection; so neonatal outcomes are supremely important and the only outcomes that are clinically relevant. Surrogate outcomes have plagued medical literature for decades and unfortunately still do.
  • Studies disagreed widely about who should be enrolled. Some studies enrolled women who simply complained of contractions, or had a certain number of contractions per hour, or who were contracting with some degree of cervical dilation even if no demonstrated cervical change. Studies might exclude women with ruptured membranes or women dilated more than 2 or 3 cm, etc. This lack of standardized criteria makes things like multivariate regression analysis even more important.
  • Early studies rarely accounted for unmatched variables – even simple things like parity or cervical dilation at time of enrollment.
  • There were almost no statistical analyses performed. Even the most basic tests of statistical significance were rarely performed, let alone more mathematically intense multivariate analyses (it was, after all, an age when CPU cycles were expensive and scarce).
  • Most studies were either unblinded or inadequately blinded. Randomization techniques were also problematic.
  • Few studies were prospective or placebo-controlled. In many studies, the study arms were not pure either; if a patient was felt to be “breaking through” the allocated intervention, other interventions were often layered on by the treating physician.

Indeed, a lack of awareness about the natural course of preterm labor or at least the placebo-affected course of preterm labor on the part of physicians led to an overestimation of the importance of tocolytics in the 1970s. If more than 70% women who presented in preterm labor were reported to stay pregnant for some interval of time, say one week, then the drug was felt to be effective. But a placebo-controlled arm would have shown a similar rate for no intervention.

Enter The Magnesium

As obstetricians were gaining experience with magnesium for the treatment of preeclampsia and eclampsia, an anecdotal body of knowledge developed. By the 1950s and 1960s, most obstetricians had managed the labors of preeclamptic women who were on magnesium for seizure prophylaxis. In 1959, Hall et al. published a paper that claimed that uterine contractions were slowed in preeclamptic women on magnesium. Hutchison in 1964  made similar observations. In vitro studies conducted in Germany and Japan in the 1960s had shown that myometrial tissue bathed in magnesium had slowed muscle contractility. Hutchison actually stated that “magnesium sulfate is capable of reducing uterine tone with subsequent enhancement of uterine contractions.”

Lamont in France started using magnesium for tocolysis in 1965. It was also used as a tocolytic starting in 1969 at Columbia-Presbyterian in New York and by Petrie at the University of Virginia in 1970. Petrie in 1976 reported that magnesium appeared to slow uterine activity but also said,

These data refer only to uterine activity. No attempt is made to correlate these results to an effect on the course of labor. … Uterine activity is an integral aspect influencing labor but it probably cannot be correlated directly to the progress of labor.

Petrie, who made this comment after 6 years of informal experimentation, was ahead of his time. One of the great cognitive distortions that has plagued obstetricians is the idea that contractions are correlated to labor. Sounds bizarre? The vast majority of contractions that a woman experiences in pregnancy do not lead to cervical change, even very powerful contractions in some cases (as opposed to Braxton Hicks type contractions). Only a very few contractions (less than a 100 in many cases) can lead to complete dilation and delivery of a woman at term who is ready to deliver (while the 1500 she had the prior ten weeks did nothing more than lead to perhaps 2 cm of dilation). Labor requires two things: the background cervical ripening and remodeling first, then sufficient uterine contractions to push the baby out of a ready cervix.

We can observe when contractions happen but we don’t really yet understand when the cervix is prepared for labor; consequently, the majority of women thought to be in preterm labor are not and therefore even placebo is sufficient to prevent over 70% of women from “laboring.” At the same time, non-labor contractions are effectively calmed with rest, hydration, a tincture of time, and any tocolytic one might care to use. But this suppression of uterine activity has not been shown to change the timing of eventual delivery, and this was Petrie’s point.

I might also add that in the management of term labors, we have seen over-utilization of cesarean delivery because providers cannot understand how so many hours of strong uterine contractions has not effected cervical change; but the cervix in those cases (usually inductions or augmentations) was not ready, so the time is less relevant. This exaggerated sense of the importance of uterine contractions in labor has lead to substantial harm to pregnant women over the decades and still wrongfully dominates our thought processes.

Because of this thinking, though, physicians of the era were very excited to see anything that would lead to diminishment of uterine activity, even ethanol, let alone something with a better side effect profile, like magnesium or indomethacin. By the end of the 1970s, the first clinical trials relating to magnesium tocoylsis were published.

  • Steer and Petrie, in 1977, published the first trial. It compared magnesium to ethanol, assuming that ethanol was an effective agent, and the outcome was cessation of contractions for 24 hours. A small number of patients were given dextrose as a “control” group. They collected no neonatal data. 71 women total were enrolled, with 9 receiving dextrose, 31 receiving alcohol, and 31 receiving magnesium. Two thirds of the enrolled patients were dilated 1 cm or less. There were no statistical tests performed. They concluded that “if the cervix is dilated 1 cm or less it is very likely that a successful outcome will be obtained regardless of the method of treatment.” However, they also included this damning sentence, “We have found that delivery can be delayed with intravenous magnesium sulfate for the required 48 hours (for corticosteroids) in the vast majority of instances.” However, the authors did not include a 48 hour endpoint in the study (the defined success was remaining pregnant for 24 hours). This statement, however, was repeated and republished for the next twenty years, establishing magnesium (and tocolysis in general) as an important tool to keep women pregnant through the “steroid window.” The study was poorly controlled and underpowered, studied the wrong outcome, and published false conclusions, but had a lasting effect on a community desperate to abandon ethanol as a treatment and eager to give women a full course of the new miracle drug, betamethasone.
  • Spisso, with the group at UVA, published the next clinical trial in 1982. Their study was a case series of 192 patients: some had ruptured membranes, some were contracting, some had cervical change. Some patients also received beta-mimetics. There was no control group. They stated that magnesium was “successful” in 70% of women with intact membranes and 60% of women without intact membranes. The main problem with the study, of course, is no control group. Recall that 70%+ success is what one would expect with placebo.
  • Elliott, in 1983, published a retrospective review of 355 women at risk for preterm labor, including women with chorioamnionitis or abruption. There were no controls. Women were treated with magnesium sulfate mainly but also beta-mimetics if contractions persisted. He concluded that 84% of women remained pregnant if they were initially dilated less than 2 cm for at least 48 hours, while only 37% remained pregnant for 48 hours if they were initially dilated between 3 and 5 cm. Since there were no controls, it is impossible to make any conclusion from this study, though, like the others, it does show that women who aren’t really in labor yet (those dilated less than 2 cm, for example) are likely to stay pregnant for a while.

All three of these early trials lacked appropriate randomization and placebo-control. But due to both a visceral dislike of ethanol as a tocolytic and the promise that magnesium was at least as good as ethanol, magnesium sulfate tocolysis became the de facto standard of care before a single randomized controlled trial (RCT) was performed. Let’s look at those trials:

  • Cotton et al. in 1984 randomized 54 women to magnesium, terbutaline, or placebo. There was no difference in the three groups in regard to delay to delivery of 48 hours or longer, nor in fetal outcomes.
  • Cox et al. in 1990 randomized 156 women at Parkland Hospital to magnesium (up to 3 gr/hour after a 4 gr bolus) or placebo and found no difference in duration of pregnancy, birth weight, neonatal morbidity, or perinatal mortality. In fact, there were 8 perinatal deaths in the magnesium group compared to just 2 in the control group, though the difference was not statistically different. Though 156 patients does not sound like a large study, at the time it was the largest randomized trial ever done comparing any tocolytic to placebo, and one of the first using modern statistical techniques.
  • Fox et al. in 1993 randomized 90 women between 34-37 weeks to magnesium versus placebo. They did not administer corticosteroids. They found that the women in the control group had better neonatal outcomes, likely as a result of a greater gestational age at delivery, which was statistically significant. In other words, the first statistically significant finding in any RCT of magnesium found that patients were better off with the placebo.
  • How et al. in 2006 randomized 54 women between 32-35 weeks to receive either magnesium plus follow-up oral nifedipine or nothing. They found no differences in timing of delivery or any neonatal outcome.

These are the only four placebo-controlled, randomized trials of magnesium as a tocolytic, and the conclusion is inescapable: it is worthless. There are other RCTs which compare magnesium to different tocolytic classes.

Magnesium has been compared to beta-mimetics in the following RCTs:

  • Miller et al. in 1982 found no difference in outcomes compared to terbutaline.
  • Tchilinguirian et al. in 1984 found no difference in outcomes when magnesium was compared to ritodrine.
  • Cotton et al. in the 1984 study mentioned above, found no difference compared to terbutaline or placebo.
  • Beall et al. in 1985 compared magnesium to ritodrine and terbutaline and found no difference in outcomes but an unacceptable level of maternal side effects with terbutaline.
  • Hollander et al. in 1987 compared magnesium to ritodrine and found no difference in outcomes with fewer side effects with magnesium.
  • Wilkins et al. in 1988 also compared magnesium to ritodrine and found no difference in outcomes, again with fewer side effects with magnesium
  • Chau et al. in 1992 compared women in preterm labor receiving IV and oral magnesium versus subcutaneous and oral terbutaline. They found no difference in outcomes.

Thus, no differences (except fewer side effects) were found when comparing magnesium to beta-mimetics (and placebo in one case). Six RCTs have compared beta-mimetics to placebo. Three found no difference compared to placebo, while three poorly controlled studies showed slight prolongation of pregnancy. The largest and best designed of these studies, the “Canadian Ritodrine Study,” randomized 708 women to ritodrine or placebo and found no differences in perinatal mortality, birth weight, or prolongation of pregnancy.

Magnesium similarly has been compared in prospective trials to calcium channel blockers:

  • Glock and Morales in 1993 compared magnesium to nifedipine and terbutaline and found all three to be equally effective (or perhaps we should say ineffective).
  • Floyd et al. in 1995 compared magnesium to nifedipine and found no difference in outcomes.
  • Haghighi in 1999 compared magnesium to nifedipine and found no difference in efficacy.
  • Larmon et al. in 1999 compared magnesium to nicardipine and found no difference in time of delivery or neonatal outcomes.
  • Lyell et al. in 2007 compared magnesium to nifedipine and found that more women remained pregnant at 48 hours with magnesium but fetal outcomes were no different.

Here again magnesium and calcium channel blockers are no different with respect to neonatal outcomes or overall in respect to timing of delivery. Magnesium has also been compared to COX-inhibitors:

  • Morales and Madhav in 1993 compared magnesium to indomethacin (plus oral terbutaline in some cases) and found no difference in on-going pregnancies at 48 hours.
  • Schorr et al. in 1998 compared magnesium to ketorolac and found no difference in timing of delivery or neonatal outcomes.
  • McWhorter et al. in 2004 compared magnesium to rofecoxib and found no difference in outcomes.
  • Borna and Saeidi in 2008 compared magnesium to celecoxib and found no difference in outcomes.

So too COX-inhibitors show no differences in outcomes compared to magnesium. Recall that ethanol was compared to magnesium by Steer and Petrie and no statistically significant difference in outcomes was observed either.

There are no placebo controlled trials for either calcium channel blockers or COX-inhibitors. Interestingly, these agents are held out today as the last remaining hope for tocolysis due to their favorable side-effect profiles compared to other (equally ineffective) agents, and because, in a small number of poorly designed studies, they compare favorably to beta-mimetics.

These are the available RCTs regarding magnesium. Put another way: magnesium, ethanol, beta-mimetics, calcium channel blockers, and COX-inhibitors are all equal in effect to placebo. Does this sound too bizarre to be true? Well don’t take my word for it. Let’s look at some systematic reviews:

  • In 1993, Higby et al. analyzed 328 studies of various tocolytics. They concluded that magnesium is “ineffective in preventing preterm birth” and “is no better than placebo and has potential serious adverse effects in mother and fetus. It should not be used to treat premature labor.” The same review concluded that beta-mimetics and calcium channel blockers are equally ineffective.
  • In a 1999 meta-analysis, Gyetvai et al. concluded that magnesium did not prolong pregnancy and that no tocolytic, including magnesium, beta-mimetics, indomethacin, atosiban, and ethanol, was associated with improved neonatal or perinatal outcomes and all were associated with significant maternal side effects. They concluded, “Our finding of no reduction in any of the reported adverse perinatal outcomes … is of concern” and that “despite the lack of clear tocolytic effects, magnesium sulfate is one of the most popular tocolytics in North America. Reports from nonrandomized studies suggest that magnesium sulfate might reduce risk of cerebral palsy. However, evidence from a recent RCT found it associated with a significant increase in total pediatric mortality.”
  • Crowther et al. in a 2002 Cochrane review of magnesium concluded that, “Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, and its use is associated with an increased mortality for the infant.” In fact, they concluded that the relative risk of perinatal mortality was 2.8, with no difference in the risk of delivery at 48 hours, and no reduction in preterm or very preterm delivery.
  • Pryde et al. in a 2001 review of 170 articles concluded that “magnesium sulfate … should be abandoned entirely as a tocolytic.”

In 2006, David Grimes wrote an editorial in the Green Journal about magnesium tocolysis, which at that time some 80% of obstetricians were continuing to use it as a tocolytic, despite having been repeatedly demonstrated as ineffective. All available data at that time also indicated that it was associated with a significant increase in total neonatal mortality, accounting for as much as 7% of total pediatric mortality. He concluded,

“Further use of this agent is inappropriate unless in the context of a formal clinical trial with institutional review board approval and informed consent for participants…Tocolysis with magnesium sulfate is ineffective, and the practice should stop.”

His editorial was widely attacked or ignored  as magnesium’s use continued among maternal fetal medicine specialists. In fact, it created a backlash among magnesium’s most ardent supporters. Elliott, author of one of the original three studies on magnesium, wrote in a letter to the editor in 2009:

“Magnesium sulfate is effective in delaying delivery for at least 48 hours in patients with preterm labor when used in higher dosages. There do not seem to be any harmful effects of the drug on the fetus, and indeed there is a neuroprotective effect in reducing the incidence of cerebral palsy in premature newborns weighing less than 1,500 g.”

These comments were completely unsubstantiated and ignore every clinical study performed.

In 2009, Mercer and Merlino wrote the definitive analysis on magnesium sulfate for preterm labor in a Clinical Expert Series review in the Green Journal. They concluded that studies have,

“…failed to demonstate that magnesium sulfate is effective in preventing preterm birth or reducing newborn morbidities or mortality as compared with alternatives or no tocolytic treatment. Alternatively, beta-mimetics, calcium channel blockers, and cyclooxygenase inhibitors were not found to be superior when compared with magnesium sulfate treatment. Recent meta-analyses and randomized controlled trials do not provide consistent evidence of a reduction in newborn morbidities or mortality with these other tocolytic classes. … We did not find improvements in delivery at 48 hours, respiratory distress syndrome, or intraventricular hemorrhage with magnesium sulfate, and we did not find any other tocolytic class to be superiors to magnesium sulfate regarding these. It is disappointing that tocolytic treatment with magnesium sulfate and other agents has been so widely accepted in practice despite the relatively small number of patients studies and lack of evident benefits… Practitioners should reconsider their current practices regarding tocolysis with magnesium sulfate and other classes of tocolytic agents.”

Indeed. It is embarrassing that in over 5oo trials of tocolytics, none show fetal benefit and next to none show prolongation of labor. We would expect to find about 25 positive trials just based on a 5% rate of type 1 errors; but we do not. Mercer and Merlino conclude that it is appropriate to withhold magnesium sulfate as a tocolytic from women in preterm labor, and also appropriate to withhold treatment with beta-mimetics, calcium channel blockers, and COX-inhibitors.

If you have read so far, you are probably in disbelief. Alas, there is simply no scientific support of any tocolytic, especially magnesium. Nifedipine and indomethacin have filled the void for those who are trying to abandon magnesium, but not because those agents have been shown to help babies, but because they have a better side effect profile and it makes us feel good to do something for women in preterm labor. This should remind you of how magnesium replaced ethanol: we thought ethanol worked (it didn’t), ethanol had undesirable side effects, magnesium was as effective as ethanol (and placebo) in treating preterm labor, so we substituted. But it is time to start using the equally effective treatment which provides the lowest risk of harm to mother and baby: placebo. First do no harm is, after all, supposed to be our guiding ethic.

There are several lessons to be learned from all of this:

  • Practice patterns today and in the past have little to do with available scientific evidence.
  • Firmly held beliefs and dogmas are resistant to even the most compelling contradictory evidence.
  • Physicians are desperate to help patients in need; but our cognitive biases combined with this zealotry often lead us to harm patients, as in the case of DES and so many other interventions thrown at patients before evidence of benefit is available and then continued far too long, even after evidence of harm or at least a lack of benefit emerges. “That’s how I was trained” or “This seems to work for my patients” or “Everyone else is doing it” are not legitimate reasons to do something.
  • We too quickly follow after the next panacea without understanding the risks and benefits in real terms. Fads today include things like universal screening for GBS, salpingectomy to reduce the risk of ovarian cancer, and the subject of Part 3 of this series, the use of magnesium to prevent cerebral palsy.
  • A clear understanding of the rigors of evidence based medicine and a Bayesian application of available data would have in the past and will in the future prevent these types of mistakes. There was never any evidence that ethanol, for example, was effective in the first place. But physicians are an anecdotal bunch and are often undisciplined when it comes to interpreting literature.

Magnesium was a wonder drug for women who had preeclampsia or eclampsia. But it was not a panacea. Nearly 50 years has been wasted on magnesium as a tocolytic, with countless women and neonates harmed; what’s more, research into more effective interventions has been stymied. Even in the last 5 years, scores of new “magnesium as tocolytic” publications are being published by the die-harders. And we still haven’t learned the lessons: tocolytics, including magnesium. are still overwhelmingly used in the treatment of preterm labor in the US and abroad.

It’s very hard to go back on deeply held dogmas. Entire careers have been spent by many physicians believing that magnesium was an effective treatment for preterm labor. Egos have been necessarily bruised by the data, however. So what’s a doc to do when he has spent an entire career giving this drug unnecessarily to patients? Find a new use or a new benefit; turn “evidence based medicine” back against those who discredited magnesium in the first place. The new savior of egos: prevention of cerebral palsy.