Preterm Birth: An American Tragedy

Yesterday, while I was presenting a talk on preterm birth (PTB) to a large family practice group and their 29 residents who practice obstetrics, an FDA advisory panel was reviewing an application from Adeza Biomedical Corporation to bring the drug Gestiva® to market for the prevention of preterm labor. Gestiva® is a compounded formulation of a synthetic progesterone (17-α-hydroxyprogesterone caproate) in oil, now affectionately referred to as "17-P," that is administered by intramuscular injection on a weekly basis and has been shown in one clinical trial (Meis P, et al., NEJM. 2003; 348:2379-85) to reduce by about one-third the risk of preterm labor and delivery in a population of women who had delivered prematurely in the past. If the FDA grants final approval for this to Adeza, they will become the exclusive distributors of this compound, an issue I will return to later in this post.

Before I knew about the FDA meeting, I had already decided to write a series of posts on preterm labor. It is a BIG problem in this country, and unfortunately, it is a growing problem. In 1972, the incidence of PTB (delivery less than 37 weeks') was 7-8%. By 2003 this rate approached 13% of all deliveries and was as high as 15-17% in certain lower socioeconomic groups. To put this in perspective, of the 4 million deliveries that year, almost 500,000 were premature. This means that on an average day in the U.S., 1300 babies are born too early and of these more than 200 are considered to be very preterm (less than 32 weeks'). Prematurity, rather than birth defects, is now the leading cause of neonatal mortality in this country, accounting for 25% of infant deaths during the first month of life.

In 2002, PTB accounted for more than 45% of all healthcare spending for infants ($15.5 billion)! The average cost of a hospital stay for a preterm baby was $79,000 compared to $1,500 for a normal term delivery. It is important to understand that this represents just the initial costs to the healthcare system. With advances that have been made in neonatal intensive care, now more than 90% of infants born weighing less than 1500 g survive. However, more than 50% of very low birthweight infants, weighing less than 1000 g, have disabilities by 30 months' of age. Overall, preterm delivery is associated annually with more than 100,000 casese of severe disability, including cerebral palsy, mental retardation, vision and hearing impairment, and chronic lung diseaese. These chronic conditions add multiples to the initial cost of care for these infants across their lifetimes.

In my next posts, I will discuss risk factors associated with preterm birth, diagnosis of preterm labor, and management algorithms. But before I conclude today, I did want to return to the Gestiva® story mentioned in the first paragraph. Very few drugs have been “approved for use in pregnancy” by the FDA over the years. Based on the clinical trial referenced above, it appears Gestiva® has the potential to reduce preterm deliveries, or perhaps lengthen pregnancy, in women at high risk for recurrence of PTB. Funny thing is that we used a 17-P compound many years ago for the same indication, even though we did not have good clinical studies to support its efficacy and safety. That drug, Delalutin®, was produced by Bristol-Myers Squibb Co. and was never FDA-approved for use in pregnancy. It was removed from the market in 2000 for no reason to my knowledge other than that no one used it for anything anymore. Once efficacy of 17-P was shown, several compounding pharmacies around the country began producing and distributing the drug for use in preterm labor prophylaxis. It is my understanding that these pharmacies obtained the active ingredient (17-P) from Adeza.

When it became clear that there might be a market for 17-P, Adeza jumped in and filed the application that would restrict production of the compound to their own facilities. Most of us predict that the FDA will approve the application with the admonition to Adeza that careful long-term studies of safety are done on both pregnant women and the babies exposed to the drug during pregnancy. Although no significant risks of 17-P were reported over almost 50 years' of use, no methodical clinical trials were ever performed to document its safety in pregnancy either. With FDA approval will most certainly come a two- to four-fold increase in cost (currently between $100-200 for a course of therapy), probably, with very little improvement in quality over that which is now available from the compounding pharmacies. Hopefully, this will not put the drug outside the expense that can be borne by patients themselves, many of whom will be from lower socioeconomic risk groups, or the third party payers (especially Medicaid) for its indicated use.

Use of 17-P will be no panacea for the problem of PTB because preterm labor is a symptom and not a disease that is going to require concentrated, multidisciplinary, social, as well as medical, intervention if we are to achieve a significant reduction in rates. However, this is one problem in which every little bit helps. When I was medical director at the East Tennessee Regional Perinatal Center, I used to tell our residents that if we could prevent just 1 or 2 preterm deliveries at 24-26 weeks' annually, we could fund the entire program for another year with the savings. At the least I would hope that any furor over the marketing of 17-P translates into enhanced public awareness of the problem of PTB and, perhaps, "grass-roots" activism among women for support of programs that might eventually have a real impact on this problem.

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"In the beginning...": Determining Gestational Age and Due Date

The other day, I repeated a conversation I have had countless times. I was finishing up an early ultrasound on a very young woman and informed her that she was 8 weeks’ pregnant and congratulated her on coming in early for prenatal care. At that point her also very young boyfriend glared at me and at her and she burst into tears saying, “I can’t be 8 weeks pregnant. I only had sex 6 weeks ago and that was the first time in my life.” “That’s perfect,” I replied, “In obstetrics, the way we figure things, you are considered to be two weeks pregnant the day you conceived, so you probably got pregnant just when you thought.”

From the looks of disbelief and mistrust, I knew they didn’t understand, so I went on to explain. When women have regular menstrual cycles every 28 days, they usually ovulate (hatch an egg)around day 14 (counting from the first day of the last period). Once they ovulate, they have only about 24 hours that the egg can be fertilized and fertilization actually occurs in the fallopian tube. Over the next 3-4 days, the fertilized egg divides several times as it travels down the tube to an implantation site within the uterus. Since most women have fairly regular menstrual cycles, and long before we knew when conception actually occurs, the tradition was begun that the due date was calculated from the beginning of the last period. "Thus, as I was saying, you are two weeks’ pregnant the day you got pregnant. It’s a tradition we have continued for convenience and for the confusion of our patients."

From the first day of the last period in women who have regular periods, the due date is approximately 280 days, corresponding to 40 weeks. This can be estimated by counting 9 calendar months from the first day of the period and adding 7 days. Alternatively, you can pick up a pregnancy “wheel” or use an online “calculator.” Today, estimates of gestational age by ultrasound are generally accurate within 3-5 days in the first trimester of pregnancy, within 10-14 days in second trimester, and become much less reliable (no better than +/- 2-3 weeks) after that. Prior to ultrasound, we confirmed gestational age by the time of "quickening" (the first perception of fetal movement by the mother) and the first detection of the fetal heart tones by a special stethoscope (a fetoscope), both of which generally occur at about 18-20 weeks. Pregnancy dating is important because we use it to schedule certain laboratory studies (e.g., serum screening for neural tube defects and chromosomal abnormalities; screening for diabetes) that can only be interpreted reliably if the “dates” are known. We also depend on accurate dating to schedule fetal testing in women at risk for complications and for elective deliveries by cesarean section or induction of labor.

“So,” I said, “we now know how pregnant you are and as a result we now have a firm due date that will not change, even if the baby is bigger or smaller on follow-up studies.” Her only response was “Doctor, so how many months does that make me?” I could only sigh...."Lunar months or calendar months?" I asked.

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"To B or not to B...": Comments on FDA Approval of Plan B

In my last post, I discussed the high rates of maternal mortality related mostly to complications of bleeding and infection in the U.S. prior to the era of modern care that really began in the 1940’s with the availability of antibiotics and blood products. What I intentionally omitted from the discussion was that many “obstetrical” deaths prior to this and, unfortunately, for many years afterwards, were the result of illegal abortions. Today, in developing nations and in countries that ban abortion, “unsafe abortion” is still a major cause of maternal morbidity and mortality.

With regard to the above, August 24, 2006, marked a milestone that should be noted in its significance even in a blog devoted to obstetrical care and childbirth. That milestone is the FDA approval of Plan B® as an over-the-counter (OTC) medication for emergency contraception in women 18 years and older. Plan B® provides another option to women for prevention of a pregnancy that is not planned or desired. It has been available as a prescription medication since 1999, and a prescription will still be required for women less than 18 years of age.

Plan B® contains a synthetic progesterone (levonorgestrel) only that has been used in birth control pills for more than 35 years and has a well-established safety record. Progesterone is the hormone that dominates the second half of the menstrual cycle after ovulation occurs and its continued production is important for the maintenance of a normal pregnancy. As such Plan B is highly unlikely to cause interruption of a pregnancy that is already established.

Plan B® should not be considered a substitute for regular and ongoing contraception in women who do not wish to conceive. It is also not inexpensive, costing approximately $40.00 per two-tablet course of therapy, and will only be dispensed from a pharmacy to a woman with proof of age. However, it does obviate the need, the delay, and the additional expense and lack of privacy associated with a physician appointment or a trip to the local emergency room or urgent care center. It should not replace a visit to a professional in instances of rape or exposure to a partner at high risk for carriage of a sexually transmitted infection.

The first tablet of Plan B® should be taken within 72 hours of failed contraception and, the earlier, the better. The second tablet is taken 12 hours after the first. Side effects are usually minimal, including nausea, vomiting, dizziness, breast tenderness, and aberration of normal menstrual bleeding. Overall success rates are in the range of 90%. If menstrual bleeding does not occur within a week of the expected time, the woman should get a pregnancy test performed. If the patient is pregnant already, or conceives despite having taken Plan B®, the drug is unlikely to cause birth defects.

Two years ago The FDA turned down the application to provide Plan B® as an OTC product amid accusations of “political pressure.” Despite denials of this, the FDA did appear to make a decision that largely ignored the data supporting the safety of Plan B® and stretched for reasons to deny the application. The reversal of this initial decision is a victory not only for women, but also for the scientific process of “evidence-based” medicine.

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"It was the best of times, it was the worst of times..."

Yesterday, shortly after rounds with our residents, I was called urgently to the postpartum floor because a patient of ours was “coding” (cardiopulmonary arrest). She was a 31 year old woman who had just delivered her sixth child the day before. Her labor was uncomplicated but she had had a fever since delivery. Despite her pleas to go home, we had just finished convincing her that she really needed to stay for further evaluation. Actually, her husband had been the one to convince her with the prophetic statement that she “didn’t need to go home if she was just going to die there and leave me with six kids to raise by myself.” We left the room to make arrangements for her chest x-ray, she talked with her own mother on the phone, and moments after hanging up, clutched her chest and stopped breathing.

After an hour of heroic efforts by the code team to revive her, she was pronounced dead, probably from a massive pulmonary embolus (blood clot to her lungs). I walked out of the room with the resident, both of us with tears in our eyes, to tell her husband that the efforts to bring her back had failed. He was sitting at the end of the hall, a large man, definitely rough around the edges with tattoos decorating at least half of his body. He already knew the outcome from the expressions on our faces and before we could reach him, he collapsed in grief, sobbing inconsolably that “I know I don't look like much, but I love my children and now they will take them away from me.”

Ironically, just two days before, I had been asked by a local journalist to comment on home births. The lay midwife who had cared for the couple featured in the article was quoted as saying that “women had given birth for thousands of years, and I might add, do it very well.” When I read this, my initial thoughts were that with good screening, the risks could be minimized, but they are still greater for both mother and baby than they would be delivering at the hospital.

My reluctance to endorse the practice without reservation stems from my view that pregnancy appears to be one of the most dangerous and powerful forces of “natural selection” that has helped to mold the human race. You don’t have to be a Darwinist to recognize this. The biblical authors of Genesis had this perspective as well! At the turn of the 20th century, one out of every 100 women died during pregnancy in the U.S. Today that rate stands at less than 1 in 10,000. It is an ongoing tragedy, however, that worldwide more than 500,000 women still die annually during pregnancy, most of these in developing nations. In parts of sub-Saharan Africa, for example, mortality rates are as high as 1 in 10 to 20.

Before the modern era in obstetrical care (1940’s), women died most frequently in pregnancy from hemorrhage, infection, and arrest of labor. (This is still the case in developing nations). The availability of blood products, antibiotics, and operative deliveries (cesarean sections) under sterile conditions greatly reduced the risks of these complications. Today, the most common causes in the U.S. are thromboembolic (blood clot) events, hypertensive disorders, and trauma.
Experience has taught us that when problems arise in obstetrics from these and other causes, they can arise quickly and unexpectedly and if you are not in a situation to address them, immediately, the opportunity for a good outcome is greatly diminished for mother, baby, or both. As we all learned yesterday sometimes even being in the right place at the right time isn’t good enough.

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The New "Normal" Pregnancy

Every day is different and every pregnant woman is unique. Pregnancy is a dynamic process in which the mother’s physical state changes daily from the moment of conception until many weeks after delivery. The hormonal, physiologic, and immunologic changes that occur account for the common complaints of pregnancy (e.g., “morning sickness”), the common complications of pregnancy (e.g., gestational diabetes) and account for the more serious, though still common, problems associated with pregnancy (e.g., preeclampsia). These changes determine the success of pregnancy from the time of implantation through delivery. If you already have medical problems, they may worsen, improve, or have no effect during a pregnancy. Previously undiagnosed medical conditions may surface only during the pregnancy and sometimes only after the baby is born in the postpartum period. And occasionally the fetus may put both the mother and the pregnancy at risk.

As an obstetrician, I am always mindful of a woman’s desire to have a “normal” pregnancy while being constantly vigilant for evidence of maternal and fetal complications. When problems are recognized, I try to be straightforward and truthful, yet remain sensitive and empathic. Explanations regarding complications, particularly those related to the baby’s well-being, demand careful forethought. Balancing these issues can make pregnancy an emotional roller coaster for both the family and the healthcare providers who care for them.

We have seen remarkable advances in medicine over the past three decades, but progress in obstetrics has been painfully slow and spotty.

For instance, the survival of newborn infants born at less than 27 weeks, almost unheard of in the 1970’s, has jumped to 30-50% when born between 23-24 weeks and with access to neonatal intensive care units. During the same time period however, preterm labor rates have actually increased from 8% in 1979 to more than 13% (15-17% in certain high risk groups, depending on geographical location and ethnic group), in the U.S. today, adding billions of dollars to healthcare costs in both the short- and the long-term care of these children.

When the new technologies of electronic fetal monitoring and real-time ultrasonography were introduced in the 1970’s, we hoped that these would improve both maternal and fetal outcomes. Yet, despite their widespread use, there has been essentially no impact of fetal monitoring on the incidence of cerebral palsy, 90% of which has been found to occur prior to the onset of labor, and limited success of interventions during the pregnancy for fetal abnormalities detected by ultrasound.. Indeed, some would argue, albeit simplistically, that the greatest impact of these interventions has been to increase cesarean delivery rates from 12-16% during the 1970’s (6.5% in 1965) to more than 30% at many hospitals across the nation today.

Not all has been to the downside. It is true that today infertile women and women with serious medical conditions, who could never have conceived in the past, are achieving pregnancies with the help of sophisticated assisted reproductive technologies. But, with that has come a whole new set of challenges and ethical considerations (as well as job security for me!).

Perhaps my greatest source of frustration is the low priority that is given to pregnant women in terms of health care and research dollars. Despite the universal proclamations that “our children are our greatest resource,” this statement has not been backed by the support, financial and political, that is required to make sure that every fetus really has the best start on life. This is in stark contrast to the megabucks handed out for patient care and research related to midlife medical conditions such as cardiovascular disease.

Admittedly, things improve for care after the fetus becomes an actual newborn, but we have already learned, as demonstrated by the success of folic acid supplementation of foods, that the best prenatal care begins prior to conception.

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