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Tracking Tools: Follow the Herd

November 29th, 2009 by avatar

This article is part of the Understanding Research series.

So you found a few good articles, but you wish you could have found more. Sometimes all it takes is finding one good study, and you can use that one to find more!

There are several ways to do this:

1. Most studies will have a section discussing the literature previously published on the topic. Dig up some of those studies using the information listed at the end. And then check the bibliographies of THOSE studies, too. In the research world, this is called “backwards chaining,” and works best with a more recent study. Sometimes you’ll get lucky and in the database you’ll see a list of the studies cited by the one you’re looking at, like this list of references connected with a study I found on EBSCO:

CitedReferences

2. Unless your study is brand spanking new, there’s a good chance someone else has cited it in a newer study. So as you’re searching, watch for places where you can see a list of studies that cite the one you’re reading. Google scholar nearly always includes a “Cited by” link under each search result. Meta-analyses and systemic reviews are GREAT finds if you can find one, as they tend to look at many studies all at once. This particular example of studies that cite the one I was interested in comes from EBSCO:

TimesCited

3. In the database where you found the study, look at the “related articles” that share key words with your article. Google Scholar and PubMed generally have excellent links to related articles. They may be articles that share keywords, authors, etc. with the study you are looking at. PubMed flags any articles that are a critique or review of another article as well.

PubMedRelatedArticles2

4. In most databases, the author’s name is a link. Clicking on it will search for any other articles by that author. Since researchers sometimes tend to focus on particular topics, you can often find similar studies. Sometimes this works very well – as in the case of someone like Susan Ludington-Hoe, who has published quite a bit on the topic of kangaroo care. She also has a very distinctive name. If you find a study by someone with a more common name, like say MJ Anderson, there may very well be more than one of those. You could revise those results or combine an author search with a keyword search in this case.

I’ve said it before in this series and I’ll say it again. The BEST way to get good at finding articles is practice, practice, practice! Try different indexes, try different approaches, and talk to a librarian for the tips and tricks!

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Consider the Source: An interview with Cord Clamping Researcher, Judith Mercer

November 17th, 2009 by avatar

Consider the Source is a new series of interviews with prominent researchers working to improve the health outcomes of women and infants around the time of childbirth.

A member of the faculty at the University Rhode Island, Judith Mercer, PhD, CNM, FACNM, is the Principal Investigator on a randomized controlled trial at Women & Infants Hospital examining the effects of delayed cord clamping on outcomes of preterm, very low birth weight babies. She and her multi-disciplinary research team reported short-term outcomes in 2006 in the journal Pediatrics, and outcomes of infants at 7 months of age appear in an upcoming issue of the Journal of Perinatology.

2ndLeveldo_badge1Dr. Mercer graciously agreed to be the first to participate in our Consider the Source series, answering questions about her research in honor of National Prematurity Awareness Month and the March of Dimes’ Bloggers Unite to Fight for Preemies Event. I especially appreciate Dr. Mercer’s research journey because it started with her observations of physiological birth. Her quest to more deeply understand normal physiology led her to improve care for sick and high-risk babies.  Lamaze International would like to express our gratitude to Dr. Mercer, her research colleagues, and her collaborators at Women & Infants Hospital.

Science & Sensibility: You have studied how timing of umbilical cord clamping affects health outcomes in preterm infants. What compelled you to study this?

Judith Mercer: In 1975, I vividly remember reading Frederick Leboyer’s book Birth Without Violence in which he advocates not cutting the umbilical cord until the infant has successfully completed her transition between her two worlds – the fetal world of water and placental respiration and the neonatal world of air and breathing. He says “For a few minutes the baby straddles two worlds…then, slowly, slowly she can cross the threshold from one to the other peacefully and easily with safety…as long as we don’t interfere [by premature clamping of the cord].”  I adopted the practice of delaying cord clamping to ensure a more gentle birth and have used it for more than 30 years.

I had an epiphany at a home birth in 1979. An infant was born very rapidly with the cord 2 and 1/2 times around his neck. He was as pale as the white sheet his mother had on her bed and limp and breathless. I was very afraid that I would not be able to resuscitate him.  I placed him on the bed and immediately unwrapped the cord from around his neck and dried and stimulated him with no response. His heart rate was well over 100 and the cord was pulsating vigorously.  I noticed that his color was changing from the pale white to pink as his body gained the blood back into it. His heart rate was always over 100. In about 1 and 1/2 minutes, he flexed his extremities, opened his eyes and took a gentle breath.  He looked at us like “What is the fuss?” and never cried.  I tried as hard as I could to get him to cry as I believed at that time that he should do but I could not get him to.  He nursed very well and was a normal child at one year of age when I last saw him.

I knew that I had seen a miracle and one that I would never have seen in the hospital.  In the hospital, we would have cut the cord and taken the infant to a warmer to resuscitate him. In doing so, we would have denied him exactly what he needed – the opportunity for the blood squeezed out of him in the birth process due to the tight cord around his neck to flow back into his body.  This event marked the beginning of my research career.  I vowed that at some point in my life I would research what I had seen but did not fully understand.

So it was my personal clinical experience that lead me into my area of research. When I began to ask colleagues and other practitioner about their cord clamping practices, I found a wide variation in practice and beliefs. When I turned to the literature, I found a general lack of evidence-based recommendations for cord clamping practice. All appeared to be opinion-based or based on flawed or inconsistent research findings. Yet, at the same time, I noticed that the etiology of many newborn problems was not known and remain unknown today.  The symptoms are often the opposite of what happens when one delays cord clamping. I also noticed that these problems rarely occur in settings where the infant has a normal physiologic transition. I wondered if immediate cord clamping may be causing some of these problems.

After midwifery jobs with no opportunity to do research, I joined the faculty at the University of Rhode Island where Dr. Margaret McGrath, a well-funded nurse-scientist, offered to mentor me.  She introduced me to Dr. William Oh at Women and Infants Hospital who agreed to sponsor me. With their excellent support, I was able to build my research program.

In 2001, I published an integrative review of the literature on delayed versus immediate cord clamping and found many controlled trials demonstrating beneficial effects of delayed clamping in both term and preterm babies. These included increased blood volume of up to 40%, reduced likelihood of anemia, increased blood flow to vital organs and higher body temperatures in the delayed clamping groups. None of the studies demonstrated harm from delayed clamping and none replicated findings from a poorly-controlled – but often cited – study done in the 1960’s that showed more jaundice and polycythemia in infants with delayed clamping.

At URI, I developed, with a colleague from Rochester, NY,  the Blood Volume Model for Neonatal Transition and published Neonatal Transitional Physiology: A New Paradigm.  While theoretical, it is entirely based on solid research from many different studies. We sought to develop a cohesive theoretical model that explained the relationships among oxygen transport, red blood cell volume, and initiation of breathing, and predicted the effects of early versus delayed cord clamping. We think that in the first one to two minutes, blood plays a larger role in physiological transition than air and that interrupting the process can harm the infant.

Judith Mercer, DNSc, CNM

Judith Mercer, PhD, CNM

Based on these findings, my colleagues at URI, collaborators at Women and Infants Hospital, and I decided to do a pilot randomized controlled trial of delayed versus immediate cord clamping in babies born between 24 and 32 weeks. We had funding from the University and our local chapter of Sigma Theta Tau. We chose to focus on preterm infants because these infants have many problems after birth.  Prevention or reduction in the occurrence of any of these problems would make a huge impact.  Also, the preterm infants are followed very closely in our developmental follow-up clinic so we could examine their outcomes in a cost-effective manner.

Doing a small pilot allowed us to test the feasibility of a larger trial, develop an appropriate protocol and determine how many mothers we would need to recruit in the larger trial. Our study design proved feasible and findings were promising. We did not detect any harms of delayed clamping and the 16 babies in the delayed clamping group had higher blood pressure, higher initial blood glucose, and were less likely to be discharged on supplemental oxygen. With these initial findings, we were able to secure funding from the National Institute of Nursing Research for a larger clinical trial.

Science & Sensibility: How did you design the randomized controlled trial? What were your findings?  Were there any surprises?

Judith Mercer: All women admitted to Women and Infants’ Hospital between 24 and 31.6 weeks gestation with symptoms of preterm labor were candidates for inclusion in the study.  From these women, 72 very low birth weight (VLBW) infants were delivered and represent the sample. Since gestational age is a major risk factor for preterm infants, we used block stratified randomization to assign the intervention to the subjects above and below 28 weeks with a pre-specified equal probability to help avoid unequal numbers of participants in each gestational age group as the study progressed. Exclusion criteria included: obstetrician’s refusal to participate, prenatally-diagnosed major congenital anomalies or multiple gestations, intent to withhold or withdraw care, frank vaginal bleeding or placenta abruption, placenta previa. Women had to be admitted to the hospital at least 2 hours before delivery to allow time for screening enrollment.

Just prior to birth, eligible patients were randomized to receive either standard care (immediate cord clamping (ICC)) or the intervention (delayed cord clamping (DCC)). For the standard care group, the obstetrician clamped the umbilical cord immediately (< 5-10 seconds) For the intervention group, the obstetrician clamped the cord at 30 to 45 seconds and held the infant in a sterile towel or blanket approximately 10-15 inches below the mother’s introitus or incision.  Care was taken that no tension or traction was placed on the cord. A stopwatch was used to mark the time of birth and then the time elapsed was counted out in ten second intervals to the obstetrician.  At 30 to 45 seconds, the obstetrician clamped and cut the umbilical cord, and the infant was moved to the warmer for neonatology management.

If the baby appeared jeopardized in any way, the obstetrician could alter the protocol for the safety of the infant and a protocol violation form was completed although no protocol violations occurred because of an infant’s appearance.  The subsequent clinical management of the infants was at the discretion of the neonatologists. Because of the obvious nature of the intervention, the study could not be blinded to those at the birth.  Due to safety considerations for the infant, pediatric staff was always in attendance.  However, staff who attended each birth adhered to the principal investigator’s request not to reveal the infant’s grouping in the infants’ medical records.

Research assistants who were registered nurses and the Principle Investigator (PI) shared an on-call schedule to screen potentially eligible women, enroll them, or attend the births of enrolled women. Women had equal probability of assignment to the groups.

The primary outcomes we considered, based on our previous research and that of other researchers, were oxygen use at 36 weeks gestational age and suspected or confirmed necrotizing enterocolitis (NEC). We found no statistically significant differences between the groups in these primary outcomes. But additional planned data analyses revealed the most exciting findings.  Infants in the delayed cord clamping group were found to have fewer incidences of any level of intraventricular hemorrhage (IVH) defined by the reports of cranial ultrasounds routinely ordered during the first 28 days in the NICU.  The incidence of IVH was equally divided between the stratified groups (ICC 7/7, DCC 2/2) although the majority occurred in infants less than 30 weeks gestation.  One infant in the DCC group was a protocol violation, meaning that the cord was clamped prior to 30 seconds in violation of the study protocol. In addition, infants in the DCC group were less likely to have blood culture-proven (confirmed) sepsis during the NICU stay.

For our follow-up study, we saw surviving babies at an average age of 7 months corrected age at our clinic. Trained, certified psychologists administered a validated test for motor and mental development, known as the Bayley Scales of Infant Development-II (BSID-II).  A physician or nurse practitioner also conducted a complete medical history and physical examination. The staff was masked to the assigned study groups. In this phase of the study, we found no overall differences in the BSID scores between the DCC and ICC groups. However, after controlling for several factors, male infants in the DCC group had higher motor scores. Preterm male infants are known to be at higher risk for mortality and developmental delay than female infants, a phenomenon that is not well understood. Our study suggested that delayed cord clamping may be protective against motor delay in preterm male infants.

Science & Sensibility: Immediate cord clamping is the standard of care and is stubbornly defended despite a growing body of evidence of its harms. Did the attitudes of care providers or other staff get in the way of the conduct of your study? Have attitudes changed at your facility since the study began?

Judith Mercer: Due to the excellent cooperation of the obstetricians, fellows and residents, there were only 7 protocol violations.  Six occurred in the DCC group with cord clamping time and were mainly as a result of miscommunication.

This study was a Phase I trial. Phase I trials are generally small and test the safety of a particular intervention. Institutional changes are not usually instituted on the basis of outcomes from a Phase I study.  We used the information gained from this study to design a Phase II study which tests the protocol on a much larger group.  We were awarded a $2.5 million dollar grant from NIH, National Institute for Nursing Research, to carry out this study which is now underway.  Our sample size is 212 infants and we are current almost half-way through. To determine the mechanism of effect, we will measure red cell volume, cytokines, and stem cells, each of which may play a role. We expect that this trial will confirm our findings and we hope it will also help us understand why IVH is more common with immediate clamping.

Science & Sensibility: What other research is needed to improve transitional care of newborns? What studies are you hoping to conduct next?

Judith Mercer: In addition to our Phase II trial, a group of Australian neonatologists and others is beginning a large government-funded multi-center trial on delayed cord clamping in preterm infants.  I serve on there advisory board.  They plan to publish a meta-analysis of their data, my data, and any other data generated in the meantime.

My colleague, Dr. Debra Erickson-Owens and I plan to submit a proposal to fund research on term infants in the near future. Well designed trials and meta-analyses have documented more anemia of infancy at two and three months in full-term infants with immediate cord clamping. Betsy Lozoff, MD, at the University of Michigan has documented a relationship between anemia and poorer developmental outcomes in several publications displaying her body of work. She had found that perinatal iron deficiency harms the developing brain in animal studies interfering with the myelination that must take place in the first few months of life for the brain to develop fully. She was able to demonstrate poorer behavioral and developmental outcome (10 points less IQ when controlling for confounding variables) more than 10 years after treatment for iron deficiency in infancy. She also found evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo in that they had delayed maturation of auditory brainstem responses. These findings raise concern about possible adverse developmental and behavioral effects from immediate cord clamping, but no one has studied these effects, which we are planning to do. As with the preterm study, we plan to conduct a pilot study on full term infants and, later, a funded full study.

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Disputed Territory: A doctor reviews “Birth Territory and Midwifery Guardianship: Theory for practice, education, and research”

November 16th, 2009 by avatar

This is a guest contribution from Katharine Hikel, MD. Dr. Hikel is a writer on women’s health for Medscape/WebMD. Peer-trained in feminist women’s health clinics, she is also a graduate of Harvard and the University of Vermont College of Medicine. She lives in northern Vermont with her family.

Birth TerritoryReview:
Birth Territory and Midwifery Guardianship: Theory for practice, education, and research
.
Edited by Kathleen Fahy, Maralyn Foureur, Carolyn Hastie.
Butterworth Heinemann (Elsivier): Books for Midwives. 2008

The next vital revolution in maternity care may well be the overhaul and redesign of the birthplace. In “Birth Territory and Midwifery Guardianship,” writers describe the relationship of the birth setting to the emotional-physiological state of laboring women.  In this regard, ‘Birth Territory’ encompasses not only physical space, but also personal relationships, power structures, and access to knowledge.

Maternity care as we know it has evolved along divergent roads: the midwifery, expectant-management ‘natural’ approach; and the obstetric, interventive, ‘actively-managed’  model.  Midwifery care is a woman-centered approach; it relies on relationships which support women’s natural abilities to give birth. The obstetric model, designed by and for doctors, operates on  principles of academic exclusiveness, described by Louis Menand:

It is a self-governing and largely closed community of practitioners who have an almost absolute power to determine the standards for entry, promotion, and dismissal in their fields. The discipline relies on the principle of disinterestedness, according to which the production of new knowledge is regulated by measuring it against existing scholarship through a process of peer review, rather than by the extent to which it meets the needs of interests external to the field…

[T]he most important function of the system is not the production of knowledge. It is the reproduction of the system. To put it another way, the most important function of the system, both for purposes of its continued survival and for purposes of controlling the market for its products, is the production of the producers

Academic obstetrics is impervious to knowledge and input from other disciplines; it exists in a closed, parallel world; it exists not for the purpose of taking care of women, but for the purpose of taking care of itself. The chief concern of any obstetrical unit is the viability of the department, of the program; if outcomes figure into that, well and good; but women’s actual experiences and opinions, because they are not part of the published literature, are of no concern.  Small wonder, then, that so little thought has been given to the environment of hospital birth, other than for the convenience of hospital practitioners.

Meanwhile, midwives have continually concerned themselves with what the authors of Birth Territory and Midwifery Guardianship call ‘the elements in the geography, architecture, and metaphysics of birth spaces to which women will consciously and unconsciously respond.’

In their book, the writers – midwives, and an architect of birth spaces – asked women what they wanted in their birthing places. Responses included:

  • A pleasant place to walk
  • Sufficient pillows, floor mats, bean bags
  • Availability of snacks and drinks
  • En suite toilet, shower, bath; a birth pool
  • Comfortable accommodations for companions and families
  • A homey, non-clinical environment
  • Control over temperature
  • Control over brightness of light
  • Privacy; not being overheard by others
  • Not being watched
  • Control over who comes into the room

The majority of birthing women surveyed did not have these options. The authors argue that lack of a woman-centered birthing environment, and little control over that environment, are reasons for high rates of obstetric intervention. Labor and birth are whole-being experiences; the autonomic nervous system will shut the whole process down if the woman perceives stress, threat, or danger.  In typical hospital settings, with shift changes, strangers walking in and out, bright lights, confinement to bed and monitor, and restricted oral intake, it is no wonder that the process doesn’t go as smoothly as it could. “Failure to progress” – the diagnostic reason given for 50% or more cesareans – is largely an environmental issue.

Katharine Hikel, MD

Katharine Hikel, MD

Birth territory is also defined by relationships; yet medical obstetrics has constantly worked to sequester birthing women away from all sources of comfort, including non-medical practitioners; only in the 1960s were fathers and partners invited into hospital delivery rooms; and only lately, with the advent of doula practices, has one-to-one attendance – the cornerstone of midwifery – become recognized as a significant predictor of good outcome.  But few hospital practices are relationship-centered. Prenatal visits are fifteen or twenty minutes long, mainly focused on weight gain and lab work. There’s usually a team of doctors and midwives; the person who’s available at the time of one’s birth is not a matter of preference, but of the practice’s call schedule.

Obstetrics is statistics-based, not relationship-based; obstetricians know that the average due date is 40 weeks from the last menstrual period; they know that if a woman is laboring (in a hospital) with waters broken for over 12 hours, her chance of infection skyrockets; they know that the Friedman labor curve shows that the average progression of dilation is one centimeter per hour; they know that the average pushing phase is under two hours. They are under pressure to make everyone fit those statistical norms, and they have the tools to make it so; and that’s what they do.

The best birth territory requires the best attendants. Fahy and her coauthors argue that birth is a reflection of relationships – with oneself, and with others; that relationships depend on love, and spiritual development (words you will never see in any obstetrical textbook).  In developing the best birth attendants, they see open-heartedness as a requirement for good practice; they describe the characteristics of a good practitioner in Buddhist terms of ‘right relationship’: empathy; ethical behavior; self-awareness; capacity for love. In a chapter called “Reclaiming the sacred in birth,” they describe the conditions for nurturing ideal midwives: ‘to know and nurture themselves within their own families and communities,’ and emphasizes working on personal development, as well as clinical skills, with a supervisor or professional partner. The training environment of midwives should encourage the development of nurturing and intimate, though professional, relationships with her clients; it is that relationship that forms a necessary part of optimal birth territory.

The territory of obstetrics residents is largely devoid of patient-relationship considerations; it is rather consumed with concerns about on-call hours, clinical rotations, numbers of procedures, and one’s place in the departmental hierarchy. The knowledge itself is based in pathology – ‘problem-oriented’ – a diagnostic/treatment approach that assumes there’s trouble, and goes about finding it. This works well in the rest of medicine, which is really about disease; but colors the teaching approach to the normal, healthy event of childbirth.  The knowledge that’s important – taught and practiced – is all within the limits of academic obstetrics, which ignores, if not devalues, ‘nonscientific’ knowledge. The ‘permitted’ knowledge supports what the authors call the ‘metanarrative’ of academic medicine: the postmodern myth that the safest and best place to give birth is under obstetric management. Any knowledge that counters that myth is disputed or ignored.

The history of obstetrics is also viewed differently from within the specialty than without. The obstetricians’ view, reproduced in most obstetrical textbooks, is the development of one intervention after another, all by men – from forceps to vacuum extractions. The authors present a larger-scale view:

Medicine in the late 19th and early 20th centuries was composed almost entirely of men who shared the same power base as other dominant males: they were white, well-educated and from economically richer families. It was these males who owned or managed every institution of society: the army, the church, the law, the newspapers, the government, etc. These privileges, combined with an informal brotherhood of dominant men, created a powerful base for the success of the medical campaign to subordinate midwifery.

The authors describe the territory of hospital birth as disputed ground, where the biological requirements of birthing women are at odds with the design of institutions.  They provide ample evidence about how the dominance of obstetricians’ needs over women’s welfare has contaminated the culture of birth. In a wonderful section on oxytocin – the hormone of love, bonding, social interaction, birth, and lactation – they describe the effects of this natural hormone:

[T]he higher the level of Oxytocin, the more calm and social the mother; thereby stress is reduced; levels of the stress hormone cortisol drop; pain threshold is increased…  body temperature is regulated… and heart rate and blood pressure are lowered… Women’s response to stess may not be the automatic ‘fight or flight’ response seen in men, but is more likely to be the ‘calm and connection’ system integrated by Oxytocin.

These oxytocin-mediated events are most necessary during labor and birth; they are best enabled if the birth territory includes oxytocin-positive relationships.  Oxytocin is thought to be the source of women’s power to endure labor and birth; and its pathways are the most likely to be deranged by the institutional birth environment – the lack of oxytocin-facilitating relationships of trust and love, as well as the routine administration of oxytocin-blocking drugs such as epidurals and Pitocin – a form of artificial oxytocin that has never been proven safe in long-term outcome studies. Blocking oxytocin, whether through fear, disturbance, or Pitocin, leads to disrupted or painfully difficult labors.  These authors suggest that disruption of normal oxytocin pathways, and supplanting them with intrapartum Pitocin exposure, may also result in serious mental health problems on the love-and-relationship axis: schizophrenia, autism, drug dependency, suicidal tendencies, and antisocial criminal disorders. It’s not just the mother who’s affected by the birth territory.

But what is the best birth environment?  In a chapter called “Mindbodyspririt architecture: Creating birth space,” architect Bianca Lepori describes her designs for hospital-based birth rooms that are meant to enhance, not counteract, women’s abilities to give birth. She created suites of rooms with “Space and freedom to move; to be able to move to the dance of labor; to respond to the inner movements of the baby; to walk, kneel, stretch, lie down, lean, squat, stand, and be still.” The rooms have “Soft and yielding surfaces; or firm and supportive surfaces; different textures; the right temperature; soft curves; darkness or dim light.” A birthing woman can be ‘immersed in water, flowing or still; respected, safe, protected, and loved.”  Access to the suite is through an antechamber; the bed is farthest away from the lockable door, and not visible from it, so that privacy is respected.

Lepori’s birth architecture reproduces the comforts of home. There is access to the outdoors, and private walking places. There are birth stools, exercise balls, bean bags, hooks for hammocks or ropes for stretching. Tubs and beds are large and accessible from both sides. There are accommodations for families. There are comfortable chairs for nursing. Medical equipment – supplies, oxygen – is tucked behind a screen or put in a closet. A refrigerator and light cooking equipment is available. This ‘birth territory’ certainly outshines the typical hospital OB floor; though it begs the question: Why not just stay home?

The answer, of course, is that, for those four to ten percent of births that truly need intervention, the OR is right there. It’s better not to have to transport a woman whose labor has turned complicated; it makes sense – for many – to have all the birth territory under one roof.

This birthing-suite design indeed takes into account the all-encompassing, body-mind-spirit event of childbirth. It honors laboring, birthing women and families; it respects the process. It worked well for a designated maternity hospital in New Zealand – a facility already designed for childbearing. But most US hospitals are multi-use facilities; and though obstetrics is among the best money-makers for hospitals, childbirth is the only event that occurs there that is not related to illness or trauma.

The real question is, why not remove birth completely from the pathology-centered hospital model? Why not redesign birth territory to maximize best outcomes, minimize intervention, and replace the present medicalized view of birth as a disaster waiting to happen with the more normative, expectant-management, midwifery view? Move the whole shebang, from the waiting room to the surgical suite, out of the hospital and back into the community where it belongs.

Why not indeed. The major obstacle to any redesign of the territory of birth is resistance from the field of obstetrics. The American Congress of Obstetricians and Gynecologists (which recently changed its name from the American College of Obstetricians and Gynecologists, reflecting a major shift in interest from academics to politics) has a 23-member lobbying arm, “OB-GYNS for Women’s Health PAC”, which describes itself on its web site:

Ob-Gyns for Women’s Health and Ob-Gyn PAC help elect individuals to the U.S. House of Representatives and Senate who support us on our most important issues. Individuals who understand the importance of our work, who care about the future of our specialty, who listen to our concerns, and who vote our way. In only a few short years, Ob-Gyn PAC has helped elect ob-gyns and other physicians to the U.S. Congress, and has become one of the largest and most influential physician PACs in America.

Only five of the 23 members are women; all ten of its board of directors are men. Current issues occupying the group are “Stopping Medicare payment cuts, ensuring performance measures work for our specialty, preserving in-office ultrasounds” (though there are still no long-term studies on the effects of ultrasound on the developing fetus, or on women, for that matter); and “winning medical liability reform,” which means limiting liability for malpractice.
Meanwhile,  the Medicaid Birth Center Reimbursement Act – Senate Bill #S.1423 (House Bill HR 2358) – is not on the list of bills that ACOG supports, even though this expansion of birth territory would probably better outcomes, and certainly cost less than the hospital OB model.

The only bad thing about “Birth Territory and Midwifery Guardianship” is that obstetricians will not read it.

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Does Progesterone Treatment Prevent Preterm Birth? A Case of “Skim Milk Masquerades as Cream”

November 11th, 2009 by avatar

This is off my usual beat, but a relative asked me to investigate progesterone treatment to prevent preterm birth. In her first pregnancy, membranes ruptured at 31 weeks and the baby was born a week later. (The baby was fine thanks to her mother taking good care of herself in pregnancy, steroids to mature her lungs, and her mother’s colostrum and breastmilk.) Pregnant for the second time, this woman had been told that progesterone injections would be given weekly beginning at 20 weeks to prevent a second occurrence. Being a member of my family, she wasn’t quite so willing as the average pregnant woman to automatically agree to this plan.

ResearchBlogging.orgI started with the Cochrane Database of Systematic Reviews, the granddaddy of systematic review collections and a highly respected source. (A systematic review is a study of studies. Reviewers collect and analyze research on a specific issue using prespecified criteria. If the studies are sufficiently alike, statistical techniques can be used to pool their data.) The Cochrane had a review current as of 2008 that included four trials of progesterone treatment for women who had a preterm birth in a prior pregnancy. Progesterone was administered either as weekly injections or as a daily vaginal suppository, depending on the trial. Here is what the study summary said:

Progesterone was associated with a statistically significant reduction in the risk of preterm birth less than 34 weeks’ gestation (one study; 142 women; risk ratio (RR) 0.15; 95% confidence interval (CI) 0.04 to 0.64); [and] preterm birth less than 37 weeks’ gestation (four studies; 1255 women; RR 0.80; 95% CI 0.70 to 0.92).

For those of you unaccustomed to interpreting statistical lingo, let me translate: The reviewers’ statistical analysis revealed that compared with untreated women, one small study found that treated women were much less likely to deliver before 34 weeks’ gestation, and when data in four studies were pooled, women were somewhat less likely to deliver before 37 weeks’ gestation (the demarcation for full term). In neither case does the CI (confidence interval) cross one, which means differences between groups was probably not due to chance. In other words, progesterone treatment appears to be highly effective. The reviewers also found no short-term or longer-term differences in adverse outcomes for mother or child, but deemed the body of evidence on safety inadequate primarily because there is only one small follow-up study of 274 children. (We’ll come back to this study in a minute.)

This sounded extremely promising, but appearances can be deceiving. I knew that the Cochrane rules for conducting a systematic review do not capture all the possible problems with an individual trial, and reviewers, however well-intentioned, unconsciously will bring their biases along with them. Accordingly, I decided to get the four trials and evaluate them myself. A very different picture emerged when I did:

Trial #1 was published in 1975 and included only 43 women. I wasn’t able to get a copy of it, but we can ignore it as it didn’t contribute much to the review’s conclusion.

Trials #2 and #3 were published in 2003, and when I was searching for the papers, I found they had been critiqued in a commentary by Marc Keirse. Dr. Keirse is one of the authors of the bible of evidence-based maternity care, Guide to Effective Care in Pregnancy and Childbirth, and a professor at an Australian medical school. I verified his criticisms with my own copies of the two trials.

Trial #2 took place in Brazil. It was a vaginal suppository trial of progesterone versus placebo in 157 women. Dr. Keirse pointed out a number of serious problems that indicated that the investigators either did not know how to analyze their data properly or deliberately manipulated the statistics to get the “right” answer. Chief among them is that investigators collected data on 157 women, even though they had calculated before the trial that 90 women would be sufficient, and getting all 157 participants involved collecting data for a full two years longer than planned. One reason they might have done this is that their findings were not statistically significant when they reached 90 participants, so they kept collecting data until differences emerged (a process that is not ethical in research). This is akin to flipping a penny as many times as it takes for “heads” to show up with the desired frequency. Also important, investigators excluded women from the results if they had a preterm birth for reasons other than spontaneous preterm labor, mostly (10 of 15 cases) for preterm rupture of membranes. But preterm birth is preterm birth. If the study was supposed to determine whether progesterone prevented it, those women should not have been excluded. Add them back in, and the gap between treatment and placebo groups closes.

Trial #3 was of weekly progesterone versus placebo injections. It was carried out at 19 U.S. medical centers and included 463 women. This trial was conducted and reported properly; however, Dr. Keirse points out that the difference between groups was not because progesterone treatment reduced preterm births. Preterm birth rates in the treatment group were identical with that anticipated in women not having treatment based on an earlier study of similar women conducted at hospitals in the same medical center network. The difference lay in women in the placebo group having much higher preterm birth rates than anticipated. Furthermore, the theory behind administering progesterone is that it will prevent contractions, but similar percentages in both groups made hospital visits for preterm labor and tocolytic therapy. It seems that whatever was going on, progesterone wasn’t preventing preterm birth.

Investigators in trial #3 also noted an adverse effect not considered in the Cochrane review: the weekly injections were painful and could result in soreness, swelling, and bruising. This would be trivial if progesterone injections prevented preterm birth, but does it?

Trial #4 was published after Dr. Keirse’s critique. This trial, so far as I can judge, was a well-conducted international multicenter trial of progesterone in vaginal suppositories. The largest trial, it included 659 women allocated to either progesterone gel or placebo. It reported no difference in rate of preterm births (42% progesterone vs. 41% placebo), preterm labor, or any other adverse outcomes.

The follow-up study, of 194 treated children and 84 untreated children (the trial allocated to groups on a 2 to 1 basis) from trial #3 at around age 4, is too small to detect differences in uncommon adverse effects. Even if the study were big enough, age 4 is far too young to evaluate potential effects on sexual maturation and reproductive capacity. We should not be complacent about the safety of exposing fetuses to weeks of excess levels of a sex hormone. Keirse points out that the use of another hormone confidently prescribed to pregnant women, DES, became notorious for causing devastating effects in the offspring. The damage did not become apparent until children reached their teens, but continues to severely impact the health of the grandchildren of the women prescribed DES.

We’re not done yet. Had the trials shown unequivocally that progesterone treatment was effective, we do not know if their results can be generalized to all women with prior preterm birth. The trials included both women who had prior preterm births preceded by preterm labor and women whose preterm births were preceded by preterm rupture of membranes. Those situations overlap in that one can lead to the other, but the mechanism behind the two is different. In my family member’s case, rupture of membranes occurred out of the blue and was attributed to a silent infection. Leaving aside that the trials did not find that progesterone prevented preterm contractions, prior preterm labor was not her problem. How, then, even if it worked, would progesterone treatment benefit her?

My family member plans to decline progesterone treatment. Unfortunately, clinicians at her hospital and others like it will go on prescribing it in the belief that the evidence shows that it works and is harmless.

The progesterone review illustrates a general problem: Conscientious clinicians who want to practice evidence-based care cannot possibly review the research on every pertinent topic. They must rely on recommendations derived from systematic reviews, but the “black box” nature of these reviews makes it impossible to distinguish “cream” from “milk.” Until such time as systematic reviewers universally engage in critical thinking, the danger will remain as Mark Twain put it: “Researchers have already cast much darkness on the subject and if they continue their investigation, we shall soon know nothing at all.”

Citation: Dodd JM, Flenady V, Cincotta R, & Crowther CA (2006). Prenatal administration of progesterone for preventing preterm birth. Cochrane database of systematic reviews (Online) (1) PMID: 16437505

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Calling All Bloggers (Again)! Healthy Birth Blog Carnival #3

November 7th, 2009 by avatar

We’ve had two successful Healthy Birth Carnivals and it’s time to make it to the half-way point through Lamaze’s Six Healthy Birth Practices. We’ve heard what bloggers had to say about letting labor begin on its own and movement in labor. Next up?

Bring a loved one, friend, or doula for continuous support.

Here are some Lamaze resources to get you thinking about continuous support in labor:

Participation in the Healthy Birth Blog Carnival is easy:

1.  If you are a blogger, write a blog post on the Carnival theme (Bring a loved one, friend, or doula for continuous support). Post it on your blog by Monday, November 23. Make sure the post links back to this blog post, to the Healthy Birth Practice Paper, or to the video above. You may also submit a previously written post, as long as the information is still current.
2.  Send an email with a link to your post to amyromano [at] lamaze dot org.
3.  If you do not have a blog but would like to participate, you may submit a guest post by emailing it to me.
4.  I will compile and post the Blog Carnival here at Science & Sensibility the week of November 30.

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