Announcer: From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, welcome to another installment of NICHD Research Perspectives. Your host is the Director of the NICHD, Dr. Alan Guttmacher.
Dr. Alan Guttmacher: Hi, I'm Alan Guttmacher. Thanks for joining us for this month's podcast from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, or NICHD. My guests are Dr. Rose Higgins, Dr. Lou DePaolo, and Dr. Alice Kau, who all work with me at NICHD. Today we will talk about some very interesting findings from recent studies with which they have been involved. First we'll look at hypothermia for infants who experience oxygen deprivation at birth; next we'll consider the use of progestin, a common first step in infertility treatment for polycystic ovary syndrome; and we'll end by discussing an intervention to enhance vocabulary development of children with autism. My first guest is Rose Higgins, from the NICHD's Pregnancy and Perinatology Branch. Rose is the senior author of an interesting study, published this past month in the New England Journal of Medicine, which found that a treatment to reduce the body temperatures of infants who are deprived of oxygen at birth has benefits into early childhood. Rose, can you tell us more about the study?
Dr. Rose Higgins: Sure. This was a followup study of school-aged children who were enrolled in an NICHD trial from 2000 to 2003. Until the first studies were published for head- and whole-body cooling, there was no specific therapy for encephalopathy or birth asphyxia other than supportive care. When the original NICHD study was published, it was the first study to show the overall benefit that cooling might be effective for babies who suffer from birth asphyxia. Ultimately, other studies came up with the same finding, and the theory was deemed to be extremely promising, but folks were concerned about longer-term outcomes studies, as this information was not yet available. Definitive proof, therefore, was lacking until our study at six to seven years was completed. This followup study has shown that lowering the body temperature of a baby who failed to received sufficient oxygen during the birth process decreases the rate of death or having an IQ below 70 from 62 percent of the children in the standard care to 47 percent in the group that receive the cooling therapy. The rate of death was significantly reduced in the children who had the cooling treatment to 28 percent, versus 44 percent for the standard treatment.
Dr. Guttmacher: That's a really wonderful study. It's so important, and probably too rarely done, that we get studies that really follow results long term, instead of just, 'what are the immediate consequences?' It's really reassuring to know what the longer-term impact of this therapy is. Can you tell us a little bit more about the cooling technique itself and how exactly it was found to be beneficial?
Dr. Higgins: Right. The cooling technique involves using a cooling blanket, and with this technique cold water circulates inside a waterproof blanket beneath the infant. The cool water reduces the baby's temperature as low as 91.4 degrees Fahrenheit, compared to the usual 98.6 temperature. And this temperature is maintained for 72 hours, after which the care providers allow the baby's temperature to return to normal. The lower body temperature slows the baby's metabolism and therefore confers protection to the brain, as there is less need for energy during the cool period when the baby is recovering from the initial asphyxial insult.
Dr. Guttmacher: I see. Given those findings, do you anticipate any additional uses for hypothermia as a treatment for birth asphyxia?
Dr. Higgins: Yes. The results are extremely reassuring and provide evidence for both safety and benefit of cooling. Many NICUs around the world are routinely performing cooling as per the protocols that were conducted for babies who have moderate to severe encephalopathy.
Dr. Alice Kau: So, Rose I have a question. Was the hypothermia treatment effective in reducing the severity of disability among infants who survived?
Dr. Higgins: So, we did not see any increased rate of disability among the survivors, and that's a question that has come up many times. Are you saving children from death and therefore increasing the rate of disability? And we reassuringly did not see an increase in disability among the survivors.
Dr. Kau: Also, infants in this study were treated with whole body cooling. Is head-only cooling still an accepted practice? And, if so, would you anticipate similar findings for infants who received a head-only cooling?
Dr. Higgins: Right. So the head-only versus body cooling is a question. And given the rareness of this disease, I don't think there is going to be a head-to-head trial on comparing head cooling with body cooling. However, the one trial that did publish head cooling, authored by Peter Gluckman, showed benefit at 18 to 22 months. And they also have recently published findings, although they only have about half of the children back. That showed that half of the children that they saw had similar results to results seen at age 2 years of age. So, basically, the benefit goes across head cooling also.
Dr. Kau: Thank you.
Dr. Guttmacher: Thanks very much, Rose. That really was very interesting to hear more about.
Our next stop on this tour of recent research from NICHD, I guess, emphasizes how broad is the mission of NICHD and how varied is the research that we are involved in. Our guide for this stop will be Lou De Paolo, who is chief of the Reproductive Sciences Branch in the Center for Population Research at the NICHD. His branch recently supported a study that found that progestin, part of the common treatment in women with polycystic ovary syndrome (PCOS), appears actually to reduce the chance of becoming pregnant. Lou, could you please describe the study findings?
Dr. DePaolo: Yes, Alan. This was quite surprising, this followup analysis of data collected from an NICHD-supported clinical trial found that, indeed, the use of progestin prior to ovulation induction of infertile women with PCOS actually lowered the chance for conception and live birth compared to women whose ovulation induction protocol was not preceded by progestin administration. What I would like to just note is, why would progesterone be given in the first place? Well, during the normal menstrual cycle, blood levels of progesterone, which is a progestin, increase and decrease during the latter half of the cycle. The increase in P levels prepares the uterus for implantation and pregnancy initiation. It is the purpose of the menstrual cycle. If pregnancy does not occur, P levels drop, progesterone levels drop, and menses ensues as a result of the shedding of the uterine lining. This initiates another cycle. Women with polycystic ovary syndrome (PCOS) are infertile due to the inability to ovulate. Women with PCOS have irregular menstrual cycles and prolonged intervals between menses. Intervals may be as much as 3 to 4 months and even longer between menses. Women with PCOS often seek treatment to induce ovulation. So if no menses occurs at the time of their visit, clinicians will oftentimes induce a menstrual-like bleed with administration of a progestin or progesterone-like drug. The decline from the progesterone levels from this administration induces the menses. So, in an NICHD-supported trial that compared two ovulation induction drugs, secondary analysis of the data showed that PCOS women not given a progestin prior to ovulation-inducing medications were four to five times more likely to conceive and have a live birth than PCOS women who were given a progestin to induce menses or PCOS women who had a spontaneous menses as result of a drop in their endogenous P levels.
Dr. Guttmacher: So, if I'm understanding correctly then, progestin did prove to be helpful in achieving ovulation but not in achieving conception, is that right?
Dr. DePaolo: Not really, Alan. In this study the ovulation rate in response to ovulation-inducing regiments were similar whether or not the progestin was used.
Dr. Guttmacher: So it made no real difference then in ovulation, but clearly did make a difference, and not even the one that maybe people would have thought going into the study, in terms of conception. How can you explain that effect?
Dr. DePaolo: Well, there are several explanations that the authors of this study provided. The one that I gravitate to is the, perhaps deleterious effects of the progestin on the endometrium, which adversely affects implantation.
Dr. Guttmacher: So how does that finding, and study in general, affect future research do you think?
Dr. DePaolo: Well, first of all, being a secondary analysis, it needs to be confirmed in a randomized control trial. And, additional studies also need to be done on the basic research level to understand the mechanism by which progestin and progesterone, have a detrimental effect on the uterus, on conception, and on live birth.
Dr. Higgins: What were the pregnancy rates for the women who experienced the endometrial sheading without the use of progestin?
Dr. DePaolo: Well, they did not differ…for the women who had a spontaneous menses and the women who were provided progestin to induce menses, there was really no significant differences in the conception and life birth rates.
Dr. Higgins: How might the research affect current management of infertility in women with polycystic ovary syndrome?
Dr. DePaolo: Well, I think it will, if it is confirmed in a trial, it's likely that women with PCOS may actually need to wait for a spontaneous menstrual period to start ovulation induction regiments.
Dr. Guttmacher: Thanks, that really is an interesting study and, I guess, highlights to me the importance that we not just assume that we understand the biology of things and that we can make interventions and have the impact that we assume they will have, but that we need to have evidence-based medicine. We really need to develop the evidence to see if the true impacts of our interventions are what we would predict and maybe think we are seeing. But to do the kind of rigorous trials this is and perhaps the randomized clinical trial that you suggest might be a logical followup to see what the real, true impact of these are. And it ties into the first study we were talking about— that we need to look into the longer-term outcomes of the kinds of interventions we use to really see whether they're worthwhile for us.
Now we'll move on to our third topic. And this is about a study published in April of 2012 which found that children with autism who received a targeted social communication behavior intervention were more likely to develop advanced language skills than were children who did not receive the intervention. Alice Kau is part of the Intellectual and Developmental Disabilities Branch here at the NICHD, and that's the branch that supported the study. Alice, tell us something about the intervention and what the study found?
Dr. Kau: Sure. This is one of the few long-term followup studies for autism intervention. The intervention took place when the participating children were 3 to 4 years old, while attending the same hospital-based early intervention program for 30 hours each week. They were randomized to one of three conditions, joint attention intervention, symbolic play intervention, or control condition. The joint attention and symbolic play groups received their prospective intervention 30 minutes daily for 6 weeks. The goal of intervention was to advance the level of joint attention or symbolic play skills based on the developmental level of each participant. The intervention strategies are similar for both groups. For example, the therapist followed the child's lead and interest in activities, talked about and expanded on what the child was doing, repeated back what the child was saying, made eye content, and made environmental adjustment to engage the child. The study examined the cognitive and language outcomes of these children. Five years after receiving early intervention, the results show that 80 percent of children had achieved a functional use of spoken language at 8 years of age. Of those children who developed a functional use of language, based on predictors of later outcomes, include: earlier age of entry into the study; initiating joint attention skill; play level; and assignment to either the joint attention or symbolic play intervention group. In addition, children who showed greater flexibility in playing with objects at age 3 or 4 demonstrated better memory and other cognitive skills at age 8.
Dr. Guttmacher: That's very interesting. I think most of us can probably understand the importance of early language development, but can you tell me something more about what joint attention really is and why that might be important for language development?
Dr. Kau: Yes. Joint attention is a very interesting phenomenon and very important to all aspects, in my view, of a child's development. Joint attention refers to child's capacity to coordinate attention with others through pointing, showing, and coordinating looks between objects and people. For example, a child may initiate joint attention by showing a toy to someone or may point to an object or show coordinated attention to a person and a toy by looking back and forth. The interaction provides a social platform for language to emerge. For example, the child may vocalize or grunt and say "Look" while the child is pointing to something. And the adult who the child was point the object to may say, "Oh yes, it's a balloon, it's an airplane," and provide positive praise: "Very good!" and "Good job!" So, this is how the language emerges. You can see it's based on a social context. And, longitudinal studies have shown the importance of joint attention skills to later language developmental outcomes, particularly spoken language. For example, initiating joint attention at age 2 is associated with better language outcome at age 5.
Dr. Guttmacher: I see, that does make some sense. And, so how then might the findings of this study influence what we know about language development and social communication skills in children with autism?
Dr. Kau: This study shows that therapy focused on simply basic skills, such as pointing, sharing, and engaging in play can have considerable long-term and long-lasting benefits for the language outcome of children with autism.
Dr. Guttmacher: I see. The study certainly seems to generally support the belief, and there's some other evidence for this, of course, that beginning treatment as early as possible is associated with a better outcome for children with autism. Do you think that there is value in starting the intervention earlier than 3 to 4 years of age?
Dr. Kau: Well, you know, due to the success of early identification of children with autism, most toddlers at risk or with a diagnosis of autism are already receiving treatment. At the same time, the quality of community treatment has also improved, making it very challenging to demonstrate a treatment effect when one is to conduct a study. However, there are many ongoing intervention projects for toddlers with autism. For example, Dr. Kasari found greater joint engagement between caregivers and toddlers with autism after a parent mediator joined attention intervention. So, it's hard to show, but I think the investigators are embracing the challenge and finding a way to show what kind of treatment can work.
Dr. DePaolo: Alice, I'm wonder if the level of intensity of the intervention critical to achieving these benefits?
Dr. Kau: Well, the National Research Council, in 2001, recommended a minimum of 25 hours of educational intervention for children with autism under eight years of age. So, that's the standard that we were comparing to, but we have to pay attention to this current study. There are two levels of treatment intensity involved. The intensity of the target intervention is 30 minutes every day for 6 weeks. The intensity of the background interventions is 30 hours every week. So, it makes it very challenging to compare studies that use different density of treatment, different duration, different approaches, and different content of intervention. But in this study, since all the children, regardless of assignment, received 30 hours each week of early intervention, the differential outcome can be attributed to the targeted 30 minutes of joint attention or symbolic play intervention.
Dr. DePaolo: Very interesting Alice. How do you think this finding would influence research on language development in children with and without autism?
Dr. Kau: Well, you know, currently intervention efforts have focused on children in a pre-verbal age or pre-school age, trying to help them develop language. One other future direction may focus on those school-age children, who are at a lower functioning level or they remain minimally verbal after receiving years of intervention.
Dr. Guttmacher: Well, thanks, Alice, for talking with us about the study, and knowing some of the other autism research that is in the pipeline that NICHD is involved with, I look forward to having you back on future podcasts to talk about some more research developments in autism. And with that we come to the close of our podcast for this month. I'd like to thank Dr. Higgins, Dr. De Paolo, and Dr. Kau for joining us today, and I'd also like to thank our podcast listeners for joining us. For more information on any of these topics and many related topics, visit www.nichd.nih.gov. That's www.nichd.nih.gov. I'm Alan Guttmacher, and I hope you will join us for more podcast installments as they are posted each month.
Announcer: This has been NICHD Research Perspectives, a monthly podcast series hosted by Dr. Alan Guttmacher. To listen to previous installments, visit nichd.nih.gov/researchperspectives. If you have any questions or comments, please email NICHDInformationResourceCenter@mail.nih.gov.
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