The ROP FAQ
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The following posts from the ROP list explore possible factors which may contribute to the development of ROP. The ROP list was moderated by Dr. Scott Richards until August, 2002. The list is now hosted at YahooGroups.
Date: December 2, 1998
From: Scott Richards
Genetics and ROP - I don't have any solid answer, but I'm betting that genetics plays a strong role in at least some sense. I believe that many of the causes of ROP today are intrauterine rather than something that happened in the NICU, and intrauterine factors would be controlled in many cases by genetics. I have seen mothers who have had multiple pregnancies resulting in small preemies, but I don't know if their tendency towards preterm labor is due to genetics (placental insufficiency, etc) or poor lifestyle choices (drug abuse, poor nutrition, abusive spouse, etc.)
Date: January 30, 1999
From: Michele Alcorn
I am a mom of 3-1/2 year old triplet boys (former 26 wkrs) one of which has ROP and is blind in his left eye (Stage 5 w/plus disease) with low vision in his right (Stage 4b with plus disease). Would you kindly provide more information about ROP occurring intrauterine? I would be very interested in learning more about this.
Besides fighting for his life, fighting a few infections, receiving two blood transfusions, and requiring oxygen in the NICU, Robbie had a pretty uneventful stay in the NICU. Nothing compared to his brother Andrew who had numerous complications because of NEC. I am very curious about the information on ROP occurring intrauterine because a few months ago I took Robbie to the dentist for his 3 year checkup and the dentist told me that the enamel on his two front teeth had been affected (he did tell me the technical name which at the moment escapes me) and was caused while in utero at approximately 2 to 3 months gestation and was due to lack of oxygen. This could be very far fetched but I'm wondering if the ROP is related in any way.
Date: January 30, 1999
From: Helen Harrison
Enamel hypoplasia is common in preemies and appears to be particularly common among those who have ongoing sensory and/or neural problems. Probably something does happen "in utero" that sets a baby up for prematurity and the subsequent ongoing problems. High risk obstetricians are now finding clues to preterm delivery in the amniotic fluid as early as the 16th week of gestation. These "clues" include the presence of "cytokines" -- substances that mediate inflammatory and infectious processes. More and more, chronic infection is being seen as a major cause of prematurity -- especially in those cases in which preterm labor begins for no apparent reason or in which the membranes rupture spontaneously. Another clue that a baby (or babies) might be born prematurely can be seen in the first trimester by ultrasound and involves the size of the fetus. Those fetuses that appear smaller than normal at that stage (even by a few days of growth) are more likely to be born prematurely.
In addition, cytokines and other signs of infection and inflammation have been found in excess amounts in the amniotic fluid of children who later develop BPD and CP. To my knowledge none of this has been directly related to enamel hypoplasia or to ROP, but it does indicate that the tendency to deliver prematurely as well as the problems of prematurity (especially the severe ones) often begin very early in pregnancy. Also apparently some babies are born with the eye changes typically of ROP.
This is fairly new information, at least as of the last 5-10 years. It is part of a larger reevaluation of the role of infection and inflammation in the causation of many diseases from ulcers to heart disease to schizophrenia. The connection between cytokines, infection, preterm delivery, BPD and CP was just presented (with a number of different researchers giving their data) at Hot Topics in Neonatology in Washington, DC (December 1998). Although the various bits and pieces of data have been out there for some time, this was the first attempt I am aware of to tie it all together. In the process, the new theory has called into question many obstetrical and neonatal practices such as the use of tocolytics (labor stopping drugs). After all, if a baby is being damaged in utero by exposure to cytokinesnd microbes, is it good to try to keep the baby there? No easy answers here, but lots of new questions.
Some good articles on all this are:
Goldenberg and Rouse "Prevention of preterm birth",_New England Journal of Medicine_ 1998;339:313- 320.
Mc Gregor et al. "Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation." _American Journal of Obstetrics and Gynecology_1995;173:157-67,
Nelson et al. "Neonatal cytokines and coagulation factors in children with cerebral palsy" _Annals of Neurology_ 1998;44:665-675.
There are many more, but these are the first ones in my files.
You might also want to read the cover article of the February 1999_Atlantic Monthly_ which discusses the new appreciation of the role of infection in many chronic disease processes. Preterm birth isn't mentioned in the Atlantic piece (it *should* have been, IMHO) but CP is. The article is about the work of Dr. Paul Ewald at Amherst who is working on theories of virulence in microorganisms. (My brother is doing similar work on parasite-host relationships and the development of virulence with the Smithsonian in Panama and has been interviewed along with Ewald in a recent issue of _Science News_ so I have many reasons to be interested in all this. )
The study on the size of fetuses in the first trimester is:
Smith et al. "First trimester growth and the risk of low birth weight" _The New England Journal of Medicine_ 1998;339:1817-22.
By the way, the organisms involved in many preterm births are those that cause bacterial vaginosis. It is thought that they get into the uterine lining and cause chronic inflammation (but often no detectable symptoms). Other organisms implicated in preterm birth include those that are present in gum disease (gingivitis). Apparently they get into the bloodstream from the gums and cross the placenta. Gum disease is also now being seen as risk factor in heart disease, and that's probably just the start....
To help prevent preterm birth, see your dentist, floss, etc. and most importantly go to a high-risk OB who will check you before conception (and early and often during pregnancy) for vaginosis, and promptly treat any infection that is found.
I can give further references and info if people want it. I hope this isn't too far off topic for the ROP group.
Erin writes:
"Yes there is now a test that they do around 24weeks to see if you are at risk for another premature delivery,its just a vag.swab and then they send to lab and supposedly the results are pretty accurate."
This is probably the test for "fetal fibronectin" which is a marker for the infectious/inflammatory process in the uterine membranes. It can be detected in the vagina from 20 to 30 weeks. The cytokines can be detected at least as early as week 16 by amniocentesis. And ultrasound can detect the early growth retardation that may mean prematurity, but it is not all that reliable. The fetal fibronectin test is the easiest to perform, and if any of the other two factors are present, it is HIGHLY predictive of a preterm delivery.
About 80% of deliveries before 30 weeks are believed to be caused by infection/inflammation (and are thus potentially preventable). After that, other causes (pre-eclampsia, etc.) tend to predominate.
Date: January 31, 1999
From: Helen Harrison
"Are women ever put on antibiotic prophylactically to prevent infection/inflammation???"
I'm not sure.
Here is what Dr. James McGregor of University of Colorado at Denver (one of the high risk OBs in the forefront of this new approach to prematurity) has written. I have added some comments and explanations in brakets. Again, I apologize if this is considered off-topic:
"An accumulating body of research indicates that infection and inflammation are a primary cause of preterm labor and premature rupture of the membranes (PROM). Data show that about 60% to 80% of the time, women with preterm labor are positive for bacteria on PCR analysis. Moreover, infection is the only cause of prematurity that is completely and easily treatable.
"As such, clinicians should screen and treat all pregnant women for bacterial vaginosis (BV), chlamydia, trichomoniasis, HIV, Trachomatis, GBS [group B strep] bacteriuria, UTI/ASB [urinary tract infections; asymptomatic bacteria], syphilis, hepatitis B, gonorrhea and microbial virulence factors. Because the highest risk from infection occurs during the first trimester, clinicians also should consider screening and treating women who are planning pregnancy, especially those who will be undergoing in-vitro services.
"Bacteria from infection initiates a type of chain reaction in the body, which eventually can lead to preterm labor and PROM. Bacteria produces prostaglandins, endotoxins and digestive enzymes such as proteases and collagenase, which cause the cervix to loosen. Bacteria then work their way from the vagina through the cervix and endocervix where they activate the decidua [membranes surrounding the baby] and the bag of waters.
"Prostaglandins can then cause uterine activity. In cases of PROM, proteases and collagenase reduce the strength and elasticity of the bag of waters making it brittle and more prone to rupture.
"Intervention studies point to the success of aggressive antimicrobial treatment of infection in pregnant women. One study demonstrated that the risk of preterm birth can be reduced 60% to 70% -- to that of uninfected women -- when patients with bacterial vaginitis are treated with antimicrobial agents effective against BV. Another study using erythromycin as an intervention showed a decrease in the incidence of PROM from 17% to 6% and in preterm labor from 6% to 1.7%. Research has shown that metronidozole is the most effective antimicrobial treatment available.
"The best results are obtained when screening is performed early and often in pregnancy. Trigger times for screening include the patient's first visit, 18-20 weeks gestation and at 28 weeks gestation. Women with high-risk pregnancies should be cautioned against changing sexual partners during pregnancy because of the risk of contracting a new infection. [Male sexual partners should be similarly cautioned.] [Dr. McGregor then gives the drugs and dosages used to treat these infections or preterm labor or PROM -- I am not going to repeat them here but it usually involves several days of intravenous antibiotics (he mentions clindamycin, erythromycin, or ampicillin/sulbactam) followed by several more days of oral antibiotics for a total of at least a week on antibiotic therapy. Vaginal treatment with antibiotic cream is ineffective.]
"If possible, the patient's partner should also be treated to avoid reinfection. This protocol of aggressive screening and treating can significantly reduce preterm labor and PROM that results from infection -- and the cost is equivalent to just 20 minutes in the NICU at $2 a minute ($2,880/day)." _Perinatal Outlook_ (Report from the 8th annual conference on Prevention of Prematurity and Neonatal Mortality presented by Matria Healthcare) Vol 2, Issue 1, October 1997.
Several comments: Bacterial vaginosis or vaginitis is not generally considered to be a sexually transmitted disease. It is caused by a disruption in the normal vaginal flora and can result from antibiotic treatment, douching, etc., although changing sexual partners also somehow seems to disrupt the normal vaginal "ecology." The organisms involved tend to be ureaplasma, mycoplasma, gardnerella, and/or peptostreptococci, however this is only a partial list. Attempts to treat partners have not always proved to be very effective in cutting down on these infections and reinfections. Nevertheless, I think it is probably wise to treat partners as part of a wider strategy, just in case.
Researchers have found that a certain type of lactobacillus is effective at preventing the vaginosis bacteria from thriving. This lactobacillus is a cousin to the type of lactobacillus found in yogurt (although the strain found in yogurt doesn't grow in the vagina). The "good" lactobacillus that researchers are interested in produces both lactic acid and hydrogen peroxide. These substances not only counteract bacterial vaginosis but also the spread of HIV and other STDs. Dr. Sharon Hillier of the University of Pittsburgh Magee-Women's Hospital is currently carrying out studies to see whether vaginal insertion of the peroxide and lactic acid producing lactobacillus will be effective in curbing vaginosis and in cutting the transmission of AIDS. It should also be useful for women at risk for preterm delivery because of BV. For more on Dr. Hillier's work see the article "HIV's Quiet Accomplice? Imbalance in vaginal flora may link to the AIDS epidemic" by Jeffrey Brainard in _Science News_ 1998;154:158-9.
However, much of the newer research points to the fact that even if the bacteria is eliminated in the vagina, it may have already taken hold in the uterine lining prior to pregnancy. I don't know how such a condition can be easily diagnosed, but treating it would seem to require systemic antibiotic treatment followed by aggressive efforts to prevent new vaginal infection such as the use of lactobacillus implants if this, in fact, does prove effective.
I also want to emphasize that bacterial vaginosis is only one possible cause of infection that results in preterm delivery. As I mentioned in an earlier post, the bacteria in gum disease have also been implicated in preterm labor and delivery -- really just about anything that can get into the bloodstream can cause pre-term birth.
In my own case, my son Edward was born prematurely because of a food-borne infection known as listeriosis. This very serious disease (which can kill both mother and baby) has recently been in the news when cold cuts produced by Sara Lee and Oscar Meyer caused 13 deaths and several stillbirths and miscarriages. It can also cause the preterm birth of a VERY sick infant. In my own case I came down with a high fever and a severe head and backache. At the hospital ER I was told I had the flu and to go home and take aspirin. Edward was born a week later, nearly dead, and listeria was cultured from his cord blood.
The Wednesday, January 27, 1999 issue of _The New York Times_ has a very good article about the threat of listeria in an article by Marian Burros entitled "A Food-Borne Illness Still Not Getting Enough Attention." [page B11 in my edition of the Times] Here is a quote from that article:
"Public Health officials strongly urge those at greatest risk (pregnant women, the elderly, people with immune impairments, etc.) to stay away from all soft cheeses like Roquefort and Camembert. They also say it is essential to cook hot dogs until the internal temperature reaches 165 degrees either by steaming or frying. Cooking in the microwave is not recommended. And unless people at risk are willing to turn salami into salami and eggs or eat corned beef and salami hot -- in other words, cooked again, they should not eat them at all. 'Listeria hasn't been on anyone's radar screen,' Dr. Tauxe [of the CDC in Atlanta] said. 'But it's something pregnant women should be made aware of. At this point, as far as I can tell the number of pregnant women who are aware of this is zero.'"
So if you are pregnant, take these precautions, and if you do come down with flu-like symptoms see your doctor immediately and mention the possibility of listeria. It can be a difficult infection to detect, but can be successfully treated if caught in time. It can also be carried by almost any type of food and has been found in everything from strawberries to cole slaw to ice cream.
It's enough to make a person paranoid!
Date: January 31, 1999
From: Helen Harrison
Adeen writes:
"What are your feelings about testing the amniotic fluid in women that are prone to early deliveries, ruptured membranes etc? Is it true that an amniocentesis can actually induce labour? I lost 9 babies prior to Joel (including twins at 23 weeks) due to going into spontaneous labour. I tested positive twice for "lupus anticoagulance" (where the blood clots easily and affects the placenta) and was put on heparin and aspirin for my pregnancy with Joel. (I was told that this got me through to the 24 weeks) Subsequently, I have tested "negative" to the Lupus Anticoagulance and was told that "these things come and go". (whatever that means!!!) Do you know of any studies on this?"
I think each couple would have to weigh the pros and cons of testing amniotic fluid just for cytokines. It *is* a risk! However, if an amnio was planned anyway...
Probably testing for BV using vaginal swabs, urine cultures etc. is the safest way to proceed, although some cases may be missed this way.
The whole issue of Lupus Anticoagulants and related signs of immune disorders in pregnancy is a very complicated mystery I do not feel equipped to address except to say what you probably already know, which is: some people have suggested treating pregnant women with these test results with prednisone and low doses of aspirin, but this approach is highly experimental and unproven.
By the way, have you been tested for anticardiolipin? Have the placentas from your pregnancies ever been examined for signs of injury? What signs and symptoms (if any) did you have before Joel's delivery?
My main source of information on lupus anticoagulant and related issues is in a chapter on "Rheumatologic and Connective Tissue Disease" by Hollinsworth and Resnik in _Maternal/Fetal Medicine_ edited by Creasy and Resnik, 2nd edition, WB Saunders 1989. I'm sure there are more recent references and I will try to find them for you, but it may take a while. What I *do* have on hand is the study I referred to in a previous post by Karin Nelson et al. "Neonatal cytokines and coagulation factors in children with cerebral palsy" _Annals of Neurology_1998;44:665-675. Nelson and her coworkers found lupus anticoagulant and anticardiolipin in blood samples of some children who developed cerebral palsy, but found none in the blood of control babies who did not develop CP so it is up there with cytokines as a marker for CP.
I feel fairly certain that behind (or connected to) the scenario of infection causing preterm birth is another layer involving the immune system, and that is where things really get complicated!
PS: If you do not have access to a medical library and would like copies of the chapter from Creasy and Resnik concerning lupus anticoagulant and the Karin Nelson CP study, send me your address and I will send them to you.
Date: February 1, 1999
From: Guido Bracke
I have not much to add to Helenīs comments. She is far more an expert concerning prematurity than me.
My general statement (ROP can occur intrauterine) is cited from ophthalmological papers. ROP ("enhanced" growth of vessels) seems to be a disorder of growth for a unknown reason either extra- or intrauterine. Presently, the only proven treatment is laser or cryo by destroying the cells which promote the growth.
Date: April 9, 1999
From: Sarah J. Blake
Oxygen was the first causal factor studied. For a long time it was just assumed to be fact that too much oxygen was the cause. Some adults don't even know the name of the condition, either by the old or the current name. They just have been told and therefore believe that their blindness was caused by receiving too much oxygen as a baby. This is how I believed for a long time, and I was born many years after the recommendations for oxygen use were circulated.
But other studies have investigated the role of Vitamin E deficiency and exposure to light, and some letters have reported ROP in babies with too little oxygen in the blood. I've also seen mention of transfusions of adult blood as a factor, and I believe I've seen at least one author suggest that in utero factors may play a role. Nobody really knows is the answer I've come up with now, and I will get very fired up when I read or hear people talking about oxygen like it's the answer to all life's mysteries.
As for the therapeutic oxygen, I have seen a study or two which suggests that during certain phases of ROP, use of oxygen may actually slow the progress. I cannot remember the details on this.
I was not a very sick preemie according to Mom's memories. Didn't come home on the vent. Only 80 days in the NICU. I still haven't done anything about getting my records, and I'd love to see them. Anyway, my ROP was pretty severe, although I couldn't tell you what stage. They weren't classifying back then. I've had all the standard complications. But some of my peers who were sicker, born in earlier years, etc, are walking around here with 20/200 or better, and I just don't get it at all. I'm not as unhappy about this as I was at one time, but I'm still just plain mystified. Then again some of my peers are walking around with prosthetics because their eyes atrophied. What's that term, phthisis? What determines it? Haven't a clue? What stops it for some people while it rages for others? Haven't a clue.
Date: April 10, 1999
From: Kathryn A.
This is something I am absolutely unqualified to discuss. However, for what it is worth, I thought I would share what our retina specialist told us.
According to him, when the premature baby is born her retina is not yet fully developed. Once she is out of the womb, she begins to get visual stimulation. The brain says, "Oh we need retina! Quick! Make a retina!" So then the retina production proceeds post haste.
All of the building blocks for a retina are delivered to the construction site: tissue cells, blood vessels, the stuff that makes the retina adhere to the back of the eye, etc. However, everything gets put together incorrectly and the retina begins to grow in odd directions, adheres to itself, etc.
He described it as if you were building a house and the construction crew came to build it for you. They brought concrete, ribar, lumber, insulation, roof shingles, drywall, vinyl flooring, carpet, windows, interior doors and a front door. Then they mixed it all together in a big mixture and stirred it all up. All the components of a house would be there, all stuck together with the concrete that should have formed the basement. It would all be there, but it wouldn't be anything you could live in.
I don't know if I explained this properly. Or if it makes sense the way I explained it. This is just sort of along the lines of what Dr. Deegan explained to us. He didn't say anything about O2. It sounded more like it was just being out of the womb and the brain thinking it needed these organs fast.
Date: April 12, 1999
From: Scott Richards
Causes of ROP - where to start? There are no known causative factors other than oxygen, and with the tight control on oxygen administration in NICUs these days, it probably isn't a major factor anymore. Lots of other factors have been associated with risk and severity of ROP over the years, including: Birthweight Gestational age at birth Use of Indocin for closure of patent ductus Vitamin E deficiency Intracranial hemorrhage Seizures Race Remember that these are all associations, not causative factors. In other words, kids who have intraventriculat hemorrhage are more likely to have ROP, but that doesn't tell us if the IVH causes the ROP, the ROP causes the IVH, or if there is some other factor that causes both of them. There was a great study that illustrates this point. It showed that the risk in adults of coronary heart disease in various countries is directly correlated to the number of telephone poles per capita. The effect of light on ROP is even less closely associated than the above factors, but there are some theoretical reasons why it may have an effect, so we try to control it as much as possible. I believe that much of ROP is "caused" or associated with prenatal factors. We know that the amount of oxygen getting to an infant via the placenta is not constant, and can be affected by smoking and other stressors. One of the causes of prematurity is thought to be placental insufficiency, and it is not unreasonable to suspect that this could have an effect on the risk of ROP. The bottom line, as was mentioned, is that we really don't know, but it is probably a combination of multiple factors.
The analogy of ROP being like a hurriedly constructed house doesn't quite fit with my understanding of the disease process. The retina itself is formed very early in development, is almost always intact in kids with ROP. It's the blood supply to the retina that is not yet formed, and that does seem to develop abnormally as you described.
Date: April 17, 1999
From: Helen Harrison
Sheri writes:
"I look back now to Kylie's birth she had asphyxia (no O2) for aprox 15 minutes after she was born, that is how she got her grade III & IV IVH. Asphyxia is the "Highest" cause of CP or risk factor of CP. Kylie has never had any signs of CP. She has NO effects at all that are noticed at this time. I know that's rare and thank God everyday for giving us that gift!"
Although it isn't good to have low oxygen (especially for very long periods of time) it is poor circulation to the brain and very low carbon dioxide levels (which cause poor circulation) that seem to produce the greatest danger of CP and other manifestations of brain injury. Being on a ventilator and especially being on the vent for long periods of time, or being briefly but aggressively ventilated in ways that cause low CO2, are now thought to be much more important than periods of low oxygen. This is all complex, and every medical conference I go to (about two or three a year) has something new and different to say about it. I have a new one coming up in a week or so, and some important new presentations on this will be made. I'll keep you all informed.
"Caleb never had an IVH. All his head ultra sounds where normal! I must say God must know what he's doing because I'll tell ya I was only 21 when I had Kylie and I KNOW I could have never handled all that Caleb has been through. Looking back I took for granted Kylie's semi easy NICU course. "
One half of all preemies who develop CP leave the nursery with perfectly normal ultrasounds -- i.e. no IVH. The problem is that ultrasounds are not very good at picking up the many forms of damage that can occur in the brain, and not all damage occurs as a result of IVH (which scans usually can pick up). Many preemie children who had good ultrasounds in the NICU and no bleeds, have abnormal brain scans with enlarged ventricles when looked at (with MRI) later in childhood or adolescence. Most non-IVH CP is attributed to BPD.
Ultrasounds are overrated as predictors of problems. It has been estimated that most PVL (periventricular leukomalacia) , in fact up to 70% of PVL, is missed on NICU ultrasound. (Volpe, _Neurology of the Newborn_ 1995, Philadelphia:W.B. Saunders, p.332.)
It isn't that the doctors are "wrong" as much as they don't have the information from their scanning techniques in the NICU that allow them to make accurate predictions.
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