Group B Strep & Antibiotic Prophyllaxis

Strep bacteria

 

Streptococcus is a genus of spherical (coccus) bacteria that, because of the way they divide, grow in chains, from pairs to long chains of multiple organisms. There are over 50 different species that have been identified.  Some of them cause health problems in humans ranging from dental caries (S. mutans typically) to pneumonia (S. pneumoniae). One species in particular, S. pyogenes, is implicated in a wide variety of severe disease from toxic shock syndrome, to necrotizing fasciitis, impetigo, pneumonia, sepsis, and the common "strep throat". 

 

Many Streptococcus species are harmless to humans and some even beneficial.  A number of Streptococcus species colonize the human body and form part of the human microbiome. Long thought to be largely commensual (benefitting from the human body while causing no harm), science is now beginning to understand that some and perhaps many of these species have in fact mutualistic relationship with the human body.  Both organisms derive benefit. 

 

Group B Strep

 

S. agalactiae is a variety of Streptococcus bacteria that colonizes vaginas and the lower intestinal tract of females (and the genitourinary and lower intestinal tract of males) (Bliss, 2002). It is the only known member of a subgroup termed Lancefield Group B and hence is commonly referred to as Group B strep or GBS.  The population prevalence is around 15% - 25% of women in the US.  That is, at any given time between 15% and 25% of women will be colonized with GBS.

 

 

GBS generally doesn't cause disease in healthy adult women but has been implicated in invasive disease in nursing home residents, an immune compromised population.  A typical colonization in otherwise healthy pregnant women is thought to persist for less than six weeks but may be highly variable.  

The situation becomes more complicated for women during labor and delivery. 

 

 

Microbiome

 

Humans are colonized by many types of bacteria as well fungi and viruses.  Indeed there are ten times more microbial cells than human cells in the average human body. These organisms are as important for human health as our own cells. They play a vital role in absorbing, digesting and utilizing food, and in preventing or allowing a wide range of diseases including diabetes, autoimmune disorders, obesity, allergies, and likely some cancers.  As the baby passes through the birth canal, it picks up many bacterial, fungal, and probably viral species which provide the founding species of the baby's own microbiome. 

 

The establishment of this microbiome plays a very significant role in training the immune system of the newborn about what species to attack and, importantly, what species to ignore.  The various microorganisms also keep each other in check and help to establish a healthy, stable, and necessary microbiome.  (See my blog post, We Are Not Alone)

 

 

Group B Strep during birth

 

If, however, GBS is one of those species the baby is exposed to in the birth process, it can cause infections which may be serious, even causing death of the newborn.  Prior to the widespread use of antibiotics in labor, between 1.5 and 3 out of every 1000 newborns developed invasive GBS disease (Zangwell, et al, 1992; Baker et al, 1990). That means approximately 1 of every 100 babies who are exposed to GBS will develop significant disease.

 

A smaller proportion will develop GBS sepsis or pneumonia, or more rarely menningitis, and a proportion of those babies will die as a result.  A further known complication is that GBS can cross the placental barrier and cause GBS sepsis in utero and even fetal demise.  Fortunately this event is thought to be extremely rare  (Ramus, et al, 1999).

 

 

The policy

 

In response to the accumulation of information beginning in the 1970s, the American College of Obstetrics and Gynecology began to formulate a policy, finalized and implemented by a consensus group from ACOG and the US Centers for Disease Control in 1996, to obtain recto-vaginal cultures on pregnant women at 36 weeks gestation and provide antibiotics during labor to those who screened positive. As a result of this initiative the incidence of invasive GBS disease declined from approximately 1.5 per 1000 live births to 0.5 per 1000 live births. (These results applied to early onset GBS disease of the newborn.  Another category, late onset GBS disease, was not impacted by the introduction of antibiotics) (Schrag et al, 2000).Since then universal screening of pregnant women at 36 weeks gestation and the prophyllactic administration of antibiotics during labor for those who have positive screens has become the standard of care in the US. Though this sounds like a pretty cut and dried success story, a closer look at the literature reveals some significant concerns.

 

 

The results

 

First, the studies results that were used to justify the prophylactic administration of antibiotics all focused on the incidence of GBS disease in newborns, but when researchers went looking for evidence that giving prophylactic antibiotics in labor was saving newborn lives, it simply wasn't there.  While the Intrapartum Antibiotic Protocol (IAP) did indeed cut the number of cases of early onset GBS disease in newborns, no study has ever demonstrated that IAP results in fewer neonatal deaths from GBS. In other words, providing antibiotics only to newborns who had GBS disease produced exactly the same number of newborn deaths as providing prophylactic antibiotics to every pregnant woman who had a positive screen for recto-vaginal GBS (WHO Reproductive Health Library Summary, 2014).

 

The data suggest that prophylactc antibiotics must be given to 25 women (and thus 25 in utero babies) to prevent one case of early onset GBS disease (Ohlsson and Shah, 2014). Therefore, giving antibiotics to 25 women and their in utero babies will prevent one newborn from getting GBS disease but doesn't prevent any newborn deaths.

 

Second, there were few IAP studies done and those that were done, weren't done very well.

 

The Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognized as the highest standard in evidence-based health care. A Cochrane Review published 10 June, 2014 was able to identify only three studies, all over 20 years old, that compared treatment of GBS positive women with no treatment (Ohlsson and Shah, 2014). There was inadequate randomization of subjects to treatment arms and there was no placebo control group in any study.  Further the researchers were not blinded to the treatment arms - that is, they knew which babies' mothers had received IAP and which hadn't. In the Cochrane Review authors' words:

 

"We found a high risk of bias for one or more key domains in the study methodology and execution...  There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD (GBS disease).  The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions. This review finds that giving antibiotics is not supported by conclusive evidence."

 

 

Finally, a recent study published in the infectious disease edition of the flagship British medical journal, Lancet, reports that the introduction of IAP in the Netherlands actually increased the rate of early onset GBS disease (and late onset GBS disease).  IAP was introduced in the Netherlands in 1999 following its introduction three years earlier in the US.  In a study of the entire population of the Netherlands from 1987 through 2011, researchers found that the incidence of early onset GBS disease nearly doubled from 0.11 per 1000 live births to 0.19 per 1000 live births, prompting nationwide calls for the guidelines to be reassessed and alternative prevention methods considered (Bekker, et al, 2014).  No similiar study has been undertaken in the US.

 

Clearly the jury is still out on IAP.  No mother wants her newborn to be ill and require hospitalization with IV antibiotics.  But what about the 25 mothers who receive antibiotics and did not need them? Even more importantly, what about the 24 newborns who receive antibiotics but would not have gotten sick even without them?  It is true that providing antibiotics to fifty people, 25 moms and 25 soon to be born babies, may prevent one case of GBS disease (at least in the US), but there is no evidence it will save any lives. 

 

The 25 women who received unneeded antibiotics may experience side effects ranging from mild to severe, but the evidence is accumulating that the 24 babies who received unneeded antibiotics, and even the offspring of the female newborns when they have children, may suffer from long term, debilitating, and possibly fatal sequelae. 

 

This information is not being provided to women when they consent to receive IAP, which is inconsistent with the principle and the legal obligation of informed consent.  Pregnant women are under tremendous pressure to give consent without adequate information and to accept interventions that have demonstrated dubious benefit and significant potential harm.

 

This is no small ethical issue for a profession whose prime directive is primum non nocere - first do no harm.   At the very least it should be clear that it is neither an irrational nor unrealistic position for a pregnant women to question or refuse prophylactic antibiotics for a positive GBS screen.

 

 

Works Cited:

 

 

Bliss SJ, Manning SD, Tallman P, et al: Group B streptococcus colonization in male and nonpregnant female university students: A cross-sectional prevalence study. Clin Infect Dis  2002; 34:184-190.

 

Ramus RM, McIntire DD, Wendel GD, Jr. Antibiotic chemoprophylaxis for group B strep is not necessary with elective cesarean section at term [Abstract]. Am J Obstet Gynecol 1999;180:S85.

 

Zangwill KM, Schuchat A, Wenger JD. Group B streptococcal disease in the United States, 1990: report from a multistate active surveillance system. MMWR 1992;41(SS-6):25--32.

 

Baker CJ, Edwards MS. Group B streptococcal infections. In: Remington J, Klein JO, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: W.B. Saunders, 1990:742--811.

 

Schrag SJ, Zywicki S, Farley MM, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000;342:15--20.

 

WHO, Reproductive Health Library Summary. Intrapartum antibiotics for known maternal Group B streptococcal colonization, 22 September, 2014.

 

Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B streptococcal colonization. Cochrane Database of Systematic Reviews 2014, Issue 6.

 

Bekker V, Bijlsma MW,  van de Beek D,  Kuijpers TW, van der Ende A.  Incidence of invasive group B streptococcal disease and pathogen genotype distribution in newborn babies in the Netherlands over 25 years: a nationwide surveillance study.  Lancet Infect. Dis. Volume 14, No. 11, 1083–1089, November 2014

The Myth of Menstruation?

American women are taught, and doctors generally assume, that the “normal” pattern of the reproductive cycle is to menstruate every 28 days, plus or minus a few. Of course certain things, such as pregnancy, can interrupt that cycle but the general assumption has been that on average women bleed thirteen times a year for their entire reproductive life. Indeed, the 28 day oral contraceptive regimen was intentionally designed to mimic a “normal” reproductive cycle.

 

 

The Sahel region of Mali borders the Sahara desert and shares many of it's characteristics, especially during the dry season. It is also the home of the Dogon people, a farming tribe whose beliefs and customs have changed very little over the past millennium. The Dogon women use no contraception and from menarche to menopause, confine themselves to designated huts on the periphery of the village when menstruating. This made them an excellent population for Dr. Beverly Strassmann, a biological anthropologist who studies the evolutionary origins and consequences of menstruation. Living among the Dogon for two and a half years afforded Dr. Strassmann the opportunity to establish what the actual pattern of an unfettered menstrual history looked like.

 

What she found, as expected, was that women not subject to artificial manipulation of menstrual cycles have many fewer of them, a result of more pregnancies and more years of nursing.  Dogon women menstruate seven times a year on average, between menarche and age nineteen. From twenty to thirty four, prime reproductive years, they average one menstrual cycle per year, while from thirty five through menopause the average increases to four yearly. In their entire reproductive lives few Dogon women reach one hundred total menstruation cycles. Compare that with modern western women who may menstruate over four hundred times in their lives.

 

Of course modern western women don't have an average of eight to nine pregnancies and spend around twenty years of their lives breast feeding. But that is precisely the point. One hundred life time cycles is normal; four hundred is not. Excess menstrual cycles are an artifact of birth control, and not just oral contraceptives which were designed to produce bleeding every twenty eight days to appear as natural cycles (and thus possibly be a form of birth control acceptable to the Pope), but any form of birth control. They all have the same unintended and, as we now know, detrimental side effect of hundreds of excess menstrual cycles.

 

 

Detrimental? Most assuredly. Each menstrual cycle sets in motion massive increases in the rate of cell division in the breast, endometrium, and ovary, and is accompanied by large shifts in hormone balances, changes in fat and water stores and metabolic activity. Both pregnancy and breast feeding significantly decrease the risk of ovarian, endometrial, and breast cancer. Oral contraceptives also decrease the risk of ovarian cancer even though they do not decrease the number of bleeding cycles in typical use. Why? Probably because they decrease the number of ovulations which dramatically increases the number of lifetime cell divisions. Oral contraceptives, at least in current use, may also increase the risk of some cancers. For more info see Hormones and Cancer – the reproductive years.

 

If you don't want to get pregnant but still don't want to have all those bleeding cycles, what to do? As noted above, hormonal contraceptive pills were specifically designed to create the illusion of normal menstrual cycles. They aren't normal menstrual cycles. They're only supposed to look like them. For one thing as already noted, there is no ovulation, only a monthly build up and sloughing off of endometrium. It looks like a normal cycle but is anything but. Hormones are still suppressing ovulation but are manipulated to intentionally produce an unnecessary and non-functional bleed that looks like a normal period.

 

For more on the reasons and the history behind the bleeding facade see The Pope, the Pill, and the Problem.


 

So how to stop the lifetime excess of cycles while still controlling the number of offspring you choose to bring into the world? The best option currently is still oral hormones, dosed so as to avoid creating bleeding cycles.

 

Most currently formulated oral contraceptive pills have either twenty one or twenty four "active" pills and four or seven "placebo" pills.  The so called "active" pills contain progesterone (along with estrogen). Progesterone supports and stabilizes the endometrial lining of your uterus.  The "placebo" pills may be actual placebos or more often contain only estrogen but no progesterone. Withdrawing the progesterone causes the lining to slough off and you bleed. 

 

Avoiding the bleed is accomplished by continuously taking progesterone. Essentially it requires taking a low dose oral combined estrogen and progesterone pill every day, just as one would take current oral contraceptive pills. The difference is you don't take the placebo or estrogen-only pills, the four or seven (depending on the brand) pills at the end of each pack. Instead you skip to a new pack and continue with a pill that contains progesterone and you do not bleed at all unless and until you want to!

 

It's called continuous dose oral contraception and, in theory, it's that simple.  In practice it is a bit more nuanced but it can be done, and many oral contraceptive users find it much more convenient not to have an artificially induced bleed every month.  You can get more information about it on the Contraception page.

ABC's of Emergency Contraception

Emergency, or post coital contraception has been in existence in various forms for quite a few years, starting in 1974.  But many people are not aware that emergency contraception has been available at any pharmacy, over the counter, to any person, without ID, parental consent, or a prescription since March 16 of this year.  So anyone, even you, can simply walk into a drug store and buy it with no questions asked.  But here are a few things you might want to know about EC.

 

 

What is it?

 

Although there are several kinds of EC available, only one type is available nationwide without prescription. It is a 1.5 mg dose of levonorgesterol, a synthetic progesterone.  Plan B One step is the brand name and is available everywhere, but there are also generics available in most states. 

 

Another option is ulipristal, sold under the brand name Ella.  It has a similar mechanism of action but is not available without a prescription in most states.

 

What's the difference?

 

Plan B One Step is the brand originally approved by the FDA and required, by federal court order and the FDA, to be available nationwide.  Many states and pharmacies also carry generics that are identical but less expensive. 

 

Plan B runs around $40 - $50 per dose but $10 discount coupons are available on line at the Plan B website here.  Generics run $35 - $45 in the store.  Both can be purchased on-line for less if you want to stock up, but if you plan to order on-line don't wait until you need it.

 

Plan B and generics are most effective when taken up to 72 hours (3 days) after intercourse, but is still somewhat effective up to 5 days after.

 

 

Ella still requires a prescription in most states and is more expensive.

 

You can get a prescription by having an on-line consultation at the Ella website here, for about $67 per dose.

 

Ella is as effective as Plan B One Step for the first 72 hours.  From 72 hours to 120 hours Ella is more effective.

 

 

 

Remember - If you could be pregnant, you could have a sexually transmitted disease.  Contraception does not prevent disease!

Folic Acid - The biggest experiment you didn't know you were a part of.

Americans have a love affair with vitamins and minerals, those mysterious compounds that seem to be necessary for good health yet are in reality very poorly understood. Over half the population takes one or more supplements daily despite a conspicuous lack of evidence that they offer any benefit. It's not too hard to see why we are so enamored with these amazing little pills. They are cheap, harmless, and a simple google search turns up millions of websites praising the miracles they work. One of them, vitamin C (in the form of limes), cured the British navy of scurvy and played no small part in establishing the British Empire. Others were found to virtually eliminate such 19th and early twentieth century scourges as rickets (vitamin D), pellagra (niacin), and beriberi (thiamine) in the developed world.

folate.folic acid.jpg

Even the US government has not been immune to their lure. After seeing the impact of putting iodine in salt ( dramatically decreasing goiters and hypothyroidism) and vitamin D in milk, (which essentially eliminated childhood rickets in the US) the FDA has become a proponent of adding supplements to the US food supply. The 70s saw the introduction of a number of B vitamins into the nations food supply. For the most part these were very successful efforts to treat vitamin deficiencies and the problems caused by them.

Throughout this period researchers gradually accumulated knowledge of the various bioactive substances. They began to quantify the amounts of these substances in the “average” diet and attempt to determine what minimal levels of intake were necessary to prevent the most obvious disease causing deficiencies. It became obvious that those vitamins which were fat soluble (A, D, E and K) and thus stored in fat tissue, could be over consumed and quickly become toxic, even lethal. But the rest, the water soluble vitamins were considered harmless. When I was in medical school we were taught that the you could take all the vitamin C or any of the B vitamins you wanted. Whatever was excess you simply peed out! And with few exceptions that remains the conventional wisdom in medicine today.

Folate was first isolated from Spinach in 1941 by researchers looking for a means to cure anemia. Very quickly it was discovered that folate enhanced the rate of tumor growth, which in turn led to the development of folate antagonists, the first anticancer drugs and still among the most commonly used. Folate was necessary for rapid cell growth and it was reasoned that it might be beneficial for fetal development. Clinical trials in 1991 confirmed that increasing folate intake of pregnant women decreased the rate of neural tube defects.

 

ACOG and the USPHS began recommending prenatal supplements of folate for all pregnant women beginning three months prior to pregnancy. The problem, of course, is that very few women know that they are pregnant until two to six weeks after they conceive. Even among the minority that actually does plan their pregnancy, few know three months ahead of time when that will occur. So those well meaning folk at USPHS, got together with the epidemiologists at the FDA and, beginning in 1998 had folic acid put into the flour supply of some commodities (like uncooked breakfast cereals) at a rate of 140 micrograms per hundred grams of flour. At that rate a large bowl of breakfast cereal will supply the recommended 400 micrograms of folic acid daily.

 

It worked, spectacularly. The prevalence of low folate levels in the US population dropped from 16% to 0.5% (Pfeiffer, 2005) The rate of NTD dropped as well. To be fair, the rate did not drop equally across populations. Americans of black and hispanic descent saw improvement in folate levels but not as dramatic as among whites. There is a proposal currently under study to address that discrepancy by requiring folic acid addition to the corn meal supply.

 

All was not quite as rosy as the policy makers wanted to believe however. Almost as soon as population data began to be published showing the dramatic efficacy of adding folic acid to the food supply, oncologists began publishing papers questioning the wisdom of adding folic acid to the food supply. They pointed out rightly that adding more than the Recommended Daily allowance of folate, a known promoter of tumor growth, to the food supply of a nation that was also obsessed with vitamin supplementation, ran a substantial risk of dramatically over dosing folate in some members of the population.

 

It turns out they were right to be concerned. The same study that approvingly noted the decrease in numbers of people with low folate levels also noted, without concern, that the number of people with greater than 45.3 nanomoles/liter went from 7% to 38% of the population. That corresponds roughly with the established Tolerable Upper Limit of folic acid intake of 1000 micrograms/day. The question then becomes, what is that upper limit based on?

 

It turns out that long term studies on the effects of folate at higher levels than normally found in the human body have never been done. Too little vitamin B 12 can cause severe blood disorders and neurological damage if left untreated. It was well known at the time that excess amounts of folate could mask the symptoms of vitamin B 12 deficiency. The limit of 1000 micrograms of folic acid per day was based simply on the dose that was low enough not to hide the symptoms of B12 deficiency. It had nothing to do with the potential for toxicity of high doses of folate, which were assumed to be harmless.

Nutritional surveillance studies which have been ongoing continue to report the folic acid fortification programs are a massive success story. Blood (serum to be exact) folate levels in the population of females of reproductive age have gone from 14.0 nanomoles/liter during the period from 1988 – 1994 to 37.6 nanomoles/liter between 1999 and 2010 (Pfeiffer et al, 2012). In their zeal to make sure all women who could potentially get pregnant were getting enough folate they have managed to increase the average folate content of the entire population of women between the ages of 14 and 44 to over two and a half times what used to be normal. The amazing thing is that, with very few exceptions, most researchers happily assumed this was a good thing.

 

Now, add to all of this, the current practice of the obstetric community in the US which is to automatically put all of their patients on prenatal vitamins, containing an additional 400 to 800 micrograms of folate depending on brand. Women who were born with a neural tube defect or had a previous child with a neural tube defect are often put on doses as high as 4000 micrograms, ten times the estimated average requirement, with absolutely no data that it helps or is safe. If a little is good, a lot must be better.

Fortunately, those few researchers who have been uncomfortable with employing the nations food supply to conduct a massive, uncontrolled experiment on the entire population have started to publish some data and the findings raise some significant red flags. Selhub, et al, (2009) reported significantly greater cognitive impairment in older subjects with elevated folate levels and lower B12 levels. Troen et al, (2006) reported a biphasic effect of folate levels. Both too much and too little folate impaired the function of certain immune system cells in post menopausal women.

 

The concerns for pregnant women come from two sources. First, the number of new diagnoses of autism began to sharply increase in 2000. By 2000 children children exposed to excess folate in utero in 1998 would be approaching the age at which autism is first diagnosed. In 2000 the rates of autism diagnosis were about 1 in 150 children. By November of 2015, according to the National Health Interview Survey an estimated 1 in 45 children were being diagnosed with autism, a 300% increase that just happens to correspond with the FDA folate fortification program.

 

Of course that's just a correlation and doesn't imply causality but it seems there is now direct evidence of a role for excessive folate in the genesis of autism. In preliminary results from an ongoing study of the early life determinants of autism presented at the 2016 International Meeting for Autism Research in Baltimore, researchers from Johns Hopkins have found that increased levels of folate and B12 can significantly increase the risk that a pregnant woman's offspring will develop autism. If the mother's blood folate was excessive, the risk of developing autism was doubled. If excessive B12 levels were found the risk was tripled. But if both folate and B12 levels were elevated the mother's offspring had a 17.6 times greater risk of developing autism. Ominously, the study found that 10% of women had more than 59 nanomoles/liter of folate (much higher than the recommended upper limit of 45.3) and 6% had more than 600 picomoles/liter of B12.

 

Bear in mind that these are preliminary results and more research is definitely warranted before making major changes. Certainly is it still important to get enough folate, and at the right time to impact neural tube defects. On the other hand, given the prevalence of folic acid in the food supply, in supplements, and of course in prenatal vitamins it would be wise to be cautious. What can one do?

 

Well, a survey of the foods you regularly eat and the amounts is a useful starting point. If you are inclined to eat several bowls of fortified cereal a day – stop! If you are taking vitamin supplements in addition to prenatal vitamins – stop!

 

If you have real concerns about neural tube defects or if you have neural tube defects in your family, it might be wise to have a blood folate level checked.

 

For the rest of you, probably the wisest course of action would be to keep a food diary.

For processed foods like cereal or pasta, check the amounts of folic acid on the label and multiply by the amount you eat on average. Don't forget to check the folic acid on energy bars and energy drinks, if you consume such.

 

That will give you a pretty good starting point.


Multiply the number you get by 1.7

 

That coverts folic acid to DFE – daily folate equivalents. Basically folic acid is synthetic and more bioavailable than the natural folate found in foods.

 

For unprocessed foods only a few contain significant amount of natural folate.

Liver 250 micrograms per 3 oz serving

Lentils 180 micrograms per 1/2 cup
Spinach 100 micrograms per 1/2 cup
Great Northern Beans, 90 micrograms per half cup
Aspargus 85 micrograms in four spears
Broccoli 50 micrograms per 1/2 cup
Eggs 25 micrograms per egg
Cantaloupe 25 in a quarter of a medium sized melon

 

Add up how much you eat of these then add that to the folic acid x 1.7 from above.

 

Now add the folic acid content of any vitamin supplements, prenatal vitamins – don't forget to multiply by 1.7 to convert to folate equivalents.

 

If you get less than 400 micrograms (of folate equivalents) you definitely need to be taking supplements of some sort.
If you get somewhere between 400 and 1000 total, you're probably okay, at least until more information is available.
If you get more than 1000 micrograms then you should consult your doctor about stopping your prenatal vitamin. (Or me if they aren't being helpful.)

 

Also, although most obstetricians and many midwives will tell you differently, the proper counseling for folic acid is to take it from 3 months before conception until 12 weeks after conception. That's it. After 12 weeks the neural tube should be closed and folate will have no further impact. For anyone with a relatively healthy diet I would suggest stopping prenatal vitamins altogether at 12 weeks.