Epidurals!

Epidural anaesthesia is a painkiller, usually clonidine in the case of childbirth, injected into the space between the vertebrae in the spinal cord.

Epidurals are good at relieving pain and don’t harm babies.

A meta-analysis of randomized controlled trials found that epidurals (compared to opioids, which don’t relieve pain noticeably) don’t affect fetal oxygenation, neonatal pH, Apgar score, caesarean delivery, or the use of forceps.[1] A second meta-analysis also concluded that epidurals don’t increase the rate of C-sections or forceps.[4]

Epidurals do significantly increase labor time, by a mean of about an hour. They also cause fever (in about a quarter of women) and hypotension (in about 40%).[2]

People who choose epidurals may be more likely to also get C-sections (about 2.5x in a case series of 711 patients, for instance[6]),  but randomized trials and natural experiments in which epidural utilization goes up show consistently that epidurals don’t cause increased rate of C-sections.[2]

And people love epidurals; they are significantly more satisfied with their pain relief than people randomized to opioids, p < 0.001.[2]

Now, the problem with labor delays is neonatal asphyxia. The longer you push, the more likely the baby is going to come out with a low Apgar score.  Babies who go without oxygen can get brain damage, which can cause developmental disability or cerebral palsy.

If you’re pushing for three hours, you have only 0.1x the odds of a spontaneous vaginal delivery without signs of asphyxia that you would at two hours; at two hours, you have only 0.4x the odds of a healthy spontaneous vaginal delivery than you would have at one hour.[3]

On the other hand, this effect seems not to be strong enough to lower mean Apgar scores overall when mothers are randomized to epidurals.

In an observational study of 1,028,705 Swedish newborns, only 0.76% had low Apgar scores (below 7). Epidurals were a significant risk factor, but note that difficult births are more likely to be especially painful.[5]

The evidence that associates epidurals with significant badness (low Apgar scores, higher rates of forceps use and Caesareans) is pretty much entirely observational, and the randomized trials don’t bear it out.

 

Unless you value natural childbirth for its own sake, or want the lower maternal infection risks associated with a home birth, there’s really not much of an evidence-based case for avoiding epidurals.

[1] Leighton, Barbara L., and Stephen H. Halpern. “The effects of epidural analgesia on labor, maternal, and neonatal outcomes: a systematic review.”American Journal of Obstetrics and Gynecology 186.5 (2002): S69-S77.

[2]Halpern, Stephen H., et al. “Effect of epidural vs parenteral opioid analgesia on the progress of labor: a meta-analysis.” Jama 280.24 (1998): 2105-2110.

[3]Le Ray, Camille, et al. “When to stop pushing: effects of duration of second-stage expulsion efforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia.” American journal of obstetrics and gynecology 201.4 (2009): 361-e1.

[4]Liu, E. H. C., and A. T. H. Sia. “Rates of caesarean section and instrumental vaginal delivery in nulliparous women after low concentration epidural infusions or opioid analgesia: systematic review.” Bmj 328.7453 (2004): 1410.

[5]Thorngren-Jerneck, Kristina, and Andreas Herbst. “Low 5‐Minute Apgar Score: A Population‐Based Register Study of 1 Million Term Births.”Obstetrics & Gynecology 98.1 (2001): 65-70.

[6]Thorp, James A., et al. “The effect of continuous epidural analgesia on cesarean section for dystocia in nulliparous women.” American journal of obstetrics and gynecology 161.3 (1989): 670-675.

Giving Birth: How To Reduce Risk Of Badness

First things first: the mother is basically not going to die in childbirth.  Maternal mortality rates in the US are 14 per 100,000, or a 0.0014% chance, or a few hundred deaths a year. This is not a thing to worry about. You are not gonna die.

Maternal mortality is much more likely, by a 3:1 ratio, among black mothers than white (or Hispanic) mothers. Nobody really knows why.

Most of the things that kill mothers in childbirth are hemorrhage, eclampsia, stroke, pulmonary embolism, high blood pressure, or other factors associated with the higher blood pressure and clotting associated with pregnancy.[2]

Severe maternal morbidity, or life-threatening consequences of childbirth, are more common, affecting about 65,000 women in the US per year.  This is quite a bit more common, though still unlikely overall; there is a 1.6% chance something seriously bad will happen to you during birth.

How about babies?  Perinatal mortality, or a child dying within a week of childbirth, happens at a rate of 6.24 per 1000, or 0.6%.  Perinatal morbidity (i.e. something going wrong enough to require NICU admission) has higher rates, at 77.9 per 1000 births, or 7.8%.[4]  The majority of these are low-birth-weight infants.

Want to avoid bad things happening to your baby during birth? Don’t have a preemie.

How do you avoid having a preemie again? Twins are bad; smoking is bad; treat your gum disease and vaginal infections; don’t be underweight; get cervical incompetence fixed if that’s an issue.

Badness around birth happens mostly to babies and especially to preterm babies.

Is Homebirth Safe?

According to a Cochrane Review, randomized trials on low-risk women (70%-80% of pregnant women are “low risk”) find no difference in outcomes between home birth and hospital birth.[4] Among 24,092 low-risk pregnant women, perinatal (infant) mortality was not significantly different between home births and hospital births; there was a lower incidence of low Apgar scores (OR = 0.55) in the home birth group. Home births were less likely to involve interventions such as induction or augmentation of labor, episiotomy, caesarian section, or using forceps.  A large (529,688 low-risk pregnancy) cohort study in the Netherlands also found no significant differences in perinatal mortality between planned home births and planned hospital births.[6]

However, another meta-analysis found that home birth tripled the neonatal mortality rate compared to hospital birth.[7]  This study, by contrast, included not randomized trials but cohort studies of planned home birth vs. planned hospital births.  A total of 342,056 planned home and 207,551 planned hospital births were included. Home births had significantly fewer interventions (such as epidurals, forceps, or caesarean sections) and better maternal outcomes (OR of infection = 0.27, OR of hemorrhage = 0.66, etc.)  Perinatal deaths, e.g. infant deaths within seven days of birth, were the same between home birth and hospital birth; but neonatal death, within 28 days of birth, was higher in home births (OR = 1.98).  0.2% of home births, compared to 0.1% of hospital births, resulted in neonatal death.

The authors give the explanation that intrapartum anoxia (due to laboring without a fetal heart rate monitor and not switching to caesarean or forceps as often) can cause infant mortality.

Bottom lines:

• home births definitely involve much less medical intervention
• home births involve fewer maternal complications
• home births seem to involve higher risk of neonatal but not perinatal deaths
• all of the above evidence is for low-risk pregnancies.
• If you have a low-risk pregnancy your baby is probably not gonna die either way. 0.1%-0.2% risks.

If all you care about is baby safety, it looks like hospital > home birth, even for low-risk pregnancies. If you include mother’s safety, it becomes more complicated, because maternal outcomes tend to be better with home births; but keep in mind that maternal deaths are still extremely rare either way, much more so than infant deaths. If you include maternal pain, it becomes more complicated still, because you can get an epidural at the hospital.  And if you include maternal stress, then, some people report that being in a “medicalized” environment is more worrying than being at home. The tradeoffs, as always, are individual.

 

 

References

[1]http://data.worldbank.org/indicator/SH.STA.MMRT

[2]http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pmss.html

[3]http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_08.pdf

[4]Harrison, Wade, and David Goodman. “Epidemiologic trends in neonatal intensive care, 2007-2012.” JAMA pediatrics 169.9 (2015): 855-862.

[4]Olsen, Ole, and Jette A. Clausen. “Planned hospital birth versus planned home birth.” The Cochrane Library (2012).

[5]Olsen, Ole. “Meta‐analysis of the safety of home birth.” Birth 24.1 (1997): 4-13

[6]de Jonge, Ank, et al. “Perinatal mortality and morbidity in a nationwide cohort of 529 688 low‐risk planned home and hospital births.” BJOG: An International Journal of Obstetrics & Gynaecology 116.9 (2009): 1177-1184..

[6]Wax, Joseph R., et al. “Maternal and newborn outcomes in planned home birth vs planned hospital births: a metaanalysis.” American journal of obstetrics and gynecology 203.3 (2010): 243-e1.

What Kills Babies?

Let’s start with the CDC’s statistics on infant mortality.

Babies in the US are not that likely to die. The infant mortality rate is 5.96 per 1000 live births, or about 0.6%.

Most of the risk is in neonatal mortality, deaths within the first month of life.  That has a death rate of 4 per 1000.  The whole rest of the first year only has a death rate of 1.93 per 1000.  67% of all infant deaths are in the first month of life.

The top cause of infant mortality, at 20.4% of all infant deaths, is “congenital malformations and chromosomal abnormalities.”

#2, at 17.4% of all infant deaths, is “complications of short gestation and low birth weight.”

#3, at 6.8% of all infant deaths, is “newborn affected by maternal complications of pregnancy.”

#4, at 6.7% of all infant deaths and a rate of 3.97 per 1000, is SIDS.

#5, at 4.5% of all infant deaths, is accidents.

#6, at 4.1% of all infant deaths, is complications of placenta or cord.

#7, at 2.5% of all infant deaths, is bacterial sepsis of newborn.

#8, at 2.2% of all infant deaths, is respiratory distress of newborn.

#9, at 2.0% of all infant deaths, is circulatory system disease.

#10, at 1.7% of all infant deaths, is neonatal hemorrhage.

So, you can see right here, that a big chunk of what kills babies has to do with things that occur during pregnancy: birth defects, premature babies, and complications of pregnancy.

The main stuff you can do about these problems has been covered earlier on this blog. Be in general good vascular health and neither underweight nor overweight; don’t smoke; treat your gum disease and vaginosis; take your folic acid; wash hands frequently and avoid dirt and raw meat;  avoid high-risk medications, lead, mercury, and hot tubbing.

Congenital heart defects are the type of birth defect that causes the most deaths.  They can be treatable with surgery, but usually require lifelong specialist care.

Neonatal sepsis is an infection that comes either from the mother or from the hospital. If from the mother, this can be prevented by testing for disease, esp. herpes and streptococcus.  If from the hospital, this can be prevented by avoiding long hospital stays when possible.

Neonatal respiratory distress is a condition of premature babies in which their lungs do not produce enough surfactant so they cannot breathe.  Avoiding prematurity can help prevent this.

I’ll be looking into some of these risks in further posts.

 

What is Eclampsia Anyway?

Eclampsia is the onset of seizures in a pregnant woman with pre-eclampsia.  It is a Very Bad Thing.  Complications of eclampsia can kill the mother (about a 1% chance).

Ok, so what’s pre-eclampsia? A disorder, usually in the third trimester, that involves high blood pressure, protein in the urine, and other problems such as liver or kidney dysfunction.

What causes it? It’s mostly unknown.

The hypothesis [1] seems to be something like “systemic inflammation” or an immune response of the mother to the placenta; this would explain why obesity, insulin resistance, maternal infections, and miscarriages are associated with increased risk of pre-eclampsia.  Pro-inflammatory cytokines such as TNF (chemicals produced by the body’s innate immune response) can constrict blood vessels and cause microvascular protein leakage, which is a potential cause of the high blood pressure and proteinuria.  High blood pressure, if untreated, causes edema (swelling) in various tissues, including the brain, and that pressure can cause seizures.[1]

Even typical pregnancy is characterized by a strong inflammatory response, and some believe that pre-eclampsia is simply an extreme case of what happens in all pregnant women.[1]

Pre-eclampsia occurs in 2-7% of pregnant women.  Usually, the high blood pressure is treated with beta blockers, and sometimes magnesium sulfate is given to prevent seizures.

What are the risk factors for pre-eclampsia?

 

PIGF. Placental growth factor helps blood vessels develop around the placenta; women who develop pre-eclampsia have lower levels of it in the first trimester. The bottom tertile of PIGF levels have 28x the risk of pre-eclampsia of the top tertile.[5] A larger study found that women in the bottom quartile of PIGF levels had an odds ratio of 19.6 compared to the top quartile.[6]  Failure to grow new blood vessels seems to result in failure of the placenta and endometrium to successfully mesh, which causes hypertension since deoxygenated blood can flow out of the placenta but oxygenated blood cannot easily flow in.[7]

Antiphospholipid Antibodies. The presence of these is associated with a relative risk of 9.72 of pre-eclampsia.[2]  Antiphospholipid antibodies are caused by an autoimmune problem where the body attacks proteins that attach to cell membranes, causing an increased rate of blood clotting and miscarriage.

Diabetes. Pre-existing (not gestational) diabetes is associated with a 3.56x risk of pre-eclampsia.[2]

Twins. The relative risk of pre-eclampsia in twin pregnancies is 2.93x the risk for singletons.[3]

Family history. The risk of pre-eclampsia for those with a family history of pre-eclampsia is 2.90x the risk for those without.[3]

Smoking. The risk of pre-eclampsia in smokers is 2.67x the risk in nonsmokers.[4]

Overweight. The relative risk of pre-eclampsia for those with prepregnancy BMI > 25 is 2.47.[3]

High blood pressure. The relative risk of pre-eclampsia for those with systolic BP > 130 at the start of pregnancy is 2.37 compared to those with BP < 130 at the start of pregnancy.[3]

Bottom Line:

As for many of the disorders of pregnancy, being in “general good vascular health” is helpful. (It’s better not to smoke, not to have diabetes or high blood pressure, not to be overweight, etc.)  Predisposition to pre-eclampsia also seems to have a strong genetic component; family history increases risk, as does having previous pregnancies with pre-eclampsia, or previous miscarriages; inherited issues like antiphospholipid antibodies, and potentially other genes, increase risk.  Once you’re pregnant, there doesn’t seem to be that much you can do to prevent pre-eclampsia, though detection and treatment can keep it from progressing to eclampsia or other dangerous problems.

 

References

[1]Sibai, Baha, Gus Dekker, and Michael Kupferminc. “Pre-eclampsia.” The Lancet 365.9461 (2005): 785-799.

[2]Walker, James J. “Pre-eclampsia.” The Lancet 356.9237 (2000): 1260-1265.

[3]Duckitt, Kirsten, and Deborah Harrington. “Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.” Bmj 330.7491 (2005): 565.

[4]Ødegård, Rønnaug A., et al. “Risk factors and clinical manifestations of pre‐eclampsia.” BJOG: An International Journal of Obstetrics & Gynaecology107.11 (2000): 1410-1416.

[5]Thadhani, Ravi, et al. “First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.” The Journal of Clinical Endocrinology & Metabolism 89.2 (2004): 770-775.

[6]Levine, Richard J., et al. “Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.” New England Journal of Medicine355.10 (2006): 992-1005.

[7]Wang, Alice, Sarosh Rana, and S. Ananth Karumanchi. “Preeclampsia: the role of angiogenic factors in its pathogenesis.” Physiology 24.3 (2009): 147-158.

How to Avoid Gestational Diabetes

Gestational diabetes is high blood sugar that first develops during pregnancy, usually in the third trimester.

Gestational diabetes is bad because it can lead to babies being large for gestational age (which causes birth complications such as need for C-sections).  It can also cause problems in neonates if untreated: hypoglycemia, jaundice, respiratory distress syndrome, and other chemical imbalances.  Women who have gestational diabetes are at risk for later developing Type II diabetes — 9.6x greater than women who didn’t get gestational diabetes.[2] Usually gestational diabetes can be treated with diet (low-carb or low-glycemic-index) and/or medications like insulin and metformin.

Risk Factors

Maternal Age > 40. Older mothers have an odds ratio of 7.0 for gestational diabetes.[1]

Obesity. Prepregnancy BMI > 35 is associated with an odds ratio of 6.1 for gestational diabetes.[1]  Prepregnancy BMI > 25 is associated with an odds ratio of 4.14.[3]

Being Asian. White women are the least likely to have gestational diabetes, while Asian women are the most: a study of 11205 women attending a clinic in the UK found that Asian women were 8-18x as likely as white women to get gestational diabetes.[5]  The highest rates of gestational diabetes in the world are found among the Pima Indians.[5]  In a NYC clinic, a retrospective study of 329,988 births found that the prevalence of gestational diabetes in Asians was 2.5x that in whites.[6]

Lack of Exercise.  Women who exercised at all in the year before pregnancy had 0.44x the risk of gestational diabetes of women who didn’t, and women who exercised at least 4.2 hrs/week had 0.24x the risk of sedentary women.[4]

Treatment

Treating gestational diabetes helps prevent bad outcomes!  Compared to placebo, a “treatment program” consisting of dietary modification, glucose monitoring, and insulin as necessary, resulted in fewer large-for-gestational age infants (7.1% vs 14.5%), less shoulder dystocia (1.5% vs 4.0% — this is when the baby’s shoulder gets stuck in the birth canal during delivery), and fewer C-sections (26.9% vs 33.8%).[7]  A different study found no effect on C-section rates but a significant drop in perinatal complications in the treatment group (1% vs 4%.).  A meta-analysis of relevant studies found that treatment significantly reduced the incidence of large for gestational age infants and shoulder dystocia, but didn’t significantly reduce C-sections or perinatal mortality.[9]

Bottom Line

To a first approximation (which is all I’m going to do), gestational diabetes is pretty straightforward. “Eat healthy and exercise.”

References

[1]Teh, Wan T., et al. “Risk factors for gestational diabetes mellitus: implications for the application of screening guidelines.” Australian and New Zealand Journal of Obstetrics and Gynaecology 51.1 (2011): 26-30.

[2]Lee, Anna J., et al. “Gestational diabetes mellitus: Clinical predictors and long-term risk of developing type 2 diabetes a retrospective cohort study using survival analysis.” Diabetes care 30.4 (2007): 878-883.

[3]Cypryk, Katarzyna, et al. “Gestational diabetes mellitus-an analysis of risk factors.” Endokrynol Pol 59.5 (2008): 393-7.

[4]Dempsey, Jennifer C., et al. “Prospective study of gestational diabetes mellitus risk in relation to maternal recreational physical activity before and during pregnancy.” American journal of epidemiology 159.7 (2004): 663-670.

[5]Reece, E. Albert, Gustavo Leguizamón, and Arnon Wiznitzer. “Gestational diabetes: the need for a common ground.” The Lancet 373.9677 (2009): 1789-1797.

[6]Rosenberg, Terry J., et al. “Maternal obesity and diabetes as risk factors for adverse pregnancy outcomes: differences among 4 racial/ethnic groups.”American journal of public health 95.9 (2005): 1545-1551.

[7]Landon, Mark B., et al. “A multicenter, randomized trial of treatment for mild gestational diabetes.” New England Journal of Medicine 361.14 (2009): 1339-1348.

[8]Crowther, Caroline A., et al. “Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.” New England Journal of Medicine 352.24 (2005): 2477-2486.

[9]Horvath, Karl, et al. “Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis.” Bmj 340 (2010): c1395.

Risk Factors for Low Birth Weight

Low birth weight is defined by the WHO as an infant weighing less than 5 pounds 8 ounces.  It’s a significant predictor of infant mortality in the first week of life, as well as other negative consequences; low-birth-weight children do worse in school and tests[1] by about half a standard deviation [2] and have more problems with attention and executive function.  Low-birth-weight infants also grow up to be slightly more likely to be overweight, have hypertension, and have diabetes.[3][4]

The CDC estimates that 8% of American babies are low-birth-weight.[5]  This is fairly high, for developed countries; only 4% of Finnish or Korean babies are low-birth-weight. [6]  Low birthweight is responsible for about a third of the US’s higher infant mortality than Europe’s.

So, what causes low birthweight?

There are two types of low birthweight: prematurity, and intrauterine growth restriction (or low birthweight for gestational age.)   IUGR infants are far more likely to have stunted growth later in life.  Premature infants are more likely to have dangerous diseases of infancy such as infant respiratory distress syndrome (one of the top causes of infant mortality).[7]

Intrauterine growth retardation can be caused by multiple factors, including chromosomal abnormalities in the fetus (about 20% of IUGR infants), maternal vascular disease which starves the fetus of nutrients (about 20-35% of IUGR infants) and maternal malnutrition.  So we should expect the risk factors for birth defects and miscarriage to also be risk factors for low birthweight.[12]

Low Weight

Gaining less than 15 pounds during pregnancy was associated with an odds ratio of low birth weight of 3.38 for preterm births and 4.08 for full-term births.[8]  Being underweight before pregnancy was associated with an odds ratio of 2.36 of small-for-gestational-age infants.[13]

Spousal Abuse

Being abused by one’s partner was associated with an odds ratio of low birth weight of 3.29 for physical abuse and 3.78 for nonphysical abuse.[8]  A meta-analysis gives an odds ratio of 1.4 for any abuse during pregnancy.[9]

Diabetes

Pregestational diabetes was associated with an odds ratio of 3.3 for intrauterine growth restriction.

Poor education

Not finishing high school was associated with an odds ratio of 2.69 of intrauterine growth restriction.[11]

Social Isolation

“Never or seldom meets friends” was associated with an odds ratio of 2.42 of intrauterine growth restriction and an odds ratio of 1.20 of prematurity.  This effect persisted even after adjusting for maternal education.[11]

Smoking 

Smoking was associated with an odds ratio of 2.28 for low birthweight in full-term births.[9]

 

Basically, to the extent that we can separate low birthweight from prematurity, it still has a lot of the same risk factors. Low socioeconomic status and the things that correlate with it; diabetes; smoking; low weight.

References

[1]Weindrich, Diana, Manfred Laucht, and Martin H. Schmidt. “Late sequelae of low birth weight: mediators of poor school performance at 11 years.”Developmental Medicine & Child Neurology 45.7 (2003): 463-469.

[2]Aarnoudse-Moens, Cornelieke Sandrine Hanan, et al. “Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children.” Pediatrics 124.2 (2009): 717-728.

[3]Curhan, Gary C., et al. “Birth weight and adult hypertension, diabetes mellitus, and obesity in US men.” Circulation 94.12 (1996): 3246-3250.

[4]Rich-Edwards, Janet W., et al. “Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976.” Bmj 315.7105 (1997): 396-400.

[5]http://www.cdc.gov/nchs/fastats/birthweight.htm

[6]http://www.unicef.org/publications/files/low_birthweight_from_EY.pdf

[7]Kramer, Michael S. “Determinants of low birth weight: methodological assessment and meta-analysis.” Bulletin of the World Health Organization65.5 (1987): 663.

[8]Campbell, Jacquelyn, et al. “Physical and nonphysical partner abuse and other risk factors for low birth weight among full term and preterm babies a multiethnic case-control study.” American Journal of Epidemiology 150.7 (1999): 714-726.

[9]Campbell, Jacquelyn, et al. “Physical and nonphysical partner abuse and other risk factors for low birth weight among full term and preterm babies a multiethnic case-control study.” American Journal of Epidemiology 150.7 (1999): 714-726.

[10]Murphy, Claire C., et al. “Abuse: a risk factor for low birth weight? A systematic review and meta-analysis.” Canadian Medical Association Journal164.11 (2001): 1567-1572.

[11]Nordentoft, Merete, et al. “Intrauterine growth retardation and premature delivery: the influence of maternal smoking and psychosocial factors.”American Journal of Public Health 86.3 (1996): 347-354.

[12]Resnik, Robert. “Intrauterine growth restriction.” Obstetrics & Gynecology99.3 (2002): 490-496.

[13]Abrams, Barbara, and Vicky Newman. “Small-for-gestational-age birth: maternal predictors and comparison with risk factors of spontaneous preterm delivery in the same cohort.” American journal of obstetrics and gynecology164.3 (1991): 785-790.

Risk Factors for Prematurity

Preterm birth is the greatest single cause of perinatal morbidity and mortality in the US. 70% of infant deaths are due to preterm birth.[1] While most preterm babies survive, they’re at risk of neurodevelopmental impairments and respiratory and gastrointestinal complications.[2] Avoiding premature birth is a big deal.

About 12-13% of US births are preterm, which is twice the rate in other developed countries.  Preterm births have actually increased over time.

Preterm births, defined as birth before 37 weeks, can occur either spontaneously (through early labor) or deliberately (through medical induction when something is wrong with the pregnancy such as pre-eclampsia.)  Spontaneous preterm labor is generally thought to be a syndrome involving inflammation or infection, uterine or placental hemorrhage or ischemia, stress, and other immunologically mediated processes. So we’ll see all the standard risk factors that affect systemic inflammation.

Multiple Births

Nearly 60% of twins are born preterm, for an odds ratio of 11x baseline.[2]

Vaginal Bleeding

Because premature labor is often the result of bleeding or tears in the uterus or placenta, vaginal bleeding in more than one trimester is a risk factor for premature birth, carrying an odds ratio of 7.4.[3]

Early Bacterial Vaginosis

Bacterial infection within the first 16 weeks of pregnancy is associated with an odds ratio of 7.55 of preterm birth. (Bacterial vaginosis at any time during pregnancy has an odds ratio of 2.1.) A vaginal infection may result in a uterine infection that eventually causes contractions and labor. [8]  Vaginosis is associated with a change in the composition of the vaginal flora: a drop in the number of lactobacilli, and a corresponding rise in the number of other kinds of bacteria. It is hypothesized that either through general systemic inflammation, or through the fetal immune response, these bacterial infections cause the tissue deterioration that results in rupture and preterm birth.[13]  Vaginosis at the beginning of pregnancy is also associated with a 3x risk of pregnancy loss before 22 weeks.[12] Treatment with metronidazole can cut the risk of preterm birth in half.[11]

Douching is bad for your vaginal flora.  Douching is associated with an odds ratio of 1.21 of bacterial vaginosis[16] and frequent douching has an odds ratio of 2.35[17].  Stopping douching reduces the incidence of vaginosis.[18]  The increased prevalence of douching among black women is a possible explanation for why they have higher rates of vaginosis and lower quantities of Lactobacillus species (the “good bacteria” in the vagina.)

Systemic Inflammation Markers

Elevated levels of the cytokine IL-6 and the inflammatory marker C-reactive protein had associated odds ratios of 4.60 and 4.07 respectively of premature birth.  These are also general risk factors for heart disease, stroke, and other vascular disorders.[9]

Gum disease

Mothers with severe periodontitis had odds ratios of 4.45 for preterm delivery.[5][6]  This is less crazy than it sounds; gum disease is associated with systemic inflammation. Treatment for periodontitis during pregnancy cut the incidence of preterm birth by a factor of 5 in a randomized controlled trial.[10]

Short Cervix

Women with a short cervix are at 3.7x the risk of having a premature birth.[15]  “Cervical incompetence” results in a greater risk of the cervix tearing early and causing labor.  This can be corrected by “cerclage”, or stitching the cervix shut, which reduces the incidence of preterm birth by about half.  For women with a high risk of spontaneous preterm labor, treatment with progesterone [14] can reduce their risk of preterm delivery.

Demographics

Black mothers are 2-3x as likely to have a preterm birth as mothers of other races. Low socioeconomic and educational status are also risk factors.[2] Teenage pregnancy is associated with an odds ratio of 3.4.[7]

Previous Preterm Birth

Some mothers tend to run to prematurity; a previous preterm birth has an odds ratio of 2.5 of being followed by subsequent preterm births.

Tobacco

Smoking increases the risk of preterm birth by 2x.[2]

Underweight

A BMI of < 19.8 increases the risk of preterm birth with an odds ratio of 2.0.[4]

Bottom line: things you can do to prevent prematurity

• avoid IVF, which often results in multiple births.
• screen for and treat vaginal infections
  • note that a drugstore test for vaginal pH is a fairly accurate indictor for bacterial vaginosis; it might be worth checking while you’re trying to get pregnant
  • don’t douche!
• be in “general good vascular health” (more or less, have a healthy and active lifestyle)
• treat gum disease
• don’t smoke
• get up to a healthy weight

 

References

[1]Pschirrer, E. Rebecca, and Manju Monga. “Risk factors for preterm labor.”Clinical obstetrics and gynecology 43.4 (2000): 727-734.

[2]Goldenberg, Robert L., et al. “Epidemiology and causes of preterm birth.”The lancet 371.9606 (2008): 75-84.

[3]Harger, James H., et al. “Risk factors for preterm premature rupture of fetal membranes: a multicenter case-control study.” American journal of obstetrics and gynecology 163.1 (1990): 130-137.

[4]Goldenberg, Robert L., et al. “The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network.” American Journal of Public Health 88.2 (1998): 233-238.

[5]Jeffcoat, Marjorie K., et al. “Periodontal infection and preterm birth: results of a prospective study.” The Journal of the American Dental Association 132.7 (2001): 875-880.

[6]Lopez, N. J., P. C. Smith, and J. Gutierrez. “Higher risk of preterm birth and low birth weight in women with periodontal disease.” Journal of Dental Research 81.1 (2002): 58-63.

[7]Martius, Joachim A., et al. “Risk factors associated with preterm (< 37+ 0 weeks) and early preterm birth (< 32+ 0 weeks): univariate and multivariate analysis of 106 345 singleton births from the 1994 statewide perinatal survey of Bavaria.” European Journal of Obstetrics & Gynecology and Reproductive Biology 80.2 (1998): 183-189.

[8]Leitich, Harald, et al. “Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis.” American journal of obstetrics and gynecology 189.1 (2003): 139-147.

[9]Sorokin, Yoram, et al. “Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth< 32 weeks and adverse neonatal outcomes.” American journal of perinatology27.8 (2010): 631.

[10]López, Néstor J., Patricio C. Smith, and Jorge Gutierrez. “Periodontal therapy may reduce the risk of preterm low birth weight in women with peridotal disease: a randomized controlled trial.” Journal of periodontology 73.8 (2002): 911-924.

[11]Morales, Walter J., Steve Schorr, and John Albritton. “Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study.” American journal of obstetrics and gynecology 171.2 (1994): 345-349.

[12]McGregor, James A., 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 173.1 (1995): 157-167.

[13]Pretorius, Christopher, Anilla Jagatt, and Ronald F. Lamont. “The relationship between periodontal disease, bacterial vaginosis, and preterm birth.” Journal of perinatal medicine 35.2 (2007): 93-99.

[14]Fonseca, Eduardo B., et al. “Progesterone and the risk of preterm birth among women with a short cervix.” New England Journal of Medicine 357.5 (2007): 462-469.

[15]Andersen, H. Frank, et al. “Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.” American journal of obstetrics and gynecology 163.3 (1990): 859-867.

[16]Brotman, Rebecca M., et al. “A longitudinal study of vaginal douching and bacterial vaginosis—a marginal structural modeling analysis.” American journal of epidemiology 168.2 (2008): 188-196.

[17]Zhang, Jun, et al. “Frequency of douching and risk of bacterial vaginosis in African-American women.” Obstetrics & Gynecology 104.4 (2004): 756-760.

[18]Brotman, Rebecca M., et al. “The effect of vaginal douching cessation on bacterial vaginosis: a pilot study.” American journal of obstetrics and gynecology 198.6 (2008): 628-e1.

Infectious Teratogens

Certain infections, in pregnant women, put the fetus at risk for birth defects.

Cytomegalovirus

Cytomegalovirus is a common herpesvirus which usually causes no symptoms in immunocompetent adults. In pregnant women, however, it can infect the fetus. Congenital cytomegalovirus is the most common cause of birth defects.  About 40,000 children a year are born with congenital cytomegalovirus, causing an estimated 400 deaths and 8000 permanently disabled children (due to hearing loss, vision loss, or intellectual disability.)[1]  Congenital cytomegalovirus is more common than fetal alcohol syndrome, Down syndrome, or spina bifida.  1-4% of pregnant women get the virus, and of those, 1% pass it to the fetus. My back-of-the-envelope estimates are that the risk of permanent disability given congenital cytomegalovirus is about 40x the baseline risk of birth defects.  Cytomegalovirus is most often transferred by contact with young children’s bodily fluids (saliva, urine, etc).

To avoid cytomegalovirus infection, wash hands frequently, especially around contact with small children.  There is no vaccine yet, but “passive immunization” with IgG for pregnant women with primary CMV infections cuts the risk of congenital CMV in the child by a factor of 50.[2]  If you have a mono-like illness while pregnant, you could get tested for CMV and possibly treat it with IgG.

Toxoplasmosis

Toxoplasmosis is a protozoan parasite, usually contracted from raw meat, unpasteurized milk, cat feces, or soil. It causes no symptoms in most immunocompetent adults (though it sometimes causes a flu-like illness), but in pregnant women, can be passed to the fetus.  An estimated 400-4000 babies every year are born with toxoplasmosis.[6]  While it is transmitted by cats, contact with cats is not a risk factor for congenital toxoplasmosis, while contact with soil or consumption of raw meat are. [3]  In a prospective study of pregnant women who had high antibody titers for the disease, 6.3% passed it on to the fetus; of babies born with toxoplasmosis, 15% had severe disease with cerebral and ocular involvement.[4]  Ocular toxoplasmosis infects the retina and causes a loss of visual acuity.  Other possible symptoms include prematurity and low birth weight, hearing problems, seizures, and intellectual disability.  Up to 80% of children born with congenital toxoplasmosis develop vision or cognitive impairments later in life.[5]

To avoid toxoplasmosis, cook meat thoroughly and avoid contact with soil.  There is prenatal treatment for toxoplasmosis but the evidence suggests it doesn’t work [7][8], whereas treatment given to newborns successfully prevents developmental abnormalities.[9][10]

Herpes

Infants can become infected with herpes at the time of birth if the mother has active lesions in the birth canal. It is rare (about 1000 births a year) but deadly (25% mortality.)[12]

To avoid congenital herpes, get a C-section if you have active genital sores at the time of birth, and by practicing safe sex during pregnancy. (The risk of transmitting herpes is much lower if you have had it before your pregnancy; most cases of neonatal herpes result from a primary infection in the third trimester.)

Rubella

Rubella, also known as German measles, is a virus which is now rare among vaccinated people. Congenital rubella syndrome is characterized by deafness, blindness, heart defects, and sometimes intellectual disability.  The incidence of congenital rubella syndrome in the US is less than 1 a year.[11]

To avoid rubella, get your vaccine before you get pregnant.  If your parents followed standard recommendations, you should have gotten this as part of the MMR vaccine when you were 12-15 months and 4-6 years old.

 

 

References

[1]BOPPANA, SURESH B., et al. “Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality.” The Pediatric infectious disease journal 11.2 (1992): 93-98.

[2]Nigro, Giovanni, et al. “Passive immunization during pregnancy for congenital cytomegalovirus infection.” New England Journal of Medicine 353.13 (2005): 1350-1362.

[3]Cook, A. J. C., et al. “Sources of toxoplasma infection in pregnant women: European multicentre case-control studyCommentary: Congenital toxoplasmosis—further thought for food.” Bmj 321.7254 (2000): 142-147.

[4]Desmonts, Georges, and Jacques Couvreur. “Congenital toxoplasmosis: a prospective study of 378 pregnancies.” New England Journal of Medicine290.20 (1974): 1110-1116.

[5]Carter AO, Frank JW. Congenital toxoplasmosis: epidemiologic features and control. CMAJ. 1986;135:618–23.

[6]Jones, J. E. F. F. R. E. Y., Adriana Lopez, and Marianna Wilson. “Congenital toxoplasmosis.” American family physician 67.10 (2003): 2131-2146.

[7]Serranti, Daniele, D. A. N. I. L. O. Buonsenso, and P. I. E. R. O. Valentini. “Congenital toxoplasmosis treatment.” Eur Rev Med Pharmacol Sci 15.2 (2011): 193-8.

[8]SYROCOT (Systematic Review on Congenital Toxoplasmosis) study group. “Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’ data.” The Lancet 369.9556 (2007): 115-122.

[9]McAuley, James, et al. “Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial.” Clinical Infectious Diseases 18.1 (1994): 38-72.

[10]McLeod, Rima, et al. “Outcome of treatment for congenital toxoplasmosis, 1981–2004: the national collaborative Chicago-based, congenital toxoplasmosis study.” Clinical Infectious Diseases 42.10 (2006): 1383-1394.

[11]http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html

[12]https://en.wikipedia.org/wiki/Neonatal_herpes_simplex

Why Does the US have High Infant Mortality?

A brief summary of this paper  by economists Alice Chen, Emily Oster, and Heidi Williams.

The US has about double the rate of infant mortality (defined as deaths in the first year of life) as other developed countries, such as Finland or Austria.  These are still fairly low rates — 6 in 1000 in the US  vs 3 in 1000 in Finland — but that still amounts to a difference of 15,000 extra US deaths a year, which is a tragedy.

So, what are we doing wrong?

First, we should ask how much of this problem is due to reporting differences. Is it just a statistical artifact?  The authors conclude that it’s not.  When you compare comparably-reported samples, the US infant mortality disadvantage shrinks but doesn’t disappear.

To drill down in what’s really causing the problem, we should distinguish between neonatal deaths (in the first week after birth) and non-neonatal deaths (among babies older than a week.)

The US has a small disadvantage in neonatal deaths, which is entirely explained by lower birth weight infants in the US compared to Europe.  Once you control for birth weight, the US is actually at an advantage relative to European countries.

Most of the US disadvantage, however, is for older infants.  67% of the geographic variation in infant mortality comes from non-neonatal deaths. And most of that is concentrated in lower socioeconomic classes.  Among the lowest education group, the US has an excess infant mortality of 1.3 deaths per 1000 compared to Finland, and 1.8 compared to Austria; among children of college-educated parents, the US’s excess mortality is only 0.04 deaths per 1000 compared to Finland, and 0.27 compared to Austria.
Within the US, geographic patterns of infant mortality follow the same trend. Neonatal mortality is pretty constant from region to region and doesn’t depend much on socioeconomic class; postneonatal mortality varies with income.

So what’s killing poor American babies?

SIDS, or Sudden Infant Death Syndrome. It kills 0.699 US babies per 1000, compared to 0.226 in Finland and 0.185 in Austria.  SIDS is a catch-all term referring to infant deaths without known cause; we currently do not know the physiological cause of SIDS.

The top categories of infant mortality are

• congenital abnormalities and low birthweight complications
• SIDS
• respiratory problems
• accident
• assault
• “other”

In every category but the first (which mostly concerns neonatal mortality), the US has at least twice the death risk of Finland and Austria.

In other words, the largest share of the US’s excessive infant mortality has to do with something around a more unsafe home environment for babies born to poorer parents.  

(While we don’t know what SIDS is, and I’ll investigate it in more detail later, we know it correlates with having things in the baby’s sleeping environment that could suffocate it.)

The excess infant mortality for the US over other European countries shrinks with household income, and disappears altogether for households earning more than $60,000 a year.

What’s the practical takeaway?

1. If you’re an affluent American parent who wants to reduce risk to your baby, moving to Europe isn’t likely to help. You’re already outside the category that has elevated risk.
2. The biggest absolute risk to a baby’s life occurs during the first week of life (this is why we want to prevent birth defects, preterm births, low birth weight, and birth complications, all of which will be covered in detail later), and this does not vary that much with socioeconomic status or geography. If you’re an affluent parent you do want to pay attention to reducing your risk here.
3. In developed countries, most of what kills babies after the first week of life is probably something like “parenting mistakes” — accidents, assaults, and whatever SIDS is.  This is also something to pay attention to, but probably less of a priority for this blog’s readers, given that it varies quite dramatically with socioeconomic status.
4. If you were making policy (which is the perspective this paper was written from), the priorities are reversed. To reduce the US’s infant mortality rate, health policy should focus less on what happens during pregnancy and around birth, and more on what happens after the baby comes home from the hospital (making sure disadvantaged parents have better resources for taking care of new babies.)

More Teratogens!

We all love Miles Vorkosigan, but we don’t necessarily want to have kids like him. (Except for the wit, charm, and leadership ability, of course.)  Here’s how to avoid poisoning your fetus!

Teratogens are poisons that interfere with the development of the fetus.  They cause about 7% of congenital malformations; the rest are genetic or of unknown cause.  Teratogens are dangerous to a fetal organ during the period when that organ is developing, mostly within the first 10 weeks of pregnancy. These fall into three categories: chemicals, such as medications, alcohol, or environmental pollution; infections; and ionizing radiation.  In this post, I’ll focus on chemical teratogens.

Antifolate drugs.  Don’t get pregnant if you have cancer and are taking chemo. You’re looking at >10% chances of major fetal malformations and spontaneous abortion.[14]  A lot of  chemo drugs (aminopterin, methotrexate, pemetrexed) are folate antagonists, which means neural tube defects, cardiac malformations, and other problems.  Other antifolate drugs which are similarly dangerous in pregnancy include sulfasalazine (a rheumatoid arthritis drug), trimethoprim (an antimicrobial), and pyrimethamine (an anti-toxoplasmosis drug).[12]

High dose vitamin A or isotretinoin. Taking more than 10,000 IU of supplemental vitamin A is associated with 4.8x the risk of birth defects compared to taking less than 5000 IU.  The topical acne medication isotretinoin, which also consists of vitamin A, causes 25x the risk of birth defects.[15] Most pregnancies in women taking isotretinoin end in miscarriage or abortion.[16]

Anti-seizure medications.  As I mentioned before, these are really bad. Valproic acid elevates the risk of a variety of birth defects: 12.7x the risk of spina bifida, 2.5x the risk of heart malformation, etc.[9] Carbamazepine increases the risk of neural tube defects by 5x.[8] Topiramate causes 10x the risk of cleft palate.[10]  Trimethadione causes a “trimethadione syndrome” involving developmental delay.[11]  Folic acid antagonists such as phenytoin and sulfalazine were associated with a 2.8x risk of neural tube defects.[12] So what do you do if you are epileptic?  You probably can’t get your risk down to baseline no matter what, but you can choose your anti-seizure drugs to minimize risk. Valproate is the worst, and lamotrigine is the best; valproate is 5x as likely to cause birth defects as lamotrigine.[13]

Lead. Having lead in your water supply while pregnant (>10 ug/L) gives you a 2.87x risk of having a child with a neural tube defect. [4]  Another study found relative risk of all congenital malformations of 2.39-2.73 for lead-exposed mothers.[5]

Mercury.  Methylmercury poisoning is an established cause of birth defects; pollution from an acetaldehyde plant in Minamata, Japan led to an epidemic of cerebral-palsy-like symptoms among newborns in the 1950’s, which became known as congenital Minamata disease. [7] Above-median levels of mercury were associated with an 8x risk of neural tube defects in a Chinese population exposed to high levels of pollution from coal-burning.[6] Mercury is present in fish, particularly fish high on the food chain such as tuna.  The FDA recommends that pregnant women do not eat swordfish, and eat no more than two meals a week of fish in general.

Most recent studies fail to find an effect of lithium on the rate of birth defects, though it was identified as a teratogen in 1970’s retrospective studies that associated it with Ebstein’s anomaly, a rare cardiac defect.[1][2][3]

References

[1]Cohen, Lee S., et al. “A reevaluation of risk of in utero exposure to lithium.”Jama 271.2 (1994): 146-150.

[2]Jacobson, S. J., et al. “Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.” The Lancet 339.8792 (1992): 530-533.

[3]Warkany, Josef. “Teratogen update: lithium.” Teratology 38.6 (1988): 593-596.

[4]Bellinger, David C. “Teratogen update: lead and pregnancy.” Birth Defects Research Part A: Clinical and Molecular Teratology 73.6 (2005): 409-420.

[5]Needleman, Herbert L., et al. “The relationship between prenatal exposure to lead and congenital anomalies.” Jama 251.22 (1984): 2956-2959.

[6]Jin, Lei, et al. “Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population.”Reproductive toxicology 35 (2013): 25-31.

[7]Harada, Masazumi. “Congenital Minamata disease: intrauterine methylmercury poisoning.” Teratology 18.2 (1978): 285-288.

[8]Werler, Martha M., et al. “Use of antiepileptic medications in pregnancy in relation to risks of birth defects.” Annals of epidemiology 21.11 (2011): 842-850.

[9]Jentink, Janneke, et al. “Valproic acid monotherapy in pregnancy and major congenital malformations.” New England Journal of Medicine 362.23 (2010): 2185-2193.

[10]Margulis, Andrea V., et al. “Use of topiramate in pregnancy and risk of oral clefts.” American journal of obstetrics and gynecology 207.5 (2012): 405-e1.

[11]Lietman, Paul S., et al. “The fetal trimethadione syndrome.” The Journal of pediatrics 87.2 (1975): 280-284.

[12]Hernández-Díaz, Sonia, et al. “Neural tube defects in relation to use of folic acid antagonists during pregnancy.” American journal of epidemiology153.10 (2001): 961-968.

[13]Hernandez-Diaz, S., et al. “Comparative safety of antiepileptic drugs during pregnancy.” Neurology 78.21 (2012): 1692-1699.

[14]Zemlickis, Donna, et al. “Fetal outcome after in utero exposure to cancer chemotherapy.” Archives of internal medicine 152.3 (1992): 573-576.

[15]Rothman, Kenneth J., et al. “Teratogenicity of high vitamin A intake.” New England Journal of Medicine 333.21 (1995): 1369-1373.

[16]Leyden JJ, Del Rosso JQ, Baum EW (February 2014). “The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions”. J Clin Aesthet Dermatol 7 (2 Suppl): S3–S21.