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.

 

How To Avoid Birth Defects

Birth defects affect 1 in 33 newborns[11].  Severe neural tube defects, such as anencephaly and spina bifida, affect about 1 in 1000.

Anti-Epileptic Drugs. Maternal valproic acid use while pregnant was associated with a 9.8x risk of neural tube defects, and carbamazepine use during pregnancy was associated with a 5x risk of neural tube defects.

Alcohol. This could be a very big topic, but for example, one study found that mothers who drank heavily had a 4.6x risk of birth defects.[8]  Fetal alcohol syndrome is usually found in children of women who had four or more drinks per day. [9]

Folic Acid Deficiency. In a randomized study of 1875 women who had a previous pregnancy with a birth defect, women who were assigned placebo had a 3.6x risk of neural tube defects compared to those who were given a folic acid supplement.[3]  The prevalence of neural tube defects declined 19% after the food supply was fortified with folic acid in the 90’s.[4]  In particular, it’s important to have enough folic acid around the time of conception.

Diabetes. Having diabetes before pregnancy increases the rate of birth defects to 3.5-5.3x baseline.[1] These are severe birth defects, like spina bifida, hydrocephaly, limb deficiency, renal agenesis — where whole organs are missing or nonfunctional.  Pregestational diabetes was associated with about 50% of the birth defect categories analyzed.

Low B12. Women with low vitamin B12 levels during pregnancy had a 2.9x risk of neural tube defects.[10]

Low Choline. Women in the bottom decile of choline levels had a 2.4x risk of neural tube defects compared to baseline, and women in the top decile had an 0.14x risk of neural tube defects, in a prospective study of more than 180,000 pregnant women.

Opioid Use. Maternal opioid use during pregnancy was associated with a 2.0x -2.7x risk of birth defects such as spina bifida or cardiac septal defects, in the large case-control National Birth Defects Prevention study.[2]

Maternal Hyperthermia. Most studies in this meta-analysis looked at fever, but heated blankets, hot tubs, and saunas were also included; women who were exposed to high body temperatures while pregnant had a 2.0x risk of having fetuses with neural tube defects.[5] A prospective study found that only high fevers during the critical period for neural tube closure around the first month of pregnancy, but not at other times during pregnancy, had higher risk of neural tube defects [6], suggesting that maternal fever is a teratogen.

Maternal smoking has a significant but smaller effect (1.0-1.2x risk) on birth defects.[7]

I’ll leave till later a more detailed discussion of medications and environmental contaminants that can cause birth defects, because there are a lot of them.

The basic bottom lines seem to be:

  • Take folic acid. No, really, it makes a big difference.  Take it as soon as you start trying for a baby.
  • Maybe also take B12 and choline.
  • Don’t drink.
  • Avoid diabetes.
  • Avoid opioids. Don’t take valproic acid or carbamazapine.
  • Get your flu shot, and generally try to stay away from febrile infections.

References

[1]Correa, Adolfo, et al. “Diabetes mellitus and birth defects.” American journal of obstetrics and gynecology 199.3 (2008): 237-e1.

[2]Broussard, Cheryl S., et al. “Maternal treatment with opioid analgesics and risk for birth defects.” American journal of obstetrics and gynecology 204.4 (2011): 314-e1.

[3]MRC Vitamin Study Research Group. “Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.” The lancet 338.8760 (1991): 131-137.

[4]Honein, Margaret A., et al. “Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.” Jama 285.23 (2001): 2981-2986.

[5]Moretti, Myla E., et al. “Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis.” Epidemiology16.2 (2005): 216-219.

[6]Chambers, Christina D., et al. “Maternal fever and birth outcome: a prospective study.” Teratology 58.6 (1998): 251-257.

[7]Hackshaw, Allan, Charles Rodeck, and Sadie Boniface. “Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls.” Human reproduction update(2011): dmr022.

[8]O’Leary, Colleen M., et al. “Prenatal alcohol exposure and risk of birth defects.” Pediatrics 126.4 (2010): e843-e850.

[9]Yaffe, Sumner J. (2011). Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9 ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 527

[10]Ray, Joel G., et al. “Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population.” Epidemiology 18.3 (2007): 362-366.

[11]http://www.cdc.gov/ncbddd/birthdefects/data.html

How to Avoid Miscarriage

Miscarriage is really common. About 10-20% of known conceptions miscarry; the real rate is probably higher, perhaps as high as 50%, as many women miscarry without even knowing they’re pregnant, usually in the first three weeks of pregnancy.  The most common causes of miscarriage have to do with mutations in the fetus, especially chromosomal abnormalities. So reducing the risk of miscarriage is an overlapping project with increasing fertility, and also with increasing the chance of having a healthy baby without birth defects. All of these things roughly correlate.

So, what increases the risk of miscarriage?

  1. Antiphospholipid syndrome.  This is an autoimmune disorder affecting 1-5% of the healthy population, in which the body attacks certain proteins binding to cell membranes, causing a high risk of blood clots.This causes miscarriage in 90% of pregnancies. (Blood clots are Bad News in pregnancy; in general, anything associated with excessive clotting increases the risk of the most common Bad Things like miscarriage, low-birth-weight fetuses, and preeclampsia.)   Antiphospholipid syndrome is more common in people with lupus (15-25% of SLE patients also have APS) and it has a strong genetic component. APS can be treated with blood thinners such as aspirin, warfarin, and/or heparin. These triple the probability of conception in women with APS and a history of miscarriage.[10]
  2. Maternal and paternal age.  The risk really starts to go up around age 35 or so; e.g. couples where both the mother and father are age 35-40 have a risk of miscarriage 3.87x baseline.[2]
  3. Maternal folate deficiency.  High homocysteine levels and low folate levels were associated with a 3.6x and 2.1x increase, respectively, in the risk of miscarriage.[3] These are signs of a folic acid deficiency and can be prevented by taking a folic acid supplement.  MTHFR polymorphisms (C677T and A1298C) are associated with a 14.2x risk of miscarriage[4]; MTHFR is the enzyme that breaks down folate.  That is, if you can’t process folate properly, you’re also at risk of miscarriage. This suggests (though there’s not direct evidence of this) that pregnant women with MTHFR mutations should be taking L-Methylfolate instead of regular folic acid, since L-Methylfolate is one step downstream in metabolism from folate; if you can’t methylate folate yourself, it may make sense to consume it “pre-methylated.”
  4. Excessive maternal exercise.  Heavy exercise during pregnancy increases risk of miscarriage. Women who exercised >300 min/week (e.g. a daily six-mile run) while pregnant had a risk of miscarriage 3.29x as high as women who didn’t exercise at all.[5]
  5. Maternal prothrombic genes.  Mutations in maternal blood clotting genes (FVL or FIIG20210A) cause a 3.19x increase[6] in the risk of miscarriage in white women. (These mutations are rare in nonwhite women.)  This is part of the same pattern of “blood clots are bad for you.”  In particular, prothrombotic genes are a risk factor for recurrent miscarriages.

In terms of what you can do to prevent miscarriages, the big ones are:

  • have kids by your mid-thirties
  • take your folate supplements (or perhaps L-methylfolate if you’re an MTHFR mutant)
  • don’t overdo the high-impact exercise

Smoking, drinking, and caffeine all increase the risk of miscarriage, but you don’t get big effect sizes until you’re looking at really high consumption; you have to drink 8 cups of coffee a day to get up to a 1.84x risk of miscarriage [7], smoke 20 cigarettes a day to get up to 1.6x risk, and drink 21+ drinks a week to get up to 1.82x risk.[8]  (Emily Oster, in Expecting Better, notes that there’s a confounding effect for coffee: pregnant women who are nauseous are less likely to miscarry, and nausea makes coffee less appealing.)

There’s a dose-response relationship for all these substances, of course, and alcohol and tobacco are unhealthy for lots of additional reasons.  (As we’ll see later, smoking increases the risk of birth complications.)

Likewise in the smallish effect size category is being underweight; maternal BMI < 18.5 causes a 1.72x increase in miscarriage rates.[9]

So, arguably, women trying to avoid miscarriage should also:

  • avoid caffeine, tobacco, and alcohol
  • get up to a healthy weight

Preemptively taking aspirin if you don’t have APS does not reduce the risk of miscarriage.[11][12] A fair number of the genetic causes of recurrent miscarriage seem to be genuinely outside your control, at least for now.

References

[1]Gezer, Sefer. “Antiphospholipid syndrome.” Disease-a-month 49.12 (2003): 696-741.

[2]de La Rochebrochard, Elise, and Patrick Thonneau. “Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study.” Human Reproduction 17.6 (2002): 1649-1656.

[3]Nelen, Willianne LDM, et al. “Homocysteine and folate levels as risk factors for recurrent early pregnancy loss.” Obstetrics & Gynecology 95.4 (2000): 519-524.

[4]Rymol, Lars, et al. “Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos.” European Journal of Human Genetics 10 (2002): 113-118.

[5]Madsen, M., et al. “Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort.” BJOG: An International Journal of Obstetrics & Gynaecology 114.11 (2007): 1419-1426.

[6]Lissalde‐Lavigne, G., et al. “IN FOCUS: Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case–control ‘NOHA first’study.” Journal of Thrombosis and Haemostasis 3.10 (2005): 2178-2184.

[7]Feodor Nilsson, S., et al. “Risk factors for miscarriage from a prevention perspective: a nationwide follow‐up study.” BJOG: An International Journal of Obstetrics & Gynaecology 121.11 (2014): 1375-1385.

[8]Armstrong, Ben G., Alison D. McDonald, and Margaret Sloan. “Cigarette, alcohol, and coffee consumption and spontaneous abortion.” American Journal of Public Health 82.1 (1992): 85-87.

[9]Maconochie, N., et al. “Risk factors for first trimester miscarriage—results from a UK‐population‐based case–control study.” BJOG: An International Journal of Obstetrics & Gynaecology 114.2 (2007): 170-186.

[10]Rai, R., et al. “Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).” Bmj 314.7076 (1997): 253.

[11]Rai, Raj, et al. “Recurrent miscarriage—an aspirin a day?.” Human reproduction 15.10 (2000): 2220-2223.

[12]Nisio, M., L. W. Peters, and S. Middeldorp. “Aspirin or anticoagulants for the treatment of recurrent miscarriage in women without antiphospholipid syndrome.” The Cochrane Library (2005).