Background and rationale for preconception/interconception care

The concept of preconception counseling can be traced to ancient and biblical writings. In writing by Plutarch, “….all the care that was possible; he ordered the maidens to exercise themselves with wrestling, running, throwing the quoit, and casting the dart, to the end that the fruit they conceived might, in strong and healthy bodies, take firmer root and find better growth, and withal that they, with this greater vigor, might be the more able to undergo the pains of child‐bearing” [3]. In a report by Jones and Smith published six months after their initial report on fetal alcohol syndrome (FAS), they presented an “historical review” containing several anecdotes implying that the ancient Greeks and Romans had a rudimentary awareness of the association between maternal alcoholism and abnormal development [4]. One of these anecdotes was an alleged Carthaginian law forbidding bridal couples to drink wine on their wedding night so as to avoid the conception of defective children.

It is estimated that approximately 50% of all pregnancies in the United States are unintended or unplanned [5]. Most births occur during the active reproductive years. In fact, by age 25, 50% of women have had at least one birth and by age 44, >85% of women have given birth at least once. Yet while most women in the reproductive years have seen a health care provider within the prior year preconception counseling may not necessarily be included as a component of that visit [6]. In a Kaiser Family Foundation report in 2005 which surveyed 2766 women >18 years of age, only 55% indicated that they talked to a provider about diet, exercise or nutrition in the past three years, 43% had talked about calcium intake and only 33% and 20% has talked about smoking and alcohol use, respectively [7]. In the US adult population an estimated 7.8% have been diagnosed with diabetes [8], 25% with hypertension [9] and 33% with obesity as defined by a BMI > 30 [10]. For reproductive age women these are conditions that lend themselves to evidenced based interventions and strategies which lead to improved pregnancy outcome and infant health.

The CDC Preconception Health and Health Care Recommendations derived from the first national summit were as follows [2]:

1. Each woman, man, and couple should be encouraged to have a reproductive life plan.
   
2. Increase public awareness of the importance of preconception health behaviors and services by using information that is relevant across various age groups, literacy levels, and cultural/ethnic groups.
   
3. As a part of primary care visits, provide risk assessment and educational and health promotion counseling to all women of childbearing age to reduce reproductive risks and improve pregnancy outcome.
   
4. Increase the proportion of women who receive interventions as follow‐up to preconception risk screening, focusing on high priority interventions (i.e. those with evidence of effectiveness and greatest potential impact).
   
5. Use the interconception period to provide additional intensive interventions to women who have had a previous pregnancy that ended in an adverse outcome (i.e. infant death, fetal losses, birth defects, low birth weight, or preterm birth).
   
6. Offer, as a component of maternity care, one prepregnancy visit for couples and persons planning a pregnancy.
   
7. Increase public and private health insurance coverage for women with low incomes to improve access to preventive women’s health and preconception and interconception care.
   
8. Integrate components of preconception health into existing local public health and related programs, including an emphasis on interconception interventions for women with previous adverse outcomes.
   
9. Increase the evidence base and promote the use of the evidence to improve preconception health.
   
10. Maximize public health surveillance.

The evidence for folic acid

There is strong evidence for daily consumption of adequate amounts of folic acid prior to conception and the first trimester of pregnancy in reducing the risk for NTDs. Folate is a water soluble vitamin essential for synthesis of thymidylate to thymidine which is needed for DNA synthesis. Folic acid is the synthetic form of folate which must be reduced to the biologically active form L‐5‐methyl – THF [11].

Supplementation with folate to prevent NTD was first shown in 1980 by Smithells and colleagues, who gave a multivitamin containing 360 mcg per daily to women who had given birth to a prior child with a NTD [12]. While the expected recurrence risk for offspring in this group of women was expected to be approximately 5%, the actual recurrence for NTD was only 0.6% for those women who received the supplemental folate [12].

In 1992 the US Public Health Service issued a recommendation that all females of childbearing age consume 400 mcg of folic acid daily [13]. In 1998 the Institute of Medicine confirmed that reproductive age women capable of pregnancy consume 400 mcg of folic acid daily from supplements or fortified foods or both in addition to natural folate received from diet [14]. In the US mandatory fortification of grain products began in January 1998 and this was followed by a drop in the prevalence of spina bifida by 22.9% [15]. Fortification of grain products increase folate levels by 100 mcg per day however this is well short of the 400 mcg recommended for reproductive age women. In addition, although the recommendation for folate supplementation for reproductive age women was confirmed by the IOM subsequent assessment showed that only 37% of non‐pregnant women age 18–45 years were in compliance with this recommendation by taking a daily vitamin containing folic acid [16]. These recommendations were reinforced by the US Preventive Service Task Force in 2009 which issued a Grade A recommendation that counseling be provided to reproductive age women encouraging folic acid consumption prior to pregnancy [17].

Normal maternal serum folate levels of >7 ng ml⁻¹ ensure robust cell division for the embryo and the fetus. Adequate levels of folate correlate with the lowest prevalence of NTDs which include anencephaly, spina bifida and encephalocele [18]. The daily preconception consumption of 400 mcg of folic acid reduces the risk for NTD by 50–80% [19]. Closure of the anterior and posterior neuropore forming the neural tube is complete by 28 days’ of embryogenesis or 42 days conception based on last normal menses [20].

Several notable trials point to the effectiveness of folic acid supplementation in the reduction of NTDs. A randomized trial conducted by the Medical Research Group Council Vitamin Study Research Group demonstrated reduction in the recurrence risk for NTDs of 72% for women receiving a preconception supplement of 4000 mcg per day of folic acid [21]. Another important randomized trial in women with no prior history of a previous offspring with NTD was conducted by Czeizel and Dudas in Hungary. For those women who received preconception folic acid, NTD occurred in 0 of 2471 women supplemented with 800 mcg per day of folic acid compared to 6 of 2391 women who did not take folic acid [22]. In a population based study in China, women in various geographical regions were given 400 mcg per day of folic acid while others were not given a supplement. For those receiving supplemental folic acid the reduction in the occurrence of NTDs by 79% for a rate of 0.65% in high incidence regions compared to 41% in low incidence regions with a rate of 0.08% [23]. Other studies further suggest that perhaps not all NTDs are folate sensitive or folate resistant and that may be up 25% of NTDs [24].

Folate is potential beneficial for other congenital defects however the evidence is less strong. There is reasonable evidence that supplementation with folate reduces the risk for congenital heart defects [25]. In a study by Czeizel in women supplemented with 800 mcg of folic acid per day there was reduced occurrence of conotruncal cardiac anomalies and urinary tract anomalies such as renal agenesis, cystic kidney, and ureteropelvic junction defects [26]. The cardiac defect risk reduction was 52% or a relative risk of 0.58 compared to controls [26]. A California population based case control study showed a 30% reduction in conotruncal cardiac defects for women using a vitamin with folic acid in early pregnancy [27].

The Evidence for chronic diseases

The incidence of chronic medical disorders such as diabetes, hypertension, and obesity has steadily increased over the past several decades in reproductive age women. These conditions not only complicate pregnancy health and outcome but also long‐term adult health.

It has been shown that preconception control of pregestational diabetes lowers the risk for congenital anomalies especially congenital heart and neural tube. In 2010, there were approximately 1.9 million new cases of diabetes diagnosed in adults age 20 years or older. Diabetes affects 25.8 million adults in the United States [8]. Of those 20 and older with diabetes, 12.6 million are women. National survey data from 2007 to 2009 indicated that diabetes affected 7.1% of non‐Hispanic whites, 8.4% of Asian Americans, 11.8% of Hispanics, and 12.6% of non‐Hispanic blacks [8].

Preconception counseling for women with diabetes continues to be suboptimal despite the evidence that suggest the importance of adequate control of diabetes in preparation for pregnancy to the benefit of the fetus and the mother. A population based study from North of England investigated the association of preconception counseling with markers of care in women with pregestational diabetes. Preconception counseling was associated with better glycemic control three months preconception (Odd Ratio (OR) 1.91, 95% CI 1.10–3.04) and in the first trimester (OR 2.05, 95% CI 1.39–3.03) and a higher preconception folic acid intake (4.88, 95% CI 3.26–7.30). Adverse pregnancy outcome was less likely in the group of women receiving preconception counseling, 6% compared to 10% [28]. In other trials, proactive counseling in teen girls [29] and women [30] with Type 1 diabetes showed sustained improvement and knowledge about planned pregnancy. These studies are relevant in view of the fact than approximately one half of pregnancies including pregnancies in teens with Type 1 diabetes are unplanned.

The risk for structural congenital abnormalities in women with pregestational diabetes is increased four to eightfold over the background risk for anomalies of 1–2% for the general population [31]. The type of abnormalities associated with diabetes are considered multifactorial in origin and include abnormalities of the central nervous system (CNS) such as NTDs, cardiovascular system as well as genitourinary and limb defects. In 1981, Miller et al. compared the frequency of congenital abnormalities based on hemoglobin A1c (HgbA1c) and determined that for those diabetes with a HgbA1c less than 8.5% the rate of abnormalities was 3.4% compared to 22.4% for those with a HgbA1c above 8.5% [32]. Similarly, Lucas et al. found that the risk for congenital abnormalities was nil with a HgbA1c less than 7%, 14% for those with a HgbA1c between 7.2% and 9.1%, 23% with a HbA1c between 9.2% and 11.1%, and 25% with a HbA1c greater than 11.2% [33]. Hemoglobin A1c reflects the level of hyperglycemia over the past several weeks in the red cells. During embryogenesis, hyperglycemia produces a teratogenic effect through disturbance in the metabolism of inositol, prostaglandins, and reactive oxygen species [34]. This leads to excessive oxygen radicals acting upon susceptible fetal tissues which inhibit prostacyclin [35]. Depression of prostacyclin leads to overproduction of thromboxanes and other prostaglandins which lead to disruption of vascularization of developing embryonic tissues and structural defects.

Euglycemia and normal HbA1c levels for several weeks prior to conception and during early embryogenesis could potentially prevent >100 000 pregnancy losses and birth defects annually in the United States [36]. Preconception care aimed at normalizing the HgBA1c has proven to be beneficial in this regard [37].

Preconception evaluation in pregestational diabetes should focus on tight glycemic control with fasting glucose levels below 100 mg/dl and postprandial glucose levels no greater than 120–140 mg mg/dl. This level of euglycemia should result in normalizing to HbA1c to <6.5%. Emphasis should be placed on following an appropriately diet, focused glucose monitoring with defined goals, exercise, and weight loss prior to conception. Hypoglycemic medications, insulin or oral, should be adjusted to a regimen consistent with the goals of achieving euglycemia along with the life‐style modifications. Insulin management has been the mainstay of management for poorly controlled diabetes but recent years have seen a rise in the use of the oral agents, glucophage, and glyburide. Glyburide has a favorable safety profile, a Pregnancy Category B classification and crosses the placenta in minimal amounts. Glucophage is also a Pregnancy Category B drug and women on this medication for preconception control of diabetes or insulin resistance can be safely continued throughout pregnancy. Glucophage increases insulin sensitivity and is commonly used for women with polycystic ovary syndrome (PCOS) and insulin resistance to improve ovulation for those women undergoing ovulation induction. For women with Type I diabetes subject to unstable blood sugars consideration should be given to preconception management with insulin pump in the motivated patient. In a study comparing those on insulin pump versus conventional insulin injections HbA1c levels were not significantly different, 7.5 vs. 7.6, respectively [38]. However, HbA1c during organogenesis was better (6.9% vs. 8.5%) and neither group experienced pregnancy loss or a major congenital malformation [38, 39].

Women with diabetes contemplating pregnancy should also be screened for vascular, renal, and ophthalmologic complications prior to pregnancy. For example, women with proliferative retinopathy should be treated with laser prior to pregnancy to prevent further ophthalmologic deterioration during pregnancy. Abnormal renal function increases the risk for hypertensive complications during pregnancy. Women with Type I diabetes should be screened with thyroid stimulating hormone (TSH) for hypothyroidism which occurs in 40% of young women with Type I diabetes.

Chronic hypertension should be controlled prior to pregnancy with the appropriate medications. The goal for blood pressure (BP) control is for the systolic BP to be less than 140 mmHg and the diastolic BP less than 90 mmHg. Chronic hypertension is classified as mild (systolic BP 140–159 mmHg or diastolic BP 90–109 mmHg) or as severe (systolic BP of 160 mmHg or diastolic BP 110 mmHg or greater). The maternal complications associated with chronic hypertension include worsening hypertension and superimposed preeclampsia which predisposes the women to cerebral vascular accident (CVA). The fetal risk includes fetal growth restriction, placental abruption, preterm delivery as a result of worsening maternal condition, cesarean delivery, and perinatal death.

Renal and cardiovascular function should be evaluated prior to pregnancy for end organ damage and a plan of management outlined with the patient. In a population study of 30 000 pregnant women with chronic hypertension maternal mortality was significantly higher compared to normotensive women (OR, 4.8; 95% CI, 3.1–7.6), and a higher risk demonstrated for CVAs (OR, 5.3; 95% CI, 3.7–7.5), pulmonary edema (OR, 5.2; 95% CI 3.9–6.7), and renal failure (OR, 6.0; 95% CI, 4.4–8.1) [40]. The risk for cesarean delivery even for women with uncomplicated chronic hypertension is increased threefold over normotensive women (OR, 2.7; 95% CI, 2.4–3.0) and the risk for postpartum hemorrhage increased twofold (OR, 2.2; 95% CI, 1.4–3.7) [41]. With regard to the fetus the risk for small for gestational age (SGA) infants is increased in women with chronic hypertension [42]. Perinatal mortality is greater than the general population [43]. In another study the risk for stillbirth for women with chronic hypertension was twofold increased (OR 2.04, 95% CI, 1.48–2.82), as was the risk for neonatal death (OR, 2.5, 95% CI, 1.69–3.74) [44].

The preconception evaluation of women with chronic hypertension should include a serum creatinine and urinary proteinuria along with a protein/creatinine ratio or 24‐hour urine for protein and creatinine clearance to provide a baseline assessment of renal function. For those with severe hypertension a baseline electrocardiogram (ECG) and ophthalmological exam further defines cardiovascular risk. The risk for cardiomegaly, ischemic heart disease, retinopathy, and renal disease is greater for women with long standing hypertension and especially for those women of advanced reproductive age [45]. For example women with advanced reproductive age, severe hypertension, and a family history of coronary artery disease are at greater risk for myocardial infarction with pregnancy [46]. Women over 40 have a 30‐fold higher risk for myocardial infarction compared with pregnancy women less than age 20 years [46]. For these women an exercise echocardiogram may be indicated in addition to an ECG to evaluate cardiovascular reserve. Acute myocardial events have been reported in older women who achieved pregnancy after in vitro fertilization [47].

Antihypertensive therapy should be adjusted by maximizing with a single medication to achieve the desired goals for BP control. Women on angiotensin‐converting enzyme (ACE) inhibitors should discontinue this medication prior to pregnancy because of the known teratogenicity associated with the drug. ACE inhibitors have been associated with fetal renal abnormalities, dysmorphia, and stillbirth [48, 49]. Although fetal renal function is not significant until the end of the first trimester, ACE inhibitors used in the first trimester have been associated with major fetal anomalies of the cardiovascular (Risk Ratio (RR), 3.72, 95% CI, 1.89–7.30) and CNS (RR, 4.39, 95% CI, 1.37–14.0) [50]. Currently recommended antihypertensive medications appropriate for use during pregnancy include labetalol, a combined alpha‐blocker and beta‐blocker which have been extensively studied. Studies indicate that oral beta blockers compared with placebo in women with mild to moderate hypertension decreased the progression to severe hypertension and need for additional medications. However, beta blockers were associated with a higher risk for SGA infants (RR, 1.36; 95% CI, 1.02–1.82) [51]

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