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Ó 2010 Wiley-Liss, Inc.

Birth Defects Research (Part A) 88:791 803 (2010)

Review Article

Preconception Care for Women with Diabetes and


Prevention of Major Congenital Malformations
John L. Kitzmiller,1* Robert Wallerstein,2 Adolfo Correa,3 and Saiyin Kwan4
1
Diabetes and Pregnancy Program, Division of Maternal-Fetal Medicine, Santa Clara Valley Health Center, San Jose, California
2
South Bay Regional Genetics Program, Santa Clara Valley Medical Center, San Jose, California
3
Division of Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia
4
Diabetes and Pregnancy Program, Santa Clara Valley Health Center, San Jose, California
Received 27 April 2010; Revised 12 July 2010; Accepted 25 July 2010

This article provides an overview of the rationale for diabetes preconception care interventions for women
with diabetes and the efficacy in reducing the excess occurrence of major congenital malformations. The prob-
lems with broad use of individualized preconception care are considered. In addition, suggestions are made
for the implementation of more comprehensive interventions in the community and usual diabetes care set-
tings, to address the multiple ongoing challenges in the prevention of structural anomalies associated with
preexisting diabetes. Based on the published evidence, successful preconception care can be considered to
include: achievement of individualized target standardized glycosylated hemoglobin levels, adequate nutri-
tion, and minimizing hypoglycemia before and after discontinuing effective contraception and during the
transition to early prenatal care. Birth Defects Research (Part A) 88:791–803, 2010. Ó 2010 Wiley-Liss, Inc.

Key words: diabetes; birth defects; preconception care; nonsyndromic congenital malformations; diabetes-
related teratogenesis

INTRODUCTION or psychological handicap. In this review, we will use


congenital anomaly or malformation to refer to major struc-
The fact that pregnancies complicated by preexisting tural defects, without recognized genetic disorders.
maternal type 1 diabetes (DM1), which results from pan- Almost any organ can be involved in malformations
creatic islet beta-cell destruction and usually leads to associated with maternal diabetes, including the cardiac
absolute insulin deficiency, and type 2 diabetes (DM2), and outflow tract, central nervous system, and the cranio-
which results from a progressive insulin secretory defect facial, gastrointestinal, musculoskeletal, and urogenital
on the background of insulin resistance (American Diabe- systems (Ewart-Toland et al., 2000; Moore et al., 2000;
tes Association, 2010), have an approximately twofold to Loffredo et al., 2001; Spilson et al., 2001, Wang et al.,
fourfold increased risk of nonsyndromic major congenital 2002; Wren et al., 2003; Nielsen et al., 2005, Frias et al.,
malformations is well established (Kitzmiller et al., 1996; 2007; Lisowski et al., 2010). The types of anomalies seen
also see Sheffield et al., 2002; Penney et al., 2003; Sharpe are similar in infants of women with either DM1 or DM2
et al., 2005; Allen et al., 2007; Correa et al., 2008; Shand (Towner et al., 1995; Schaefer-Graf et al., 2000; Farrell
et al., 2008; Carmody et al., 2009, Corrigan et al., 2009;
Banhidy et al., 2010). The published literature focusing
on diabetes generally uses the terms congenital anomalies The findings and conclusions in this report are those of the authors and do
or congenital malformations, excluding those associated not necessarily represent the official position of the Centers for Disease Con-
with recognized chromosome abnormalities or single- trol and Prevention.
gene disorders to refer to structural abnormalities present *Correspondence to: John L. Kitzmiller, 750 S. Bascom, Suite 340, San Jose,
CA 95128. E-mail: John.Kitzmiller@hhs.sccgov.org
at birth. In this literature, major congenital anomalies Published online 1 October 2010 in Wiley Online Library (wileyonlinelibrary.
have been considered to be life limiting, requiring sur- com).
gery or medical therapy, or causing substantial physical DOI: 10.1002/bdra.20734

Birth Defects Research (Part A): Clinical and Molecular Teratology 88:791–803 (2010)
792 KITZMILLER ET AL.
et al., 2002, Dunne et al., 2003; Macintosh et al., 2006). et al., 2005; Roland et al., 2005; Gonzalez-Gonzalez et al.,
Multiple malformations in the same baby, without chro- 2008; Reece, 2008; Balsells et al., 2009; Inkster et al., 2009).
mosomal defects, are characteristic of maternal diabetes The data are inadequate to determine whether the weak
of either type (Towner et al., 1995; Schaefer-Graf et al., association, when present, is independent of adequate
2000; Aberg et al., 2001, Vaarasmaki et al., 2002). Minor glycemic control. The general effects of maternal obesity
congenital anomalies also appear to be increased in on birth defects are considered elsewhere in this issue. It
infants born to mothers with diabetes, but this review is unclear whether an excess occurrence of major malfor-
focuses on major congenital malformations. mations is associated with GDM identified in the first tri-
The question of an association of genetic defects with mester (standardized glycosylated hemoglobin <6.5 or
major congenital malformations in infants of diabetic fasting plasma glucose <126 mg/dl [<7 mM] or 2-hr
mothers (IDM) needs more study. There is no evidence plasma glucose <200 mg/dl [<11.1 mM]; American
that DM1 or DM2 increases the risk for Down syndrome Diabetes Association, 2010; International Association of
(Henriques et al., 1991). The advent of chromosome Diabetes and Pregnancy Study Groups Consensus
microarray (comparative genomic hybridization) to iden- Panel et al., 2010) and/or obesity (Moore et al., 2000;
tify genetic imbalances allows for improved evaluation Garcia-Patterson et al., 2004; Martinez-Frias et al., 2005;
and identification of genetic etiology in newborns with Biggio et al., 2010), because of the challenge of excluding
birth defects, compared with standard chromosome anal- women with previously undiagnosed DM2 from
ysis (Lu et al., 2008). These tools should be applied to analyses.
IDM. Other tools to identify epigenetic modifications of
gene expression also need study in pregnancies compli- Rationale for Preconception Care for
cated by diabetes, as the modifications might influence Women with Diabetes
embryopathy (Martinez-Frias, 2010).
The prevalence of DM2 among women of childbearing The need to consider intensified preconception care for
age, before and during pregnancy, is on the rise globally women with diabetes is based on the knowledge that di-
(Feig and Palda, 2002; Cheung et al., 2005; Clausen et al., abetic embryopathy is induced early in pregnancy (Mills
2005; deValk et al., 2006; Bell et al., 2008; Lawrence et al., et al., 1979), perhaps even in the preovulatory oocyte or
2008; Ma and Chan, 2009; McIntyre, 2009 et al; Albrecht preimplantation embryo (Jungheim and Moley, 2008),
et al., 2010). Historically, the focus of interventions to and that clinical hyperglycemia is associated with con-
reduce birth defects in IDM was on DM1 (Kitzmiller genital malformations. We also consider whether other
et al., 1996). However, there is a risk of major congenital patient characteristics confound the interpretation or con-
malformations in infants of women with DM2 as well tribute to the relationship between better glycemic con-
(Verheijen et al., 2005; Galindo et al., 2006; Hillman et al., trol and fewer birth defects.
2006; Balsells et al., 2009). In recent multicenter or popu- Hyperglycemia and congenital malformations. To test
lation-based studies with large cohorts that were per- for an association between malformation risk and uncon-
formed internationally and reported outcomes for women trolled diabetes, investigators sought to use a retrospec-
with DM1 and DM2 separately, the frequency of major tive indicator of hyperglycemia (glycosylated hemoglo-
congenital malformations ranged from 2.9% to 7.5% for bin) as women with diabetes registered for prenatal care
DM1 and 2.1% to 12.3% for DM2 (Farrell et al., 2002; (Miller et al., 1981; Ylinen et al., 1984; Miodovnik et al.,
Boulot et al., 2003; Clausen et al., 2005; Roland et al., 1988). In these and almost all of many subsequent obser-
2005; Macintosh et al., 2006; Bell et al., 2008; Gonzalez- vational studies, there was a strong, positive relationship
Gonzalez et al., 2008; Lapolla et al., 2008). Compared between increasing glycohemoglobin levels and increas-
with background frequency of malformations, the fre- ing risk of major malformations (Kitzmiller et al., 1996;
quency of congenital anomalies is also increased in Inkster et al., 2006; Allen et al., 2007; Guerin et al., 2007;
women with severe hyperglycemia first recognized dur- Lisowski et al., 2010). Two investigations found no asso-
ing pregnancy (Schaefer-Graf et al., 2000; Farrell et al., ciation between maternal glycohemoglobin measured by
2002). These cases met the new criteria for probable DM1 20 weeks of pregnancy and major malformations
or DM2 newly diagnosed in pregnancy (American Diabe- (Wender-Ozegowska et al., 2005; Gonzalez-Gonzalez
tes Association, 2010; International Association of Diabe- et al., 2008). The only ‘negative’ study with data near the
tes and Pregnancy Study Groups Consensus Panel, 2010), onset of pregnancy was the multicenter prospective Dia-
as opposed to gestational diabetes mellitus (GDM), which betes in Early Pregnancy study of 347 women with dia-
is milder glucose intolerance diagnosed during preg- betes who enrolled within 21 days of conception and 279
nancy and is associated with fetal macrosomia and other women with diabetes who entered later (Mills et al.,
metabolic disorders in infants. 1988a). Malformation rates were lower in the early treat-
DM2 in pregnancy has unique aspects, including dif- ment group than in the late entry group, but malforma-
ferent management options, the danger of diabetes unrec- tion risk was not related to the early glycohemoglobin
ognized or untreated before pregnancy (Cundy et al., technique that was used. The authors concluded ‘‘that
2007), poor nutrition, and the frequent comorbidities of more sensitive measures are needed to identify the tera-
advanced maternal age, obesity, lipid peroxidation, and togenic mechanisms, or that not all malformations can be
low-grade inflammation. Minority ethnic groups in a prevented by good glycemic control.’’ However, the early
given diabetic population seem to have the greatest risk pregnancy result ‘‘justifies the attempt to achieve good
of malformations (Dunne, 2000, 2003; Farrell, 2002; metabolic control around the time of conception’’ (Mills
Verheijen, 2005; Macintosh et al., 2006). et al., 1988a).
There is inconsistent evidence for an increased risk of Many nonstandardized glycohemoglobin or hemoglo-
major malformations in association with obesity in bin A1C assays were used in the initial investigations,
women with DM2 (Schaefer-Graf et al., 2000; Clausen including immunologic, turbidometric, and various chro-

Birth Defects Research (Part A) 88:791–803 (2010)


DIABETES, BIRTH DEFECTS, AND PRECONCEPTION CARE 793
matographic methods. With the advent of the Diabetes standardized glycated protein values were associated
Control and Complications Trial (DCCT) trial, HPLC with an excess fetal loss rate (33%) before 20 weeks’ ges-
emerged as the reference A1C assay (Rohlfing et al., tation (Jovanovic et al., 2005).
2002), and efforts began to standardize the assay in labo- What about other metabolic substrates and ligands
ratories around the world (Sachs, 2000; Manley et al., that can be abnormal in diabetes and might affect pre-
2004). The term A1C is used to denote the standardized implantation and postimplantation embryos, the yolk
measurement (American Diabetes Association, 2010). sac, or differentiating trophoblast cells? Examples might
Multiple international organizations (Hoelzel et al., 2004, include beta-hydroxybutyrate, lipid peroxide, and oxy-
Consensus Committee, 2007) have agreed on standar- sterol. Data relating circulating levels of such analytes to
dized methods (Jeppson et al., 2002) and recommend congenital malformations in IDM are extremely limited
reporting A1C in percentage units (National Glycohemo- (Jovanovic et al., 1998), and they are difficult to separate
globin Standardization Program) or millimoles per mole from the probable effects of hyperglycemia. Further
(International Federation of Clinical Chemistry), along research is needed for a better understanding of the in-
with estimated average glucose (Nathan et al., 2008). dependent and joint effects of the various metabolic
Because evaluation of A1C is used in the preconception abnormalities in the development of congenital anoma-
period, it is important to note that measurements of A1C lies in humans.
level by certain methods can vary slightly by race and The influence of maternal micronutrient intake from
ethnic group (Hartland et al., 1999; Herman et al., 2009), food and supplements on the risk of congenital malfor-
by smoking status (Higgins et al., 2009), by the presence mations has been studied in infants of healthy mothers,
of silent variant hemoglobins (Schnedl et al., 2008), and with inconsistent results (Mills et al., 1989; Shaw et al.,
by iron deficiency without anemia (altered structure of 1995; Czeizel et al., 2006; Goh et al., 2006), but there is
hemoglobin, which is easier to glycate; Koga et al., 2007, inadequate information related to their potential attenua-
Kim et al., 2010). A1C levels can be decreased by fetal he- tion of the effects of maternal diabetes (Banhidy et al.,
moglobin greater than 5% (Rohlfing et al., 2008), produc- 2010). In the Atlanta Birth Defects Case-Control Study,
tion of immature erythrocytes (Gram-Hansen et al., 1990), 3278 case infants who had nonsyndromic birth defects
and ingestion of vitamins C and E (NGSP, 2008). There- that had been previously reported to be associated with
fore, interpretations of A1C results need to account for maternal diabetes were compared with 3029 infants with-
these factors. Current standardized assays in small stud- out birth defects. An increased risk of the selected birth
ies show a slight decrease in A1C levels during the first defects was observed among offspring of mothers with
trimester of normal pregnancy, with a normal upper limit onset of diabetes before the date of birth of the index
(12 SD above mean) of 5.7 to 5.9 (Hartland et al., 1999; infant, but the increased risk was limited to those who
Nielsen et al., 2004; Suzuki and Takeuchi, 2005). Norma- had not taken multivitamins during the periconceptional
tive A1C data for the onset of pregnancy beyond those period (Correa et al., 2003). In addition to being under-
for diabetic women in general are lacking. powered, this retrospective study had no information on
Recent reports using the standardized assays confirm a levels of hyperglycemia of case and control mothers with
strong association between A1C >7.0 at the beginning of diabetes, and therefore could not examine the effect of
pregnancy and major congenital anomalies in women multivitamins among women known to have hyperglyce-
with diabetes (Suhonen et al., 2000; Evers et al., 2004; mia before pregnancy. This consideration is important,
Clausen et al., 2005; Galindo et al., 2006; Nielsen et al., because not taking multivitamins could be a surrogate
2006; Inkster et al., 2009; Lapolla et al., 2010a). Because for a number of unmeasured exposures and behaviors,
the data are inadequate to determine the degree of risk including poor metabolic control, that may contribute to
associated with slightly elevated (for early pregnancy) the risk for major malformations.
values of 6.0 to 6.9, many authors recommend that Intake of folic acid supplements was described as an
women with diabetes achieve A1C values as close to nor- independent factor for reduced malformation risk in one
mal as possible before pregnancy (Suhonen et al., 2000; study of DM2 (Roland et al., 2005), but in a large case-
Evers et al., 2004; Nielsen et al., 2006; Jensen et al., 2009; control study in Hungary during 1980 to 1996, pericon-
Lapolla et al., 2010a; Lisowski et al., 2010). Formerly, the ceptional folic acid use was equivalent in women with
risk of congenital malformations was stated according to DM2 delivering infants with and without major malfor-
SDs above the mean hemoglobin A1C (Temple et al., mations (49.4% vs. 47.5%). Folic acid use was 50.6% in
2002), to account for laboratory variation. Currently, with women with DM1 whose infants had congenital anoma-
standardized assays, it should be possible to relate risk to lies, compared with 61.4% folic acid use in women deliv-
estimated average blood glucose concentration. ering babies without anomalies (Banhidy et al., 2010).
Possible confounders, effect modifiers, and coterato- The topic of macronutrient and micronutrient use and
gens. The inconsistent findings on possible effect modifi- consumable toxins in diabetes and pregnancy deserves
cation of maternal obesity are mentioned in the Introduc- much more clinical and epidemiologic investigation,
tion. What about risks of maternal hypoglycemia to the including the epigenetic effects of maternal dietary intake
embryo? The early investigators of preconception care on the early conceptus.
noted no association between severe hypoglycemic epi- Early studies suggested that diabetic microvascular dis-
sodes in early pregnancy and major congenital malforma- ease was a risk factor for major congenital anomalies in
tions in infants of women with DM1 (Fuhrmann et al., infants of women with DM1, although the apparent
1983; Steel et al., 1990; Kitzmiller et al., 1991). In the Dia- excess risk was difficult to separate from the effects of
betes in Early Pregnancy study of pregnant women with hyperglycemia (Kitzmiller et al., 1996). However, subse-
DM1 followed from 5 weeks gestation, the lowest ranges quent studies have shown that such excess risk could be
of glycohemoglobin were not associated with excess mal- reduced by maternal metabolic control before and during
formations (Mills et al., 1988a), but the lowest 3% of early pregnancy in women with nephropathy or retinop-

Birth Defects Research (Part A) 88:791–803 (2010)


794 KITZMILLER ET AL.
athy (Fuhrmann et al., 1983; Damm and Molsted-Peder- counseling, frequent self-monitoring of blood glucose,
sen, 1989; Kitzmiller et al., 1991; McElvy et al., 2000). optimized insulin therapy, and the transition to intensive
What about the influence of medication used to treat prenatal care (Kitzmiller et al., 1991, 1996, 2008a, 2008b).
diabetes on the risk of major congenital malformations in Among women with preexisting diabetes who partici-
IDM? Human or rapid analog insulin is not considered pated in such preconception care programs, the fre-
to be a teratogen per se (Sadler and Horton, 1983, Wyatt quency of congenital malformations was reduced.
et al., 2005; Lapolla et al., 2008); however, congenital mal- Ray et al. (2001) performed a meta-analysis of 14
formations have been noted in animal studies in which cohort studies of women with diabetes in 1983 to 1999,
insulin was used to produce experimental hypoglycemia with a focus on the risk of congenital malformations (Ray
(ter Braak et al., 2002). As noted, there is no clinical evidence et al., 2001). The analysis included eight prospective
for potential teratogenic effects of hypoglycemia, although studies, with a total of 794 offspring of mothers who
observational studies have been limited and underpowered. received preconception care in the 1980s and 1990s, and
There are no randomized, controlled trial data indicat- 875 infants of mothers who registered for care already
ing that treatment with oral antihyperglycemic agents pregnant. The pooled rate of major congenital malforma-
before or at the beginning of pregnancy increases or tions in the prospective preconception care groups was
reduces the risk of congenital malformations in infants of 2.1%, compared with 5.1% for those without such care
women with DM2. Retrospective observational data sug- (pooled relative risk, 0.42; 95% confidence interval [CI],
gest that there is no consistent teratogenic effect from sul- 0.24–0.74). Preconception care was associated with signifi-
fonylureas, metformin, or acarbose, and if there is, then it cantly lower glycohemoglobin levels in the first trimester.
is masked by the effects of hyperglycemia (Piaquadio Because the studies were not randomized, investigators
and Hollingsworth, 1991; Hellmuth et al., 1994; Towner could not account for potential selection bias (e.g., partic-
et al., 1995; Botta, 1997; Gutzin et al., 2003; Clausen et al., ipants in preconception care having milder or more con-
2005). One study suggested that using oral antihypergly- trolled disease) or potential confounders such as differen-
cemic agents (51 of 65 used metformin) at the beginning ces in use of vitamins or folic acid at the beginning of
of a pregnancy complicated by DM2 was an independent pregnancy between preconception care participants and
risk factor for congenital malformations. The authors nonparticipants (Ray et al., 2001).
stated that ‘‘the close interrelationship between prepreg- Since the year 2000, similar prospective observational
nancy care, use of oral hypoglycemic agents, poor glyce- studies of preconception care for women with diabetes
mic control in early pregnancy, lack of folic acid and late continued to report lower rates of major congenital mal-
booking in the antenatal clinic make it difficult to isolate formations and perinatal deaths in infants of diabetic
specific risk factors’’ (Roland et al., 2005). There are no women who participated, compared with those who reg-
clear human data relating to glitazones or incretins. Met- istered for care and were already pregnant. Examples of
formin treatment of nondiabetic women with polycystic such population-based studies reported in 2000 to 2010
ovary syndrome (PCOS), continued through early preg- are presented in Table 1 (Boulot et al., 2003; Evers et al.,
nancy, does not seem to increase the congenital malfor- 2004; Temple et al., 2006; Pearson et al., 2007; Tripathi
mation rate (Gilbert et al., 2006), but these observational et al., 2010). Such care is associated with lower A1C and
studies on PCO were underpowered and not designed to greater use of folic acid by the onset of pregnancy (Evers
rule out teratogenesis. Furthermore, hyperglycemia or et al., 2004; Temple et al., 2006; Pearson et al., 2007; Tri-
other aspects of the diabetic state can enhance or mask pathi et al., 2010). A well-funded and well-advertised,
the putative teratogenic effects of any agent, such as reti- multidisciplinary preconception care program that pro-
noic acid (Chan et al., 2002), making confounding by in- vided free care for diabetic women without insurance
dication a difficult methodology issue to overcome in was able to reduce the malformation and perinatal death
observational studies of the independent effect of treatment rates to control levels over several years in a U.S. metro-
of diabetes on the risk of major congenital anomalies. politan area. When grant funding terminated, these rates
began to rise (McElvy et al., 2000).
As noted, women who respond to the opportunity for
Use of Preconception Care of Women
preconception care may differ from those who do not. In
with Diabetes general, women who intend to become pregnant are less
Because major congenital malformations occur early in likely to report exposures in early gestation that might
gestation and are associated with hyperglycemia, investi- result in adverse pregnancy outcome (e.g., smoking, alco-
gators have sought to determine whether intensification hol use, illicit drug use, not taking vitamins), compared
of diabetes treatment before conception and continued to women with unintended pregnancies (Than et al.,
early in pregnancy would reduce the frequency of mal- 2005). The lack of randomized controlled trials to prove
formations. The focus in these studies has been on the benefit of intensified preconception care in reducing
recruiting women with diabetes before pregnancy, coun- major congenital malformations is due to the difficulty of
seling about the risks of uncontrolled diabetes at the assigning diabetic women desiring pregnancy to stand-
onset of pregnancy, evaluating complications of diabetes ard care. Women with DM1 in the intensified therapy
that should be treated or might effect the outcome of a arm of the Diabetes Control and Complications Trial and
pregnancy, and providing inpatient or outpatient multi- who became pregnant had a reduced prevalence of mal-
disciplinary patient-centered diabetes care to prevent formations in their infants compared with women in the
hyperglycemia and hypoglycemia as much as possible. conventional therapy arm, although the trial was not
The elements of preconception team care (Sacks, 2006) designed to test that hypothesis (DCCT Study Group,
included health care provider education, education about 1996).
family planning and use of contraception, medical nutri- The proposition that preconception care clinics simply
tion therapy, planned physical activity, psychosocial separate women with diabetes into a highly-motivated,

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DIABETES, BIRTH DEFECTS, AND PRECONCEPTION CARE 795

Table 1
Comparison of Rates of Major Congenital Malformations and other Adverse Outcomes Among Infants
of Diabetic Women Receiving Preconception Care and Women Receiving Intensified Care only After the Stage
of Embryogenesis/Organogenesis (Population-Based Studies Published 2000-2010)
Author, Year Region Preconception Care Registered Pregnant
Malformations (%) Malformations (%)
DPGF, 2003 France 1/140 (0.7) 12/149 (8.1)
Evers, 2004 Netherlands 11/271 (4.0) 6/49 (12.2)
Temple, 2006 Norwich, UK 2/110 (1.8) 11/180 (6.1)
Adverse Outcomes (%) Adverse Outcomes (%)
Pearson, 2007 Scotland 13/122 (10.7)* 70/301 (23.3)*
Tripathi, 2010 N England 14/240 (5.8)** 30/297 (10.1)**
*Includes spontaneous miscarriage, ectopic pregnancy, molar pregnancy, major congenital anomaly, or perinatal death.
**Perinatal death or major malformation.

well-controlled group who attend, and the remainder, women with diabetes participating in prepregnancy care
who register for care already pregnant (Gregory and Tat- (Willhoite et al., 1993; McElvy et al., 2000; Temple et al.,
tersall, 1992), is not supported by the fact that diabetic 2006; Pearson et al., 2007; Lapolla et al., 2008; Tripathi
women frequently have elevated A1C levels at intake et al., 2010). Preterm delivery before 34 weeks’ gestation
into preconception care, just as others do at intake into was significantly lower in 110 women with DM1 who
pregnancy. Because both groups then show similar received prepregnancy care, compared with 180 pregnan-
improvement in A1C as they respond to intensified care cies in women who did not (5.0% vs. 14.2%; p 5 0.02),
(Kitzmiller et al., 1991; Chew et al., 1995; DCCT Study even after controlling for smoking, parity, and duration
Goup, 1996; Temple et al., 2006), the challenge is to of diabetes (Temple et al., 2006). Furthermore, glycemic
attract more women with diabetes into preconception control in the immediate preconception period and early
care, to learn how to best educate and interact with them first trimester may optimize birth weight (Garcia-Patter-
and how to motivate them to cope with the rigors of son et al., 1997; Gold et al., 1998).
treatment, and to elucidate the components of care that An early study of a pilot California diabetes and preg-
are most effective in preventing congenital malforma- nancy care program compared with nonparticipating hos-
tions. pitals showed the program to be most cost-effective if the
Recent population-based surveys of pregnancy out- mothers enrolled before conception. The cost effective-
come also support the benefit of preconception care of ness ratio (total discounted savings to program costs)
women with preexisting diabetes. In a prospective was 6.19 for early pregnancy participants, with a savings
national study in Denmark, absence of daily self-monitor- of $6072 per participant, based on outpatient and inpa-
ing of blood glucose before pregnancy among women tient costs (Scheffler et al., 1992). Analysis of the costs
with DM1 was a significant predictor of serious adverse versus benefits of preconception care of diabetes in the
pregnancy outcome (Jensen et al., 2004). Similar associa- United States using modeling techniques showed that the
tions of nonparticipation in preconception care for increased costs of providing the care ($3676) would be
women with DM1 and DM2 with elevated A1C in early offset by lower short-term (Elixhauser et al., 1996) and
pregnancy and increased major malformations were long-term (Elixhauser et al., 1993) direct and indirect
noted in a multicenter survey in Italy (Lapolla et al., health care-related costs in the offspring (net savings of
2008) and in a region of Scotland (Inkster et al., 2009). $1720 per enrollee; benefit-cost ratio, 1.86). In a prospec-
Appropriate periconceptional treatment of diabetes and tive, observational study of 24 women with DM1 who
folic acid supplementation was associated with a lower received preconception care, hospitalization costs for
risk of major malformations in a national study in Hun- mother and infant were lower than in 74 diabetic women
gary (Banhidy et al., 2010). In a multicenter survey in who received prenatal care only (net cost saving of
Scotland, the lowest rate of pregnancy loss and major $34,000 per patient; Herman et al., 1999). Under the
congenital malformations was found in women who dis- assumption that preconception care per se does improve
continued contraception after achieving optimal A1C outcomes, the evidence suggests that preconception care
(adjusted odds ratio, 0.20; 95% CI, 0.06–0.67), and the is a cost-saving measure.
authors concluded that this is the best definition of effec- There is a large body of evidence indicating that meta-
tive preconception care (Pearson et al., 2007). bolic control before and early in pregnancy contributes to
In addition to reduced prevalence of congenital malfor- the reduction of adverse pregnancy outcomes among
mations, other perinatal outcomes may also be improved women with preexisting diabetes. This evidence includes:
with preconception care of diabetes. Excess early fetal the timing of diabetic embryopathy in human pregnancy,
loss before 20 weeks’ gestation is associated with markers the teratogenic effects of hyperglycemia consequences in
of hyperglycemia in early pregnancy (Miodovnik et al., animal studies (reviewed elsewhere in this issue of the
1985; Mills et al., 1988b; Greene et al., 1989; Hanson Journal; also Ericksson, 2009), the observational studies
et al., 1990; Rosenn et al., 1994), and the loss rate is lower of the association of increased major congenital malfor-
in diabetic women participating in preconception care mations with poor metabolic control marked by elevated
(Rosenn et al., 1991; Pearson et al., 2007). Perinatal mor- A1C levels, and the consistent observational studies
tality after 20 weeks’ gestation is also decreased for showing reduced major congenital anomalies in infants

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796 KITZMILLER ET AL.
of women with preexisting diabetes who participated in for the health system (Klinke and Toth, 2003; CEMACH
intensified preconception care. Based on this evidence, 2005, 2007; Varughese et al., 2007). Last, many primary
there are now recommendations from multiple interna- care groups do not have or use established guidelines for
tional sources that preconception care for women with providing preconception care or do not have the multi-
diabetes, designed to avoid teratogens and stabilize nutri- disciplinary and committed care team required for pro-
ent intake, metabolism, and glycemic control, should be viding preconception, pregnancy, and postpartum care
used to reduce adverse pregnancy outcome (McIntyre for women with diabetes (Korenbrot et al., 2002; Owens
and Flack, 2004; McElduff et al., 2005; Allen et al., 2007; et al., 2006).
BMJ Group, 2008; Guideline Development Group, 2008;
National Institute for Health and Clinical Excellence, Analysis of Problems in the Application of
2008; American Diabetes Association, 2010; Mahmud and
Preconception Care for Women with Diabetes
Mazza, 2010, Negrato et al., 2010).
with a View to Improving Success
Understanding the reasons, including psychosocial and
Underutilization of preconception
socioeconomic considerations, why women with diabetes
care of diabetes do not use contraception and intensified preconception
There have been no reports of ongoing population- care is important so that more effective intervention strat-
based monitoring of the prevalence of birth defects egies can be devised. The lack of effective contraception
among infants of mothers with preexisting diabetes in use and of adherence to glycemic and weight control reg-
the United States to assess the effectiveness of preconcep- imens has been related to external health locus of control
tion care programs at the population level. Observational and poor social support (St James et al., 1993; Holing
studies of cohorts of pregnant women with diabetes from et al., 1998; Hayes et al., 2000). An ‘‘external locus of con-
around the world published between 1991 and 2008, trol orientation indicates that goal attainment is attrib-
which have consistently reported an increased frequency uted to external factors outside the control of the individ-
of major malformations in their offspring, suggest that ual. The external orientation has been divided into
the effectiveness of prevention efforts in most popula- ‘powerful others’ and ‘chance’. An individual with an in-
tions has been unsatisfactory. These reports have a num- ternal locus of control believes that outcomes are a result
ber of limitations for assessing trends over time, includ- of his or her own behavior’’ (Morowatisharifabad et al.,
ing under-ascertainment of some major malformations 2010). These measurable characteristics support the wide-
not readily apparent shortly after birth, and limited spread attempts to enhance patient education and self-
details on the methods of diagnosis and classification of empowerment in diabetes care programs (Sarkisian et al.,
major congenital anomalies. There is clearly a need for 2005). Behavior is complex, and research continues to
more systematic monitoring of trends in the prevalence shed light on improved models to understand the inter-
of major congenital malformations among pregnancies actions on an individual basis.
complicated by preexisting diabetes; this would facilitate Poor metabolic control has been significantly related to
evaluations of the penetrance and effectiveness of precon- feelings of inadequacy and loss of psychological control
ception care of diabetes. The use of counseling on pre- in women with DM1 and DM2, especially in the domains
conception glycemic control and the use of family plan- of interpersonal relationships and bodily functions.
ning until glucose control is achieved has been subopti- ‘‘Multidimensional control inventories enable a more
mal in U.S. managed health care plans, in which a lack complex appraisal of the relationship between metabolic
of health insurance should not be a barrier (Kim et al., control and psychological control, and in doing so, pro-
2005). vide a way forward from problems arising from reliance
There are several important challenges for translating on [simple locus of control] constructs’’ (Surgenor et al.,
findings from studies of associations, and of barriers and 2000). Community-based, culturally oriented self-empow-
enablers of preconception care, to the diffusion of effec- erment training projects achieved better glycemic control
tive interventions to populations at risk for diabetic and fewer hospital admissions (Gilmer et al., 2005; Dis-
embryopathy. First is the increasing proportion of preg- tiller et al., 2010), and they serve as examples of feasibil-
nancies complicated by DM2, because in approximately ity approaches that should be studied in diabetic women
one third of reproductive-aged women with diabetes, the who might become pregnant.
diabetes is undiagnosed (Cowie et al., 2006). This trend A few surveys of limited numbers of women with pre-
calls for the development and implementation of popula- existing diabetes have attempted to determine the rea-
tion-based screening for diabetes among women of child- sons why they had not participated in preconception care
bearing age. Second, the extent of the problem of lower and had not used contraception in planning their preg-
participation in preconception care by women with DM2 nancies (Janz et al., 1995; Casele and Laifer, 1998; Holing
(compared to DM1) and the possible reasons for lack of et al., 1998). Although the majority of patients said they
participation are in need of further exploration. Third, at knew about the importance of preconception care for dia-
least half of pregnancies among women with or without betes, a minority recalled that they had been encouraged
preexisting diabetes are unplanned (St James et al., 1993; or stimulated to do so by their usual health care pro-
Henshaw, 1998; Holing et al., 1998; CEMACH, 2005; Kim viders. Interpretation of the authors’ conclusions is that
et al., 2005). Practical measures for increasing access to every visit with a woman with diabetes should be
and the level of participation in counseling sessions on regarded as a preconception visit, contraception should
family planning by women of childbearing age with dia- be explicitly discussed and used until metabolic control
betes are needed. Fourth, achieving sufficient metabolic is good, and the support of families and friends should
control to prevent maternal and fetal complications be elicited (Janz et al., 1995; Casele and Laifer, 1998; Hol-
remains a major challenge for women with diabetes and ing et al., 1998). Editorial opinion supports the impor-

Birth Defects Research (Part A) 88:791–803 (2010)


DIABETES, BIRTH DEFECTS, AND PRECONCEPTION CARE 797
tance of encouragement and guidance by the usual diabe- knowledge, perceived the benefits of receiving precon-
tes care providers to achieve successful preconception ception care and using effective family planning, and
care (Coustan, 1998). Because these studies were per- perceived more support regarding reproductive health
formed during the 1990s, current information would be issues (Charron-Prochownik et al., 2008; Fischl et al.,
useful. 2010). Larger and longer studies are needed to determine
In a multicultural survey of pregnant women with dia- whether this approach will reduce unplanned pregnan-
betes in the Chicago metro area, only 22% of 74 subjects cies and adverse pregnancy outcomes.
had low health literacy, evaluated by a reading test; how- Preconception counseling, providing information on
ever, compared to women with adequate literacy, the risks and treatment methods and goals, is but the first
low-literacy group was significantly less likely to have a step of an active, ongoing process of care requiring
planned pregnancy, to have talked to a doctor about repeated visits to the appropriate health care providers.
pregnancy, to have taken folic acid before pregnancy, Informal and decentralized preconception counseling
and to be of minority ethnicity (Endres et al., 2004). The may be ineffective in obtaining pregnancies with good
authors suggested methods to reach women in this glycemic control at their onset (Rodgers and Rodgers,
group. Of the women considered to have adequate liter- 1996), at least in the current general diabetes care envi-
acy, 60% had planned pregnancy and 83% were taking ronment. Good glycemic control is hard to attain and
folic acid (Endres et al., 2004). Although knowledge defi- takes time for both patients and caregivers, but it is pos-
cits about preconception health are common in women sible to attain for most women.
with chronic medical conditions (Chuang et al., 2009), Many patients need further education on how to use
interviews with pregnant women with diabetes in the short-term contraception (Kjos, 2007) and the details of
United Kingdom revealed that knowledge concerning the intensified diabetes self-management, including self-mon-
risks of pregnancy, past preconception counseling, and itoring of food intake and frequent capillary blood glu-
prior adverse outcomes did not encourage women to use cose tests every day; prevention of hypoglycemia; and
effective contraception or to attend preconception care self-adjustment of insulin doses in response to premeal
clinics. Instead, identified barriers to effective contracep- or postprandial glucose levels, changes in food intake, or
tion and attendance in preconception care clinics were symptoms of illness or stress. This type of planned preg-
disbelief in personal fertility, negative experiences with nancy or preconception care of women with diabetes has
health professionals, desire for a ‘‘normal’’ pregnancy been shown to reduce congenital anomalies and to
involving limited interactions with the medical establish- improve other perinatal outcomes.
ment, and the logistics of attending preconception care Improving preconception care for women with diabe-
clinics (Murphy et al., 2010). tes is likely to require a concerted effort by the global
The need for improved efforts to counsel adolescent public health community, health care providers, and
females with DM1 about prevention of unplanned preg- women with diabetes and their families (Holing, 2000).
nancies and preconception care of diabetes is the focus of Control of diabetes before and during pregnancy to
recent studies in western Pennsylvania. First, a national reduce the adverse maternal, fetal, and offspring effects
survey of 196 diabetes nurse educators found that 72% is likely to require the development of a translation
provided information on the importance of planning a framework that addresses the challenges associated with
pregnancy to adult females, but only 45% did so for ado- the preconception management of diabetes among
lescent females; 76% helped adult patients obtain excel- women of childbearing age.
lent control before conception, compared with 51% for Several definitive clinical guidelines are available from
adolescents. However, only 33% of diabetes nurse educa- major health organizations to enhance preconception
tors provided information on preventing an unplanned care and reduce adverse pregnancy outcomes (ACOG
pregnancy to adult females, and only 25% did so for ado- Committee on Practice Bulletins, 2005; McElduff et al.,
lescents (Michel and Charron-Prochownik, 2006). Second, 2005; Allen et al., 2007; Kitzmiller et al., 2008a, 2008b;
telephone interviews conducted with eighty 16- to 20- National Institute for Health and Clinical Excellence,
year-old female patients showed that only 25% were 2008a, 2008b; American Diabetes Association, 2010; Mah-
aware of the need to achieve good metabolic control mud and Mazza, 2010, Negrato et al., 2010). Among
before becoming pregnant. Overall, the teenagers felt that them, the basic principles for women with diabetes and
they were only moderately susceptible to becoming preg- their caregivers include: pregnancy should be planned;
nant (mean age of coitus, 15.7 years) and that severe good contraceptive advice and prepregnancy counseling
complications would not happen to them (Charron-Pro- are essential; and careful glycemic control, marked by
chownik et al., 2006a, 2006b). A1C as close to normal as possible without serious hypo-
To address the deficiencies illustrated by these surveys, glycemia, should be maintained before and during early
an interactive CD-ROM titled Reproductive Health Aware- pregnancy. The U.K. National Institute for Health and
ness for Teenage Women with Diabetes (READY-Girls) was Clinical Excellence (NICE) group adds that women with
prepared and tested by a sample of certified diabetes diabetes should be reassured that any reduction toward
educators (Cothran et al., 2009). Finally, a small random- A1C of 6.1 is likely to reduce the risk of congenital mal-
ized trial tested the educational value of a self-instruc- formations, and that women with A1C above 10.0 should
tional CD-ROM designed for teenagers with diabetes be advised to avoid pregnancy (National Institute for
over a 3- to 9-month period. The materials presented the Health and Clinical Excellence, 2008a). The American Di-
effects of diabetes on reproductive health, including pu- abetes Association (ADA) adds: starting at puberty, pre-
berty, sexuality, and pregnancy, the benefits of precon- conception counseling should be incorporated in the rou-
ception care, and the development of skills involving de- tine diabetes clinic visit for all women with childbearing
cision-making and communication. Compared with con- potential. Women with diabetes who are contemplating
trol subjects, teens who used the program improved in pregnancy should be evaluated and, if indicated, treated

Birth Defects Research (Part A) 88:791–803 (2010)


798 KITZMILLER ET AL.
for diabetic retinopathy, nephropathy, neuropathy, and of DM1 patients early in pregnancy (Temple et al., 2006).
cardiovascular disease, using medications appropriate for Women with a history of being unaware of hypoglycemic
pregnancy (American Diabetes Association, 2010). episodes and a history of previous severe hypoglycemic
The NICE report (National Institute for Health and episodes are at greatest risk in pregnancy (Evers et al.,
Clinical Excellence, 2008a) stated that there was no evi- 2002; Nielsen et al., 2008). Scheduled, frequent carbohy-
dence to suggest that women with diabetes planning a drate intake in meals and snacks must be used to prevent
pregnancy would benefit from a larger dose of folic acid hypoglycemia, along with careful adjustments of insulin
than is recommended for women who do not have diabe- doses for planned physical activity (Kitzmiller et al.,
tes, to prevent neural tube defects. Nevertheless, the 2008a, 2008b). Selected use of continuous self-monitoring
NICE guideline development group suggested that of blood glucose with alarm devices (Worm et al., 2006)
‘‘women with diabetes should take the higher dose of and continuous subcutaneous insulin infusion by porta-
5 mg per day, as for other women with increased risk of ble pumps (Gabbe et al., 2000, 2007; Lapolla et al., 2003;
neural tube defects, when intending to become preg- Volpe et al., 2009; Cyganek et al., 2010) can reduce hypo-
nant,’’ to be continued until 12 weeks’ gestation glycemic episodes, as suggested by controlled trials in
(National Institute for Health and Clinical Excellence, nonpregnant women (de Block et al., 2008; Cummins
2008a). The ADA Standards of Medical Care in Diabetes et al., 2010), although randomized controlled trials in
does not mention folic acid in the section on preconcep- pregnancy have been insufficiently powered to prove this
tion care (American Diabetes Association, 2010), but an (Farrar et al., 2007; Murphy et al., 2008). Initiation of in-
ADA-sponsored consensus panel on managing preexist- sulin analog treatment before rather than during early
ing diabetes for pregnancy stated, ‘‘Consume folate at pregnancy may result in a lower risk of severe hypogly-
600 mcg/day in the periconception and prenatal periods cemia in women with DM1 (Heller et al., 2010).
through supplementation or fortified food sources’’ (Kitz- For women with DM2, entry into preconception care
miller et al., 2008b). More research is needed to deter- may be their first exposure to medical nutrition and
mine whether the higher dose is of benefit and without physical activity therapy, self-monitoring of blood glu-
harm (Heseker et al., 2009; Lucock and Yates, 2009) in cose, and use of insulin treatment. Published guidelines
women with diabetes in good metabolic control and recommend conversion from oral antihyperglycemic
nutrition status, because there is some evidence for an agents to insulin use prior to attempting conception
increased risk of neoplasia with folic acid supplementa- (Allen et al., 2007; American Diabetes Association, 2010),
tion in nonpregnant adults (Kim, 2006; Fife et al., 2009; although the NICE report suggests that metformin can be
Figueiredo et al., 2009). The Institute of Medicine set the continued into early pregnancy (National Institute for
tolerable upper limit of folic acid intake from fortified Health and Clinical Excellence, 2008a, 2008b). However,
foods or supplements at 1000 lg/day, exclusive of food in the absence of controlled trial data from women with
folate, to avoid the risk of permanent neurologic damage DM2 in early pregnancy proving efficacy and safety, we
in vitamin B12-deficient individuals (Institute of Medi- do not support that recommendation. The use of angio-
cine, 1998). Latent forms of vitamin B12 deficiency are not tensin-converting enzyme inhibitors, angiotensin receptor
rare in women with DM1 of childbearing age (Kitzmiller blockers, and statins should also be discontinued during
et al., 2008a). preconception care of women with either type of diabe-
For health care providers, the preconception care given tes, because of their possible harmful effects on early ges-
to women with diabetes may be more effective with bet- tation (Cooper et al., 2006; Cragan et al., 2006; Kazmin
ter education and motivation of caregivers, especially et al., 2007; Forbes et al., 2008), and the possibility of
those who do not usually work with pregnant women. unplanned pregnancy. Obesity (body mass index 30
Preconception care plans and materials should be cultur- kg/m2) is a strong risk factor for poor pregnancy
ally sensitive (Dunne et al., 2003; Kendrick, 2004; Laven- outcome (Catalano, 2007, 2010; Reece, 2008), but it may
der et al., 2009). Glycemic goals must be clear, individu- be unrealistic for obese women with DM2 to lose signifi-
alized, and attainable. It must be realized that A1C can cant weight in preparation for pregnancy (Davies et al.,
reflect a balance between hypoglycemia and hyperglyce- 2010). The question of efficacy and safety of bariatric sur-
mia, and therefore its interpretation without analyzing gery prior to pregnancy (Maggard et al., 2008; Wax, 2009)
results of glucose self-monitoring can be misleading (Ker- has not been systematically addressed in women with di-
ssen et al., 2006). Although assessing estimated average abetes, although some individuals having had the sur-
glucose with A1C is a valuable tool (Gandhi et al., 2008; gery may inquire about pregnancy (Lapolla et al., 2010b).
Nathan et al., 2008), individual episodes of periconcep- The most challenging issues regarding intensified pre-
tional hyperglycemia are of unknown risk, and clinicians conception care of women with diabetes are how to get
probably should strive to minimize them and optimize more women to participate and use effective family plan-
A1C to decrease the risk of congenital anomalies. ning methods, including those in the population groups at
For women with DM1, symptomatic hypoglycemia, of- highest risk of developing diabetes, and how to achieve a
ten nocturnal, is a limitation on achieving near-normal sufficient level of glycemic control and nutrient intake in
glucose levels (Rosenn et al., 1995; Evers et al., 2002; women with diabetes who do not plan their pregnancies
Nielsen et al., 2008). In a national audit of 160 pregnan- (Kitzmiller et al., 1996; Coustan, 1998; Sacks, 2006; Reece
cies in women with DM1, 21.9% had episodes of severe and Homko, 2007). Innovative research is needed to deter-
hypoglycemia (defined as requiring assistance) in the first mine the methods of eliminating the barriers and achiev-
trimester. Those with planned pregnancies had better ing these goals (Charron-Prochownik et al., 2006a, 2006b,
glycemic control marked by A1C, but a higher risk of 2006c, 2008; Cothran et al., 2009; Fischl et al., 2010), includ-
severe hypoglycemia (Robertson et al., 2009). Other expe- ing motivation offered by health care payers. An obvious
rience in single centers showed a wide range of severe need in many localities is health insurance coverage for all
hypoglycemia from 2.4% (Kitzmiller et al., 1991) to 42% women with diabetes, in advance of pregnancy. Because

Birth Defects Research (Part A) 88:791–803 (2010)


DIABETES, BIRTH DEFECTS, AND PRECONCEPTION CARE 799
women with GDM have a high rate of developing DM2 Catalano PM. 2007. Management of obesity in pregnancy. Obstet Gynecol
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Catalano PM. 2010. Obesity, insulin resistance and pregnancy outcome.
Golden et al., 2009), putting them at risk of delivering Reproduction [Epub ahead of print].
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Schaefer-Graf et al., 2000), developing plans for and reim- pregnancy in women with type 1 and type 2 diabetes in 2002–03,
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CEMACH. 2007. Confidential enquiry into maternal and child health. dia-
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Broad community-based interventions with the national enquiry: England, Wales and Northern Ireland. London:
involvement of community health workers has been sug- CEMACH.
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professionals can be improved (Murphy et al., 2010). Cli- adolescent women with and without diabetes. Pediatr Diabetes
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