First-Trimester Ultrasound: A Comprehensive Guide

3. Maternal Comorbidities and First-Trimester Ultrasound Examination

Elena Bronshtein1, 2   and Karoline S. Puder3, 4  


Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Hutzel Women’s Hospital, Wayne State University, 3990 John R. Rd., Detroit, MI 48201, USA


2715 Melcombe Circle, Apt 401, Troy, MI 48084, USA


Harper University Hospital/ Hutzel Women’s Hospital, Detroit, MI, USA


Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, 3990 John R., 7 Bruch North, Box 163, Detroit, MI 48201, USA

Elena Bronshtein (Corresponding author)


Karoline S. Puder



First-trimester ultrasoundUltrasoundDatingPregnancyStructural abnormalitiesPregestational diabetesObesityFetal echocardiographyCongenital heart defectsFetal alcohol syndromeEpilepsyMaternal metabolic diseasesTeratogenicityDopplerUterine artery DopplerVascular diseases


Ultrasonography is one of the most important and useful diagnostic tools in obstetrics. It is a noninvasive, portable, quick, and safe technology. Ultrasound performed in the first trimester confirms an intrauterine pregnancy, establishes accurate dates, and is crucial in diagnosing early pregnancy failure and ectopic pregnancy. It is commonly used for risk assessment for aneuploidy, through measurement of nuchal translucency and identification of the presence or absence of the nasal bone. Moreover, ultrasound for fetal assessment of early pregnancy reduces the failure to detect multiple pregnancies by 24 weeks of gestation and is also associated with a reduction in induction of labor for post-term pregnancy [1]. Standard indications for first-trimester ultrasound are shown in Table 3.1. These are addressed in detail in various chapters of this book. Several maternal conditions are known to be associated with an increased risk of fetal anomalies and may justify early or more detailed fetal anatomy survey.

Table 3.1

Standard indications for first-trimester ultrasound [116]

1. Confirmation of the presence of an intrauterine pregnancy

2. Evaluation of a suspected ectopic pregnancy

3. Defining the cause of vaginal bleeding

4. Evaluation of pelvic pain

5. Estimation of gestational (menstrual) age

6. Diagnosis or evaluation of multiple gestations

7. Confirmation of fetal cardiac activity

8. Imaging as an adjunct to chorionic villus sampling, embryo transfer

9. Localization and removal of an intrauterine device

10. Assessing for certain fetal anomalies, such as anencephaly, in high-risk patients

11. Evaluation of maternal pelvic masses and/or uterine abnormalities

12. Measuring the nuchal translucency (NT) when part of a screening program for fetal aneuploidy

13. Evaluation of a suspected hydatidiform mole

Recently, several studies encouraged the early diagnosis of major anomalies after demonstrating the association of increased fetal nuchal translucency (NT) and structural defects [24]. The development of high-frequency and high-resolution transvaginal ultrasound transducers, along with substantial improvement of the technology, has resulted in the visualization of fetal anatomic structures in greater detail earlier in gestation [516]. This helps to shift the prenatal diagnosis from the standard second-trimester anatomy scan into the first trimester, and also gives the opportunity for pregnancy termination in appropriate cases of anomalies identified earlier in gestation. On the other hand, the absence of major fetal structural malformations in the first trimester can reassure patients and reduce anxiety.

While there are some anomalies that will not be evident at a first-trimester anatomy evaluation, due to the natural history of fetal malformations, and a second-trimester anatomical survey remains the “gold standard,” we will consider some patients who might benefit from first-trimester anatomy ultrasound. Diagnostic performance of first-trimester ultrasound in detecting major fetal structural abnormalities has been described as 29–78.8 %, with an overall detection rate of 50 % [1719]. The highest detection rate of 88–100 % has been reported in acrania, holoprosencephaly, hypoplastic left heart syndrome, omphalocele, megacystis, and hydrops [18]. Scanning in the first trimester may be performed either transabdominally or transvaginally. It was demonstrated that the transvaginal approach is significantly better in visualizing the cranium, spine, stomach, kidneys, bladder, and limbs. Complete fetal anatomy surveys were achieved in 64 % of transabdominal scans and 82 % of transvaginal scans at 13–14 weeks of gestation [20]. Using both transabdominal and transvaginal ultrasonography, noncardiac anatomy was seen in 75 % of fetuses with a crown-rump length of 45–54 mm and in 96 % with a crown-rump length (CRL) of more than 65 mm [21] (Figs., and 3.4).


Fig. 3.1

A four-chamber view of the fetal heart at 13 weeks of gestation. Transabdominal approach


Fig. 3.2

A four-chamber view of the fetal heart at 13 weeks of gestation. Transvaginal approach


Fig. 3.3

Kidney area of the fetus at 13 weeks of gestation. Transabdominal approach


Fig. 3.4

Kidney area of the fetus at 13 weeks of gestation. Transvaginal approach

Maternal Comorbidities

Fetal anomalies may have various etiologies, such as genetic, environmental, or multifactorial. Various maternal conditions and/or their treatment are known to be associated with structural anomalies or restricted growth. Sonographic measurements of fetal ultrasound parameters are the basis for accurate determination of gestational age and detection of fetal growth abnormalities. Crown-rump length between 7 and 12 weeks is the most accurate parameter for first-trimester dating. First-trimester growth charts and predictive equations based on CRL instead of menstrual dating are more accurate [22]. Gestational age assessment is very important in the diagnosis of fetal conditions that involve early growth abnormalities due to conditions such as maternal hypertension, autoimmune disease, and preeclampsia. Clinical application of fetal biometry in abnormal growth is also important in cases of small- and large-for-gestational-age fetuses, chromosomal aberrations, and skeletal dysplasias.

Pregestational Diabetes

Maternal pregestational diabetes is a well-known risk factor for congenital anomalies. The types of congenital anomalies in diabetic pregnancies differ from those of nondiabetic pregnancies.

The overall incidence of congenital malformations in diabetic pregnancies has been reported to be 6–13 %, which is twofold to fourfold greater than that of the general population [2325]. A higher proportion of central nervous system (CNS) abnormalities (anencephaly, encephalocele, meningomyelocele, spina bifida, and holoprosencephaly); cardiac anomalies (transposition of the great vessels, ventricular septal defect [VSD], single ventricle, and hypoplastic left ventricle); and kidney anomalies [2631] are reported. The detection rate for CNS anomalies in the first trimester has been reported to be as high as 100 % in cases of anencephaly and encephalocele and only 18 % in cases of spina bifida [1832], because the typical findings of “lemon sign” and “banana sign” do not appear until the end of the first trimester [3334].

Obesity is a well-known risk factor for and comorbidity of diabetes. Moreover, several studies reported that women with pregestational diabetes and BMI higher than 28 kg/m2 have a threefold increase in the risk of congenital anomalies, and the risk further increases proportionally with BMI [3537]. The potential role of first-trimester anatomy ultrasound in the obese gravida is discussed further below.

Rates of fetal malformation appear to be similar for type 1 and type 2 diabetes [38]. It is well known that the poorer the glycemic control is periconceptionally or early in pregnancy, the greater the risk is for congenital anomalies [3940]. Lack of proper glycemic control during pregnancy is associated with profound fetal anomalies. Maternal hyperglycemia at the time of fertilization (defined as a glycosylated hemoglobin [HbA1c] > 7.5 %) has been associated with a ninefold increase in congenital fetal anomalies and a fourfold increase in spontaneous abortion [4142].

Women with pregestational diabetes are advised to plan their pregnancy and optimize the glycemic control before pregnancy. The Canadian Diabetes Association (CDA) and American Diabetes Association (ADA) recommend HbA1c level for pregnancy to be ≤ 7 % before conception is attempted to decrease the risk of congenital malformations [4344]. They also encourage the women to take 4–5 mg of folic acid daily, although the evidence suggests that folic acid is more protective against spina bifida than anencephaly and encephalocele [45]. However, unplanned pregnancies occur in 50 % of all pregnancies and the majority of women do not seek prenatal care until after embryogenesis (4–8 weeks of gestation). Thus, we should consider the evaluation of anatomy using first-trimester ultrasound in a pregnancy complicated by pregestational diabetes. Although certain anomalies of the central nervous system may not be detected between 11 and 14 postmenstrual weeks, there have been case reports demonstrating the detection of congenital and major anomalies of the central nervous system using transvaginal ultrasonography in the first trimester [46].

While infants of diabetic mothers are at risk for a wide variety of malformations, one syndrome is strongly associated with diabetes. Caudal regression syndrome (Figs. 3.5 and 3.6) is a condition associated with hypoplastic lower extremities, caudal vertebrae, sacrum, neural tube, and urogenital organs [273042]. Sirenomelia (the Mermaid syndrome) has been described as a severe and lethal form of caudal regression sequence and characterized by a single lower extremity, absent sacrum, urogenital anomalies, and imperforate anus. The prevalence of sirenomelia has been reported to be 1–3 per 100,000. These malformations occur before the ninth pregnancy week, which has important implications in the prevention of malformations in diabetic pregnancies. The detection of sirenomelia has been described as early as 9 weeks of gestation [47].


Fig. 3.5

Sacral agenesis in patient with pregestational diabetes


Fig. 3.6

Sacral agenesis in patient with pregestational diabetes

A first-trimester anatomy ultrasound may be considered in women with pregestational diabetes in order to detect neural tube defects [NTDs] such as anencephaly and encephalocele, certain cardiac anomalies, and certain limb defects [1119].


Obesity in pregnancy, defined as maternal prepregnancy body mass index (BMI) of 30 kg/m2 and extreme obesity with BMI > 40 kg/m2, are now recognized as a major syndrome in the Western world [4850]. In the USA, more than 35.8 % of women meet obesity criteria, and its prevalence is increasing steadily among women older than 20 years old, assuming epidemic proportions [51]. It is also associated with an increased risk of congenital anomalies such as cleft palate, neural tube defect and cardiac malformations, hydrocephaly, anal atresia, hypospadias, cystic kidney, pes equinovarus, omphalocele, and diaphragmatic hernia [5255]. Thus, the ability to adequately visualize these structures at midtrimester prenatal ultrasound examination has significant clinical implications. Antenatal sonographic detection of congenital anomalies is difficult in obese patients. A patient’s body mass index significantly affects the ability of the sonographer to achieve a complete anatomical survey. As maternal BMI increases, the rate of completion of anatomic surveys decreases and the number of scans required increases [56]. The detection rate of anomalous fetuses with either standard or targeted ultrasonography decreased by at least 20 % in obese women compared to those with normal BMI [57].

Timor-Tritsch et al. proposed that ultrasound examination, with state-of-the-art equipment and in expert hands, can visualize as many structures at 13–14 weeks as it could at 16 weeks 5–10 years previously, and at 20–22 weeks 15–20 years previously [16]. Hendler et al. found that obesity increased the rate of sub-optimal ultrasound visualization for fetal cardiac and craniospinal structures and recognized that in these cases it may require visualization of these structures after 18–22 weeks using a transabdominal approach [58]. Gupta et al. recently suggested performing first-trimester fetal anatomic survey in addition to a routine second-trimester anatomy scan to improve the detection rate of congenital anomalies in obese patients [59]. Transvaginal sonography bypasses the maternal abdominal adipose tissue and the late first-trimester transvaginal scan may be the only opportunity to visualize the fetal anatomy adequately in the obese pregnant patient [60].

Maternal Conditions Associated with Congenital Heart Defects

Various teratogenic agents and maternal conditions have been implicated as the etiologic agents of congenital heart disease [CHD] (see also Chap. 4). Maternal pregestational diabetes has 2–5 times the risk of CHD. Anomalies, such as transposition of the great arteries, truncus arteriosus, visceral heterotaxy and single ventricle, are more common among offspring of diabetic mothers compared to women without diabetes [286164]. Ventricular septal defect and transposition of the great arteries are the most common cardiac defects in fetuses of diabetic mothers [61]. Establishing glycemic control before and early in pregnancy improves maternal and fetal outcomes, including reduction of CHD [6567].

Overall, CHD is the most common congenital anomaly, with an incidence of 6–8 % of all live births, accounting for 30–45 % of all congenital defects [6870]. Prenatal diagnosis of CHD may be used to optimize care and potentially be lifesaving [7173]. Fetal echocardiogram at 18–20 weeks gestation is a well-established method for evaluation of fetal cardiac structure and function. With improved technology, it has become feasible to obtain images of the fetal heart as early as 11 weeks gestation [1474]. Moreover, there is mounting evidence that an increased NT is associated with major cardiac defects in the fetus and therefore represents an indication for specialized fetal echocardiography [7577]. A recent meta-analysis showed that the use of the 99th centile (i.e., 3.5 mm) can identify around 30 % of fetuses with CHD, supporting the notion that NT is the strongest predictor of CHD in the first trimester [75]. Abnormal ductus venosus (DV) blood velocity waveform (absent or reverse A-wave) in the first trimester has also been associated with increased risk for adverse perinatal outcome, in particular for chromosomal anomalies and CHD [7879] (Figs., and 3.7). Abnormal DV blood velocity waveform in the first trimester is an independent predictor of CHD and should constitute an indication for early echocardiography. It has been reported that the use of DV blood velocity assessment increased early detection of CHD by 11 % with respect to the use of NT measurement alone [80]. The combined data from eight studies on euploid fetuses with increased NT (above the 95th centile) demonstrated abnormal DV blood velocity waveform in 87 % of fetuses with cardiac defects, compared with 19 % without cardiac defects [81]. Thus, many groups have suggested the use of DV as a secondary marker to be assessed selectively in fetuses with increased NT [8284].


Fig. 3.7

Abnormal ductus venosus (DV) blood velocity waveform at 12 weeks of gestation

Several studies have shown that complete evaluation rate of the heart increased from 45 % at 11 weeks to 90 % between 12 and 14 weeks and 100 % at 15 weeks [121385]. The visualization of the four-chamber view and the cross-over of the pulmonary artery and aorta have been reported from 44 % at 10 weeks to 100 % at 13–17 weeks [12]. Transvaginal echocardiography is reported to be superior to the transabdominal approach between 10 and 13 weeks of gestation, both methods are similar at 14 weeks of gestation, and transabdominal echocardiography is more accurate than transvaginal at 15 weeks of gestation [85]. Detection of cardiac anomalies in the first trimester varies by lesion, as noted in Tables 3.2 and 3.3.

Table 3.2

Cardiac lesions that may be detected in the first trimester [117]

1. Tricuspid atresia

2. Pulmonary atresia (with or without ventricular septal defect [VSD])

3. Mitral atresia

4. Aortic atresia

5. Hypoplastic left heart syndrome (aortic and mitral atresia or severe stenosis)

6. Complete transposition

7. Corrected transposition

8. Double inlet ventricle

9. Atrioventricular septal defect (large septal defects)

10. Truncus arteriosus

11. Tetralogy of Fallot

12. Large ventricular septal defects

13. Complex lesions in the setting of laterality defects

Table 3.3

Cardiac lesions that may be overlooked in the first trimester [117]

Developmental lesions

1. Mild aortic/pulmonary stenosis

2. Mild mitral/tricuspid valve abnormalities

3. Coarctation of the aorta

4. Cardiac tumors

5. Cardiomyopathies

Septal defects

1. Ventricular septal defects

2. Primum atrial septal defects

3. Atrioventricular septal defects


1. Tetralogy of Fallot with normal size pulmonary arteries

2. Abnormalities of pulmonary venous return

Phenylketonuria (PKU) is another metabolic disorder that is associated with CHD. Women with PKU who have elevated phenylalanine levels are at increased risk for offspring with CHD. VSD and coarctation of the aorta are most common in this population [86]. Levels exceeding 15 mg/ml are associated with a 10- to 15-fold increase in CHD [87]. The etiology of CHD is related not only to elevated blood phenylalanine levels, but also to poor protein and vitamin intake during the first trimester [88]. Diet control before conception and during pregnancy has shown reduced risk of CHD [8990].

Anticonvulsants, a class of drugs that includes phenytoin, carbamazepine and sodium valproate, are commonly used in the treatment of epilepsy. The incidence of congenital defects is 4–10 %, an approximate twofold to fourfold increase compared to the general population [9197]. Polytherapy with antiepileptic drugs (AEDs) is associated with a higher malformation rate than monotherapy [98]. Use of certain AEDs during pregnancy increases the risk for specific congenital malformations, such as neural tube defects, cleft lip and palate, and cardiovascular malformations [99102]. Valproic acid monotherapy, among the different regimens, has the highest risk of congenital abnormalities in offspring [94]. The use of valproate and carbamazepine is strongly associated with NTDs, especially with spina bifida. The prevalence of spina bifida is approximately 1–2 % with valproate exposure and 0.5 % with carbamazepine [103].

Carbamazepine exposure is associated with Tetralogy of Fallot, esophageal atresia, vertebral anomalies, and multiple terminal transverse limb defects [97]. The most common cardiac anomalies reported among offspring exposed to carbamazepine are VSD, Tetralogy of Fallot, patent ductus arteriosus (PDA) and atrial septal defect (ASD) [97100104105]. In light of these results, we should consider first-trimester anatomy ultrasound and fetal echocardiogram for women with epilepsy on AEDs.

Alcohol abuse during pregnancy is associated with health problems to both mother and fetus.

Of the four million pregnancies in the USA each year, 3–5 % of women drink heavily throughout pregnancy [106]. The fetal alcohol syndrome (FAS) is considered to be the most severe manifestation of the adverse effects of alcohol on the fetus. A diagnosis of FAS requires prenatal alcohol exposure and the following characteristics: fetal growth restriction, neurocognitive delays and/or mental retardation, and at least two facial dysmorphic features (short palpebral fissures, thin vermillion border, or smooth philtrum) [107]. FAS occurs in 4–10 % of children born to alcoholic mothers. CHD is reported in 25–50 % of infants with FAS; ASD and VSD are the most common [108110]. The findings suggest that prenatal alcohol exposure as a potential etiology of CHD may also be considered as an indication for performing first-trimester fetal echocardiogram.

Maternal Vascular Disease

Women with hypertension, renal disease, and vascular disease have a recognized increased risk of preeclampsia, fetal growth restriction, and other adverse pregnancy outcomes. While most of these women will be candidates for low-dose aspirin therapy, identification of a particularly high-risk subset may allow more intensive surveillance and targeted interventions. Abnormal placental vascular development is a basis of common obstetrical disorders such as fetal growth restriction and preeclampsia. Uterine artery Doppler has been investigated as a predictive and diagnostic tool.

It has been reported that pregnancies with an increased risk of developing hypertensive disorders and related complications have an abnormally increased UtA-PI in early pregnancy [111]. The 11- to 14-week period is characterized by an elevated UtA-PI and bilateral notching. As pregnancy progresses, UtA-PI decreases and bilateral notching is less prevalent [112113]. A meta-analysis involving 55,974 women has shown that first-trimester uterine artery Doppler is a useful tool for predicting early-onset preeclampsia, as well as other adverse pregnancy outcomes [114]. Aspirin treatment initiated before 16 weeks of pregnancy may reduce the incidence of preeclampsia and its consequences in women with ultrasonographic evidence of abnormal placentation diagnosed by first-trimester uterine artery Doppler studies [115].


First-trimester ultrasound is already a common part of our obstetric armamentarium. As our patients, their comorbidities, and the sophistication of ultrasound change, so too may we change our approach to prenatal diagnosis. While the information presented here does not reflect current standard of care, we anticipate further evolution of condition- and exposure-based recommendations, including first-trimester anatomy studies and echocardiography in selected populations.

Teaching Points

·               Ultrasound performed in the first trimester confirms an intrauterine pregnancy, establishes accurate dates, pregnancy failure, and ectopic pregnancy.

·               It is also used for risk assessment for aneuploidy, through measurement of nuchal translucency and identification of the presence or absence of the nasal bone.

·               Complete fetal anatomy surveys can be achieved in 64 % of transabdominal scans and 82 % of transvaginal scans at 13–14 weeks of gestation. This helps to shift the prenatal diagnosis from the standard second-trimester anatomy scan into the first trimester.

·               Various maternal conditions and/or their treatment are known to be associated with structural anomalies or restricted growth. Maternal pregestational diabetes is a well-known risk factor for congenital anomalies. The overall incidence of congenital malformations in diabetic pregnancies is 6–13 %, which is twofold to fourfold greater than that of the general population.

·               Obesity is a well-known risk factor for and comorbidity of diabetes. Women with pregestational diabetes and BMI higher than 28 kg/m2 have a threefold increase in the risk of congenital anomalies, and the risk further increases proportionally with BMI.

·               Congenital heart disease (CHD) is the most common congenital anomaly, with an incidence of 6–8 % of all live births, accounting for 30–45 % of all congenital defects. An increased nuchal translucency (NT) and/or abnormal ductus venosus (DV) blood velocity waveform are associated with major cardiac defects in the fetus. Complete evaluation rate of the heart increased from 45 % at 11 weeks to 90 % between 12 and 14 weeks and 100 % at 15 weeks.

·               Maternal metabolic diseases such as PKU and diabetes, and exposure to certain medications such as anticonvulsants are associated with CHD. These conditions might be considered as an indication for performing first-trimester fetal echocardiogram.

·               First-trimester uterine artery Doppler is a useful tool for predicting early-onset preeclampsia, as well as other adverse pregnancy outcomes. Aspirin treatment initiated before 16 weeks of pregnancy may reduce the incidence of preeclampsia and its consequences in women with ultrasonographic evidence of abnormal placentation diagnosed by first-trimester uterine artery Doppler studies.



Whitworth M, Bricker L, Neilson JP, Dowswell T. Ultrasound for fetal assessment in early pregnancy. Cochrane Database System Rev. 2010; (4):CD007058


Ghi T, Huggon IC, Zosmer N, Nicolaides KH. Incidence of major structural cardiac defects associated with increased nuchal translucency but normal karyotype. Ultrasound Obstet Gynecol. 2001;18(6):610–4.PubMed


Hyett JA, Perdu M, Sharland GK, Snijders RS, Nicolaides KH. Increased nuchal translucency at 10-14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol. 1997;10(4):242–6.PubMed


Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol. 2001;18(1):9–17.PubMed


Timor-Tritsch IE, Farine D, Rosen MG. A close look at early embryonic development with the high-frequency transvaginal transducer. Am J Obstet Gynecol. 1988;159(3):676–81.PubMed


Timor-Tritsch IE, Monteagudo A, Peisner DB. High-frequency transvaginal sonographic examination for the potential malformation assessment of the 9-week to 14-week fetus. J Clin Ultrasound. 1992;20(4):231–8.PubMed


Lasser DM, Peisner DB, Vollebergh J, Timor-Tritsch I. First-trimester fetal biometry using transvaginal sonography. Ultrasound Obstet Gynecol. 1993;3(2):104–8.PubMed


den Hollander NS, Wessels MW, Niermeijer MF, Los FJ, Wladimiroff JW. Early fetal anomaly scanning in a population at increased risk of abnormalities. Ultrasound Obstet Gynecol. 2002;19(6):570–4.


Michailidis GD, Papageorgiou P, Economides DL. Assessment of fetal anatomy in the first trimester using two- and three-dimensional ultrasound. Br J Radiol. 2002;75(891):215–9.PubMed


Hernadi L, Torocsik M. Screening for fetal anomalies in the 12th week of pregnancy by transvaginal sonography in an unselected population. Prenat Diagn. 1997;17(8):753–9.PubMed


Whitlow BJ, Economides DL. The optimal gestational age to examine fetal anatomy and measure nuchal translucency in the first trimester. Ultrasound Obstet Gynecol. 1998;11(4):258–61.PubMed


Gembruch U, Shi C, Smrcek JM. Biometry of the fetal heart between 10 and 17 weeks of gestation. Fetal Diagn Ther. 2000;15(1):20–31.PubMed


Haak MC, Twisk JW, Van Vugt JM. How successful is fetal echocardiographic examination in the first trimester of pregnancy? Ultrasound Obstet Gynecol. 2002;20(1):9–13.PubMed


Johnson P, Sharland G, Maxwell D, Allan L. The role of transvaginal sonography in the early detection of congenital heart disease. Ultrasound Obstet Gynecol. 1992;2(4):248–51.PubMed


Dolkart LA, Reimers FT. Transvaginal fetal echocardiography in early pregnancy: normative data. Am J Obstet Gynecol. 1991;165(3):688–91.PubMed


Timor-Tritsch IE, Bashiri A, Monteagudo A, Arslan AA. Qualified and trained sonographers in the US can perform early fetal anatomy scans between 11 and 14 weeks. Am J Obstet Gynecol. 2004;191(4):1247–52.PubMed


Borrell A, Robinson JN, Santolaya-Forgas J. Clinical value of the 11- to 13 + 6-week sonogram for detection of congenital malformations: a review. Am J Perinatol. 2011;28(2):117–24.PubMed


Grande M, Arigita M, Borobio V, Jimenez JM, Fernandez S, Borrell A. First-trimester detection of structural abnormalities and the role of aneuploidy markers. Ultrasound Obstet Gynecol. 2012;39(2):157–63.PubMed


Syngelaki A, Chelemen T, Dagklis T, Allan L, Nicolaides KH. Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11-13 weeks. Prenat Diagn. 2011;31(1):90–102.PubMed


Ebrashy A, El Kateb A, Momtaz M, El Sheikhah A, Aboulghar MM, Ibrahim M, et al. 13-14-week fetal anatomy scan: a 5-year prospective study. Ultrasound Obstet Gynecol. 2010;35(3):292–6.PubMed


Souka AP, Pilalis A, Kavalakis Y, Kosmas Y, Antsaklis P, Antsaklis A. Assessment of fetal anatomy at the 11-14-week ultrasound examination. Ultrasound Obstet Gynecol. 2004;24(7):730–4.PubMed


Salomon LJ, Bernard JP, Duyme M, Dorion A, Ville Y. Revisiting first-trimester fetal biometry. Ultrasound Obstet Gynecol. 2003;22(1):63–6.PubMed


Naeye RL. Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics. 1965;35:980–8.PubMed


Soler NG, Soler SM, Malins JM. Neonatal morbidity among infants of diabetic mothers. Diabetes Care. 1978;1(6):340–50.PubMed


Mills JL. Malformations in infants of diabetic mothers. Teratology 25:385-94. 1982. Birth Defects Res A Clin Mol Teratol. 2010;88(10):769–78.PubMedCentralPubMed


Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol. 1992;8(4):503–8.PubMed


Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics. 1990;85(1):1–9.PubMed


Lisowski LA, Verheijen PM, Copel JA, Kleinman CS, Wassink S, Visser GH, et al. Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis. Herz. 2010;35(1):19–26.PubMed


Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med. 1971;7(2):73–82.PubMed


Schwartz R, Teramo KA. Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol. 2000;24(2):120–35.PubMed


Garne E, Loane M, Dolk H, Barisic I, Addor MC, Arriola L, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol. 2012;94(3):134–40.PubMed


Taipale P, Ammala M, Salonen R, Hiilesmaa V. Two-stage ultrasonography in screening for fetal anomalies at 13-14 and 18-22 weeks of gestation. Acta Obstet Gynecol Scand. 2004;83(12):1141–6.PubMed


Sebire NJ, Noble PL, Thorpe-Beeston JG, Snijders RJ, Nicolaides KH. Presence of the ‘lemon’ sign in fetuses with spina bifida at the 10-14-week scan. Ultrasound Obstet Gynecol. 1997;10(6):403–5.PubMed


Nicolaides KH, Campbell S, Gabbe SG, Guidetti R. Ultrasound screening for spina bifida: cranial and cerebellar signs. Lancet. 1986;2(8498):72–4.PubMed


Cedergren MI, Kallen BA. Maternal obesity and infant heart defects. Obes Res. 2003;11(9):1065–71.PubMed


Moore LL, Singer MR, Bradlee ML, Rothman KJ, Milunsky A. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology. 2000;11(6):689–94.PubMed


Martinez-Frias ML, Frias JP, Bermejo E, Rodriguez-Pinilla E, Prieto L, Frias JL. Pre-gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes. Diabet Med. 2005;22(6):775–81.PubMed


Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care. 1995;18(11):1446–51.PubMed


Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev. 2001;61(2):85–95.PubMed


Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, Leveno KJ. Maternal diabetes mellitus and infant malformations. Obstet Gynecol. 2002;100(5 Pt 1):925–30.PubMed


Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol. 1994;84(4):515–20.PubMed


Greene MF. Spontaneous abortions and major malformations in women with diabetes mellitus. Semin Reprod Endocrinol. 1999;17(2):127–36.PubMed


Bhattacharyya OK, Estey EA, Cheng AY. Update on the Canadian Diabetes Association 2008 clinical practice guidelines. Can Fam Physician. 2009;55(1):39–43.PubMedCentralPubMed


American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care. 2010;33 Suppl 1:S11–61.PubMedCentral


De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med. 2007;357(2):135–42.PubMed


Timor-Tritsch IE, Monteagudo A, Warren WB. Transvaginal ultrasonographic definition of the central nervous system in the first and early second trimesters. Am J Obstet Gynecol. 1991;164(2):497–503.PubMed


Schiesser M, Holzgreve W, Lapaire O, Willi N, Luthi H, Lopez R, et al. Sirenomelia, the mermaid syndrome–detection in the first trimester. Prenat Diagn. 2003;23(6):493–5.PubMed


Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults--the evidence report. National Institutes of Health. Obes Res. 1998;6(suppl 2):51S–209S


Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;282(16):1519–22.PubMed


Gross T, Sokol RJ, King KC. Obesity in pregnancy: risks and outcome. Obstet Gynecol. 1980;56(4):446–50.PubMed


Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009–2010. NCHS Data Brief. 2012(82):1–8


Hendricks KA, Nuno OM, Suarez L, Larsen R. Effects of hyperinsulinemia and obesity on risk of neural tube defects among Mexican Americans. Epidemiology. 2001;12(6):630–5.PubMed


Mikhail LN, Walker CK, Mittendorf R. Association between maternal obesity and fetal cardiac malformations in African Americans. J Natl Med Assoc. 2002;94(8):695–700.PubMedCentralPubMed


Queisser-Luft A, Kieninger-Baum D, Menger H, Stolz G, Schlaefer K, Merz E. Does maternal obesity increase the risk of fetal abnormalities? Analysis of 20,248 newborn infants of the Mainz Birth Register for detecting congenital abnormalities. Ultraschall Med. 1998;19(1):40–4. Erhoht mutterliche Adipositas das Risiko fur kindliche Fehlbildungen? Analyse von 20,248 Neugeborenen des Mainzer Geburtenregisters zur Erfassung angeborener Fehlbildungen.PubMed


Blomberg MI, Kallen B. Maternal obesity and morbid obesity: the risk for birth defects in the offspring. Birth Defects Res A Clin Mol Teratol. 2010;88(1):35–40.PubMed


Thornburg LL, Miles K, Ho M, Pressman EK. Fetal anatomic evaluation in the overweight and obese gravida. Ultrasound Obstet Gynecol. 2009;33(6):670–5.PubMed


Dashe JS, McIntire DD, Twickler DM. Effect of maternal obesity on the ultrasound detection of anomalous fetuses. Obstet Gynecol. 2009;113(5):1001–7.PubMed


Hendler I, Blackwell SC, Bujold E, Treadwell MC, Wolfe HM, Sokol RJ, et al. The impact of maternal obesity on midtrimester sonographic visualization of fetal cardiac and craniospinal structures. Int J Obes Relat Metab Disord. 2004;28(12):1607–11.PubMed


Gupta S, Timor-Tritsch IE, Oh C, Chervenak J, Monteagudo A. Early second-trimester sonography to improve the fetal anatomic survey in obese patients. J Ultrasound Med. 2014;33(9):1579–83.PubMed


Timor-Tritsch IE. Transvaginal sonographic evaluation of fetal anatomy at 14 to 16 weeks. Why is this technique not attractive in the United States? J Ultrasound Med. 2001;20(7):705–9.PubMed


Rowland TW, Hubbell Jr JP, Nadas AS. Congenital heart disease in infants of diabetic mothers. J Pediatr. 1973;83(5):815–20.PubMed


Erickson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology. 1991;43(1):41–51.PubMed


Correa A, Gilboa SM, Botto LD, Moore CA, Hobbs CA, Cleves MA, et al. Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. Am J Obstet Gynecol. 2012;206(3):218.e1–13.


Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;199(3):2371–9.


Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM. 2001;94(8):435–44.PubMed


Wahabi HA, Alzeidan RA, Bawazeer GA, Alansari LA, Esmaeil SA. Preconception care for diabetic women for improving maternal and fetal outcomes: a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2010;10:63.PubMedCentralPubMed


Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2009;94(11):4284–91.PubMed


Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890–900.PubMed


Garne E, Stoll C, Clementi M. Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries. Ultrasound Obstet Gynecol. 2001;17(5):386–91.PubMed


Hoffman JI. Congenital heart disease: incidence and inheritance. Pediatr Clin North Am. 1990;37(1):25–43.PubMed


Wan AW, Jevremovic A, Selamet Tierney ES, McCrindle BW, Dunn E, Manlhiot C, et al. Comparison of impact of prenatal versus postnatal diagnosis of congenitally corrected transposition of the great arteries. Am J Cardiol. 2009;104(9):1276–9.PubMed


Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, Silverman NH. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation. 2001;103(9):1269–73.PubMed


Lagopoulos ME, Manlhiot C, McCrindle BW, Jaeggi ET, Friedberg MK, Nield LE. Impact of prenatal diagnosis and anatomical subtype on outcome in double outlet right ventricle. Am Heart J. 2010;160(4):692–700.PubMed


Gembruch U, Knopfle G, Chatterjee M, Bald R, Hansmann M. First-trimester diagnosis of fetal congenital heart disease by transvaginal two-dimensional and Doppler echocardiography. Obstet Gynecol. 1990;75(3 Pt 2):496–8.PubMed


Makrydimas G, Sotiriadis A, Ioannidis JP. Screening performance of first-trimester nuchal translucency for major cardiac defects: a meta-analysis. Am J Obstet Gynecol. 2003;189(5):1330–5.PubMed


Muller MA, Clur SA, Timmerman E, Bilardo CM. Nuchal translucency measurement and congenital heart defects: modest association in low-risk pregnancies. Prenat Diagn. 2007;27(2):164–9.PubMed


Clur SA, Ottenkamp J, Bilardo CM. The nuchal translucency and the fetal heart: a literature review. Prenat Diagn. 2009;29(8):739–48.PubMed


Montenegro N, Matias A, Areias JC. Ductus venosus blood flow evaluation: its importance in the screening of chromosomal abnormalities. Am J Obstet Gynecol. 1999;181(4):1042–3.PubMed


Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol. 1998;12(6):380–4.PubMed


Martinez JM, Comas M, Borrell A, Bennasar M, Gomez O, Puerto B, et al. Abnormal first-trimester ductus venosus blood flow: a marker of cardiac defects in fetuses with normal karyotype and nuchal translucency. Ultrasound Obstet Gynecol. 2010;35(3):267–72.PubMed


Maiz N, Nicolaides KH. Ductus venosus in the first trimester: contribution to screening of chromosomal, cardiac defects and monochorionic twin complications. Fetal Diagn Ther. 2010;28(2):65–71.PubMed


Bilardo CM, Muller MA, Zikulnig L, Schipper M, Hecher K. Ductus venosus studies in fetuses at high risk for chromosomal or heart abnormalities: relationship with nuchal translucency measurement and fetal outcome. Ultrasound Obstet Gynecol. 2001;17(4):288–94.PubMed


Favre R, Cherif Y, Kohler M, Kohler A, Hunsinger MC, Bouffet N, et al. The role of fetal nuchal translucency and ductus venosus Doppler at 11-14 weeks of gestation in the detection of major congenital heart defects. Ultrasound Obstet Gynecol. 2003;21(3):239–43.PubMed


Maiz N, Plasencia W, Dagklis T, Faros E, Nicolaides K. Ductus venosus Doppler in fetuses with cardiac defects and increased nuchal translucency thickness. Ultrasound Obstet Gynecol. 2008;31(3):256–60.PubMed


Smrcek JM, Berg C, Geipel A, Fimmers R, Diedrich K, Gembruch U. Early fetal echocardiography: heart biometry and visualization of cardiac structures between 10 and 15 weeks’ gestation. J Ultrasound Med. 2006;25(2):173–82. quiz 83-5.PubMed


Platt LD, Koch R, Hanley WB, Levy HL, Matalon R, Rouse B, et al. The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study. Am J Obstet Gynecol. 2000;182(2):326–33.PubMed


Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med. 1980;303(21):1202–8.PubMed


Koch R, Friedman E, Azen C, Hanley W, Levy H, Matalon R, et al. The International Collaborative Study of Maternal Phenylketonuria: status report 1998. Eur J Pediatr. 2000;159 Suppl 2:S156–60.PubMed


Matalon KM, Acosta PB, Azen C. Role of nutrition in pregnancy with phenylketonuria and birth defects. Pediatrics. 2003;112(6 Pt 2):1534–6.PubMed


Michals-Matalon K, Platt LD, Acosta PP, Azen C, Walla CA. Nutrient intake and congenital heart defects in maternal phenylketonuria. Am J Obstet Gynecol. 2002;187(2):441–4.PubMed


Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10(7):609–17.PubMed


Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344(15):1132–8.PubMed


Samren EB, van Duijn CM, Koch S, Hiilesmaa VK, Klepel H, Bardy AH, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia. 1997;38(9):981–90.PubMed


Samren EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol. 1999;46(5):739–46.PubMed


Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia. 1999;40(9):1231–6.PubMed


Kaneko S, Battino D, Andermann E, Wada K, Kan R, Takeda A, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999;33(2-3):145–58.PubMed


Holmes LB. The teratogenicity of anticonvulsant drugs: a progress report. J Med Genet. 2002;39(4):245–7.PubMedCentralPubMed


Holmes LB, Mittendorf R, Shen A, Smith CR, Hernandez-Diaz S. Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. Arch Neurol. 2011;68(10):1275–81.PubMed


Barrett C, Richens A. Epilepsy and pregnancy: report of an Epilepsy Research Foundation Workshop. Epilepsy Res. 2003;52(3):147–87.PubMed


Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol. 2002;16(1):9–17.PubMed


Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, et al. Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia. 2000;41(11):1436–43.PubMed


Lindhout D, Omtzigt JG. Teratogenic effects of antiepileptic drugs: implications for the management of epilepsy in women of childbearing age. Epilepsia. 1994;35 Suppl 4:S19–28.PubMed


Jentink J, Dolk H, Loane MA, Morris JK, Wellesley D, Garne E, et al. Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study. BMJ. 2010;341:c6581.PubMedCentralPubMed


Janz D. Are antiepileptic drugs harmful when taken during pregnancy? J Perinat Med. 1994;22(5):367–77.PubMed


Thomas SV, Ajaykumar B, Sindhu K, Francis E, Namboodiri N, Sivasankaran S, et al. Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr Cardiol. 2008;29(3):604–8.PubMed


Floyd RL, Sidhu JS. Monitoring prenatal alcohol exposure. Am J Med Genet C Semin Med Genet. 2004;127C(1):3–9.PubMed


Hoyme HE, May PA, Kalberg WO, Kodituwakku P, Gossage JP, Trujillo PM, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. Pediatrics. 2005;115(1):39–47.PubMed


Jones KL, Smith DW, Ulleland CN, Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet. 1973;1(7815):1267–71.PubMed


Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med. 1978;298(19):1063–7.PubMed


Burd L, Deal E, Rios R, Adickes E, Wynne J, Klug MG. Congenital heart defects and fetal alcohol spectrum disorders. Congenit Heart Dis. 2007;2(4):250–5.PubMed


Gomez O, Martinez JM, Figueras F, Del Rio M, Borobio V, Puerto B, et al. Uterine artery Doppler at 11-14 weeks of gestation to screen for hypertensive disorders and associated complications in an unselected population. Ultrasound Obstet Gynecol. 2005;26(5):490–4.PubMed


Prefumo F, Guven M, Ganapathy R, Thilaganathan B. The longitudinal variation in uterine artery blood flow pattern in relation to birth weight. Obstet Gynecol. 2004;103(4):764–8.PubMed


Gomez O, Figueras F, Martinez JM, del Rio M, Palacio M, Eixarch E, et al. Sequential changes in uterine artery blood flow pattern between the first and second trimesters of gestation in relation to pregnancy outcome. Ultrasound Obstet Gynecol. 2006;28(6):802–8.PubMed


Velauthar L, Plana MN, Kalidindi M, Zamora J, Thilaganathan B, Illanes SE, et al. First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women. Ultrasound Obstet Gynecol. 2014;43(5):500–7.PubMed


Bujold E, Morency AM, Roberge S, Lacasse Y, Forest JC, Giguere Y. Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2009;31(9):818–26.PubMed


American Institute of Ultrasound in Medicine. AIUM practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med. 2013;32(6):1083–101.


Carvalho JS. Fetal heart scanning in the first trimester. Prenat Diagn. 2004;24(13):1060–7.PubMed

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