The American Medical Association (AMA) voted in 2013 to recognize obesity as a disease (against the advice of its Public Health and Science Committee). AMA defended its action as a way to confer legitimacy to the condition, allowing for greater attention and better treatment. This definition was also approved in order to facilitate insurance coverage. Whether it is a condition that leads to disease or a disease itself, there is a strong worldwide consensus that obesity is pandemic and needs to be treated and, more importantly, prevented (especially in children), owing to its signiﬁcant comorbidities, mortality and costs(1).
Obesity is the most common problem in obstetrics that affects both the mother and her offspring(2). It causes short-term and long-term problems for the mother, such as increasing her risk of gestational diabetes (GDM) and preeclampsia, venous thromboembolism, and postpartum hemorrhage risk during pregnancy and the intrapartum period(3,4). Because obese women are more likely to have excessive gestational weight gain (GWG)(5), this further increases the risk of developing the metabolic syndrome later in life. The offsprings have an increased risk of obstetric morbidity and mortality(6) and, consistent with the developmental origins of health and disease, a long-term risk of childhood obesity and metabolic dysfunction(7).
The prevalence of obesity is increasing worldwide. World Health Organization (WHO) classifies obesity according to body mass index [BMI=weight (kg)/height (m2)], as following: less than 18.5: underweight; 18.5-24.9: normal weight; 25-29.9: overweight; 30-34.9: obesity class I; 35-39.9: obesity class II; 40 or greater: obesity class III(8).
BMI estimates of body fat in non-pregnant women explain 50-70% of the variance in fat mass. During pregnancy, the significant increase in total body water makes the correlation less robust. The global age standardized mean BMI in women increased from 22.1 (credible intervals: 21.7 to 22.5) in 1975 to 24.4 (24.2 to 24.6) in 2014, with a doubling of the prevalence of obesity between 1980 and 2008(9).
In Europe, WHO estimates that more than 50% of men and women are overweight or obese, and 23% of women are obese. In South East Asia, 14% of the population is overweight and 3% is obese(10). The increase in obesity is not confined to adults – there have been increases in obesity in children(10) and significant increases in birth weights among various populations(11).
Many obese women have already faced significant health challenges before they arrive for the first ultrasound evaluation. These may include ovulatory infertility, increased fetal wastage, hypertension, diabetes, venous thromboembolism, cardiorespiratory disease, and obstructive sleep apnea. Maternal obesity is also associated with increased rates of complications in late pregnancy, including gestational diabetes, preeclampsia, non-progression of labor, shoulder dystocia and caesarean section(11,12). Pregnancy and the puerperium are well established risk factors for venous thromboembolism, primarily on the basis of venous stasis, hypercoagulability and vascular damage. The risk reaches its maximum in postpartum. Pulmonary embolism (PE) is a significant cause of maternal mortality. Both obesity and pregnancy are independent risk factors for the development of deep venous thrombosis and preeclampsia, the risk of venous disease in pregnant obese women being increased about 1.4-3.6 fold compared to the normal-weight pregnant women(13).
The increased risk of fetal structural anomalies remains independent of other maternal risk factors such as diabetes, even though in most of the patients the conditions are concomitantly present. The ultrasound diagnosis of a fetal anomaly presents special challenges in the obese gravida for two main reasons: firstly, there is an significantly increased risk for the fetus to carry a congenital anomaly, and secondly, the quality of the obtained ultrasonographic images is poor due to the well represented subcutaneous fat tissue that alters ultrasound reflection. With regard to anomalies, the major anatomic areas of concern are the neural tube and heart.
Stothard et al. showed that the risk of certain fetal anomalies is signiﬁcantly higher in obese patients compared to normal population, especially neural tube defects, cardiac anomalies, anal atresia and limb-reduction abnormalities. Yet, in more than 50% of obese women the fetal anatomic survey cannot be completed at the time of the ﬁrst ultrasound examination(14). The use of systematic transvaginal examination in all obese patients increases the examination time, but also the percentage of structure that can be visualized in the first trimester.
Hendler et al. showed that the rate of poor visualization was worse in the obese group for both the fetal heart (37% versus 19%) and spine (43% versus 29%), which correlated linearly with the degree of obesity. When the ultrasound examination was repeated at 21 weeks, there was an improvement in the visualization of cardiac anatomy in all classes of obesity, although the heart could still not be adequately assessed in up to 20% of the obese population despite multiple ultrasound examinations(15). The importance of adequate views of the fetal heart in obese gravidas is paramount due to the higher incidence of heart defects in these fetuses(16). Indeed, Uhden et al. showed that the prevalence of heart defects was higher (relative risk 2.04) in overweight and obese women (BMI>25) compared to those of normal weight. And yet, the quality of insufﬁcient ultrasound images increased from 6.4% in normal weight patients to 17.4% in obese women(17). Moreover, Cedergren and Kallen observed a positive association (adjusted OR 1.3) between obesity and orofacial clefts in offspring(18). Meta-analyses support these observations, as demonstrated by Stothard et al., with respect to either cleft palate (adjusted OR 1.23) or cleft lip and palate (adjusted OR 1.2), but not isolated cleft lip. In their analysis, these findings were not significant in the overweight gravidas, again suggesting a dose-dependent relationship(19).
The fetal risks associated with poor glycemic control have long been established. In utero, the fetus is exposed to hyperinsulinemia (with subsequent neonatal hypoglycemia), cardiomyopathy (or ventricular hypertrophy), macrosomia and even stillbirth(20).
One of the underappreciated risks of maternal obesity is the propensity of the fetus to become macrosomic and the challenge of accurately assessing EFW at the upper extremes of fetal weight. Macrosomia is a well-known risk factor for adverse delivery related events in both mother (postpartum hemorrhage, anorectal sphincter lacerations, increased risk of caesarean section, prolonged labor) and the fetus, including fetal injury (shoulder dystocia, asphyxia). The incidence of shoulder dystocia and birth injury risks is positively correlated with the increased fetal weight(20,21).
Additionally, periconceptional hyperglycemia is linked to an increased number of congenital malformations of major organ systems in the offspring of diabetics, notably among those patients with pregestational diabetes or gestational diabetes with fasting hyperglycemia or evidence of poor glycemic control. Regardless, multiple lines of evidence suggest that obesity accompanies type 2 and gestational diabetes(21).
The relationship between obesity and diabetes, both gestational and type 2, is complex as many diabetic patients are obese and many obese patients are diabetic. Moreover, obesity is a known risk factor for insulin resistance which is further amplified by the physiologic insulin resistance of pregnancy, which results in a 60% decrease in insulin sensitivity. It has been suggested that the relative insulin insensitivity of pregnancy superimposed on insulin resistance secondary to obesity predisposes obese pregnant women to gestational diabetes, preeclampsia and fetal macrosomia(18).
In summary, the fetal effects of maternal obesity and hyperglycemia appear to be both synergistic and independently valid. Future studies which aim to clarify the precise metabolic pathways underlying these observations will be pivotal in ascribing the true risk of fetal malformation, and obesity and diabetes – both in isolation and interdependence – may elucidate genomic and epigenomic susceptibility factors which underlie these risks.
Screening for Down syndrome
Ultrasound is, arguably, the most commonly used diagnostic procedure in obstetrics. It is convenient, painless, yields immediate, extensive results, it is safe and widely accepted by the patients. The ultrasound is particularly useful in the first trimester for precise pregnancy dating, especially in obese patients with polycystic ovarian syndrome.
As ultrasonography has become an integral part of obstetrical care, the first-trimester ultrasound plays an important role not only for pregnancy confirmation, but also for Down syndrome between 11-13+6 days, and more recently preeclampsia screening is performed during the same period. Unfortunately, the examination of the fetus is challenging transabdominally in the first trimester, but the availability of the transvaginal high frequency probe significantly ameliorates the visualization of fetal structures. Still, the detection of Down syndrome in obese patients is lower than in non-obese patients probably due to the suboptimal visualization or accurate assessment of some (but not all) fetal structures or soft markers(22,23). A second explanation is represented by the lower values of serum markers in obese women included in Down syndrome screening due to the larger distribution volume of obese women.
Focusing on the detection of Down syndrome, the FaSTER trial enrolled participants from 13 centers in order to investigate the role of second-trimester genetic ultrasound in modifying maternal serum screening results. Likelihood ratios were calculated for risk modification with presence or absence of structural malformations or ‘soft’ sonographic markers. These markers include a thickened nuchal fold (>5 mm), an echogenic intracardiac focus (papillary muscle that is found to be as bright as bone), echogenic bowel, and renal pyelectasis (a 4 mm or greater anterior posterior diameter of the renal pelvis), shortened long bones, pericardial effusions, choroid plexus cysts, ventriculomegaly, hydrops, liver calcification, two vessel umbilical cord, polydactyly, clinodactyly, sandal gap toe, and club foot(24,25). The FaSTER trial showed that maternal serum screening in the first and second trimesters can be improved with the likelihood ratios from second trimester genetic ultrasound(24). Subsequent analysis of the FaSTER population database investigated the role of maternal body mass index in second-trimester genetic sonography. The conclusion of these secondary analysis is that maternal obesity was associated with elevated false positive results for the category of two or more sonographic markers for Down syndrome and, additionally, with increased missed diagnosis rate (MDR) of sonographic ‘soft markers’(15). Furthermore, first-trimester nuchal translucency measurements were consistently more difficult to obtain with increasing BMI(26).
While obesity does not increase the risk for aneuploidy, as previously noted, obese populations are at increased risk for neural tube defects, as well as other fetal anomalies(20,27).
First-trimester screening involves ultrasound evaluation of the nuchal translucency between 11 and 14 weeks of gestation in combination with maternal serum screening using human chorionic gonadotropin (hCG; total or free beta) and pregnancy-associated plasma protein-A (PAPP-A). The decreased ability to detect the nuchal translucency in the overweight and obese populations limits the effectiveness of first-trimester screening for trisomies(26). Additionally, an increased BMI has been shown to increase the frequency of inadequate nasal bone assessment, increased need for transvaginal ultrasound examination and an increased amount of time to obtain adequate ultrasound images(26). Second-trimester maternal serum screening is also affected by obesity due to the lower level of the parameters detected from maternal plasma(26,27).
Non-invasive prenatal testing (NIPT) and its performance in obese pregnant women
The progress of molecular techniques, including next generation DNA sequencing, has allowed the extensive use of non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA) analysis for aneuploidy detection in high-risk pregnancies. Normally, in pregnancy the trophoblastic cells are shedding into the maternal plasma, the test being able to amplify regions of fetal DNA from the maternal blood stream(28). Despite a very good sensitivity for Down syndrome, all NIPT tests are reliable at a minimum cffDNA fraction superior to 4%. The fetal fraction remains relatively stable between 10 and 21 weeks of gestation, increasing by only 0.1% per week during this period(29). In a fetal fraction inferior to 4%, the management consist in repeating the test at a more advanced gestational age (the cffDNA fraction being expected to increase, as mentioned before) or in performing a different type of test (invasive procedures in high-risk patients). In pregnant women with a normal BMI, the proportion of patients with a cffDNA fetal fraction inferior to 4 is about 0.7% in women with 60 kg, rising up to 51.1% in a patient with 160 kg(30). While the increased risk of an unreportable result in obese patients is concerning, the higher false negative rate in this population is of a greater concern. The performance of NIPT test diminished with decreasing fetal fraction. The proportion of DNA fragments mapped to the chromosome of interest (expressed as multiples of the median) overlaps more at lower fetal fractions, increasing the risk of a false negative result(32). At present, obesity-specific test statistics (sensitivity, specificity, false negative rate) are unknown and patients should be informed about the known limitations of NIPT in the setting of maternal obesity, especially those at the extremes of maternal weight.
As an alternative to NIPT tests, Ghanta et al. proposed the use of a single SNP for obese women which can increase Down syndrome detection in obese women feasible at the much lower cffDNA of only 2%(31).
Invasive procedures (amniocentesis and chorionic villus sampling)
Amniocentesis was thought to be the best method for the detection of trisomies and fetal anomalies such as neural tube defects in obese pregnant women, taking into account the increased risk of anomalies and the modest performance of serum tests in this category of patients(33). However, although maternal obesity limits ultrasonographic visualization, it may also affect the fetal loss rate associated with invasive diagnostic procedures as a result of technical challenges(34).
A BMI of 30 or higher does not appear to significantly increase the risk for fetal loss after invasive prenatal diagnostic procedures compared with non-obese women. In contrast, a higher statistically significant loss rate was noted in patients with class III obesity (BMI 40 or higher) for amniocentesis(35). Moreover, obese patients may require multiple needle insertions(35). Instead, no significant difference has been found for CVS in obese versus non-obese patients, therefore in obese patients where an invasive test is indicated, CVS is the procedure of choice(35). Therefore, the obese patients need to be correctly counseled prior to amniocentesis, before an invasive prenatal diagnostic procedure(35).
Obesity is a major health challenge for nowadays society, the pregnancy in this category of patients being related to an increased risk of complications for the mother and the fetus, but also represents a challenge for the health care providers. Preconception counseling and weight loss should be encouraged.
Maternal obesity influences the diagnostic abilities of available screening modalities (ultrasound, serum test and NIPT), but also the performance of ultrasound. Given the increased risks associated with maternal BMI, the screening limitations are concerning. Moreover, invasive procedures have a higher risk of fetal loss in morbidly obese patients. Therefore, it is important to stress prior to any examination or procedure the performance and the limitations of all these prenatal tests for obese patients.
Unfortunately, even after a successful pregnancy, obesity will have a long-time impact upon both mother and the fetus later in life.
Conflict of interests: The authors declare no conflict of interests.