Assessment of fetal thymus size in pregnancies of underweight women

Introduction

About 390 million people worldwide are underweight [1]. Women are more likely to be affected than men [2]. The most common causes are malnutrition [3], eating disorders [4] and hormonal disturbances [5]. An important parameter to diagnose underweight is the body mass index (BMI). It can be determined by dividing a person’s weight in kilograms by the square of height in meters. According to the World Health Organization’s classification a BMI lower than 18.5 is considered underweight, a BMI between 18.5 and 24.9 is normal weight and every BMI of 25 and higher is an indicator for obesity [6].

It is already known that low maternal weight is a risk factor for negative outcomes in pregnancy, such as miscarriages [7], premature birth [8], 9], low birthweight [8], intrauterine growth restriction [10]. Furthermore, studies have shown a negative influence on the fetal brain activity [11] and a reduced development of the fetal immune system [12], 13].

At the same time, low maternal weight reduces the risk for hypertensive disorders, gestational diabetes, preeclampsia, fetal macrosomia and cesarean sections [14].

As a primary lymphatic organ, the thymus plays an important role in the fetal immune system, as it enables the maturation and differentiation of T-lymphocytes.

It is located in the upper anterior mediastinum between the sternum and the big vessels – aorta, vena cava superior and truncus pulmonalis – and consists of two lobes [15].

It is an epithelial organ with a mesenchymal capsule whose development has an endodermal origin [16]. The primary function of the thymus occurs during the fetal period and childhood. Afterwards, it experiences fat involution which is characterized by an increase of fat tissue [17].

There are several studies showing that maternal diseases or complications during pregnancy have an influence on the fetal thymus size: In cases of maternal diabetes [18], assisted reproductive technologies [19], preterm premature rupture of membranes [20], chorioamnionitis [20] and chromosomal anomalies [21] the fetal thymus size was decreased, whereas it was increased in patients with HIV [22] or obesity [23]. Rheumatic diseases [24], maternal hypertension or maternal coagulation disorders did not influence fetal thymus size [25].

It is also known that malnutrition has a great impact on the thymus, leading to dysfunction and atrophy. One study showed that maternal malnutrition can reduce the development of the fetal immune system [12]. On the other hand, Yildirim et al. showed that a high maternal BMI was associated with an increase in fetal thymus size [23].

Therefore, we assumed that the thymus as an important component of the fetal immune system could also be affected by maternal underweight.

Materials and methods

This retrospective study is based on routine ultrasonographic scans of 162 women between the 19th and 34th week of gestation. These examinations were performed by prenatal specialist doctors in the Department of Obstetrics and Gynecology at the University Hospital in Münster, Germany, between 2012 and 2022.

Two groups were formed to compare the fetal thymus size: underweight women (study group, n=77) and normal weight women (control group, n=85). Inclusion criteria for the study group were healthy women over 18 years with a pre-pregnancy BMI lower than 18.5, while the control group consisted of healthy women over 18 years with a pre-pregnancy BMI from 18.5 to 24.9. Exclusion criteria were fetal chromosomal aberrations or structural anomalies, as well as maternal diseases or age below 18 years.

We used the thymic-thoracic ratio (TT-ratio) to describe the thymus size. The TT-ratio is the quotient of the anteroposterior thymus diameter and the intrathoracic mediastinal diameter.

These parameters were measured in the three-vessel view. This is a transversal view of the upper mediastinum and a representation of the pulmonal artery, the vena cava superior and the aorta. The intrathoracic mediastinal diameter was measured from the posterior edge of the sternum through the middle of the aorta to the anterior edge of the thoracic vertebrae. The anteroposterior thymus diameter was measured between the posterior border of the sternum and the anterior vessel wall of the aorta [26] (Figure 1).

Figure 1:

The three vessel view in a routine ultrasound of a fetus in an underweight pregnancy. Anteroposterior diameter (6.0 mm) and intrathoracic mediastinal diameter (19.5 mm) were measured to build the TTR (0.308).

All measurements were performed by the same person and were controlled by an independent reviewer. This was done retrospectively and only on research purpose since it is not part of the routine diagnostic in pregnancies to assess the fetal thymus size.

The following parameters were also collected for each case: BMI, week of gestation at screening, week of gestation at delivery, pH umbilical artery, weight at birth and APGAR-score after 5 min.

All data were extracted from the hospitals electronic data base (ViewPoint, GE Healthcare, Fairfield, Connecticut, USA) in 2023.

The Ethics Committee of the Westphalia-Lippe Medical Association approved our study on July 18, 2023. The reference number is 2023-309-f-S. The study was planned in accordance with the Declaration of Helsinki.

Results

The study group consisted of 77 underweight women and the control group of 85 women with normal weight. Table 1 shows the characteristics of each group and Figure 2 the comparison of fetal thymus size.

Figure 2:

Boxplots comparing the distribution of the TT-ratio between the control group (group 0) and the study group (group 1).

The following differences were found between the study group and the control group: The average fetal weight at birth was significantly lower (3,087 g vs. 3,465 g, p<0.01), they showed a lower birth weight percentile (34.2 vs. 48.9, p<0.01), babies were delivered earlier (38.29 vs. 39.76 weeks, p<0.01), and the APGAR-Score was lower (9.36 vs. 9.71, p<0.05) in the study group, while the umbilical artery pH did not differ noticeably.

There was no difference in thymus size between the two groups. Even though the mean TT-ratio in the study group was slightly higher than in the control group, no statistical significance was detected. The multivariable regression model indicates that, even when accounting for cofactors such as gestational age at screening and birth percentiles, BMI does not have a significant impact on fetal thymus size.

Discussion

Different studies have shown changes of fetal thymus size for several maternal diseases. This is the first study comparing fetal thymus size in pregnancies of underweight women to women with normal weight. We found out that the TT-ratio did not differ significantly between these two groups.

Recent studies have shown that there are several parameters that influence thymus size: a smaller thymus size was associated with a maternal Covid-19 infection [27], pregnancies after assisted reproductive technologies [19], fetal chromosomal anomalies [20], maternal diabetes [18] and preterm premature rupture of membranes [20], whereas an increased thymus size was associated with maternal HIV infection and small for gestational age-fetuses [28].

Parameters that do not seem to influence fetal thymus size are maternal hypertension or maternal coagulation disorders [25] as well as rheumatic diseases [24]. However, for some diseases different study groups reported contrary results. This might depend on different measurements of fetal thymus size or the study design.

Our study showed that a lower BMI does not affect the fetal thymus size. Yildirim et al. found out that – at the other end of the spectrum – maternal obesity leads to an increased fetal thymus size [23] and they assumed that the maternal BMI does affect fetal thymus growth.

Some studies have indicated that a higher BMI may be linked to elevated levels of inflammatory markers in the body [29]. Other studies found out that inflammation can lead to a reduced immune system [12], 13]. So Yildirim et al. discussed whether inflammatory markers from adipose tissue contribute to enlarged thymus size.

It is already known that low maternal weight can influence the pregnancy outcome in different ways. Bregar et al. found out that being underweight before pregnancy reduces the risk of fetal macrosomia, the rates of cesarean sections, hypertensive disorders and gestational diabetes [14]. As opposed to this, other studies established negative outcomes. Many underweight women are infertile [30]. Others suffer miscarriages [7] or their fetuses have to bear consequences like premature birth [9], low birthweight [9], intrauterine growth restriction [10], a negative influence on the fetal brain activity [11] and a reduced development of the fetal immune system [12], 13].

A pilot study from Tübingen used a sample of pregnant women with varying severity of eating disorder and measured the brain responses of their fetuses to auditory stimuli. They found out that higher maternal eating disorder severity was linked to delay in the fetal brain’s response [11].

Obanewa et al. found out that a balanced diet during pregnancy can help strengthen the fetus’s immune response and improve the effectiveness of routine vaccinations in infants. Malnutrition of the mother can lead to a reduced immune response in the fetus [12].

But malnutrition is only one possible cause for low maternal weight. Most studies examining the influence of low maternal weight on pregnancy or fetal outcome come from developing countries, where socioeconomic reasons for low weight and malnutrition are more common than in the cohort in this study [31]. That might explain why we did not find a significant influence of maternal underweight on the fetal thymus. It would be interesting to investigate the influence of the different causes for underweight, for example genetic disposition, hormone disorder, malnutrition and eating disorders, on the fetal immune system and specifically on the fetal thymus size.

One limitation of this study is that we did not take the aspect of weight gain into consideration. Ma et al. highlighted that both the pre-pregnancy BMI and gestational weight gain trajectory are important factors that can influence pregnancy outcomes. Women with higher pre-pregnancy BMI and excessive gestational weight gain may be at higher risk for adverse outcomes like premature birth, low birth weight and cesarean section [32].

Additionally, we found other noticeable results: fetuses of underweight women had lower weight at birth, lower percentile of birthweight, were delivered earlier and had a lower APGAR score. These findings confirm and complete the results of many other studies [8], 9], 32], 33].

The relatively small sample size is a further limitation due to the fact that in Germany only a small percentage of the pregnant women are underweight [30] and many of them suffer from miscarriage [7].

A higher sample size might lead to a clearer result. Another critical aspect is the retrospective design. Not every ultrasound picture fulfilled the criteria for measuring the TT-ratio as it was not taken for this purpose, which additionally led to a reduction in sample size. Another consequence of the retrospective design is that we only had information on routine examinations during pregnancy and not on markers for malnutrition like ferritin, B12 levels or albumin.

Furthermore, a three-dimensional organ like the thymus cannot be measured precisely in a two-dimensional picture. Other studies have shown different ways of measuring the thymus, for example using the anterior-posterior diameter [34], the circumference [35] and the transversal diameter [36].

Some even used three-dimensional ultrasound to determine the volume of the fetal thymus and showed that it is a little more precise but more technically challenging [37], 38].

Choaui et al. [26] first described the thymic-thoracic ratio which we used for our study. The TT-ratio consists of the anteroposterior thymic diameter and the intrathoracic mediastinal diameter. One of the main advantages of using the ratio is that ultrasonographic scans taken at different gestational ages can be compared more easily as it is a dimensionless variable. It is also a proved technique and delivers serviceable results [24], 25].

As this is no randomized study there is also a risk of selection bias. To reduce the risk of it, we implemented the methods outlined below. First of all, we used a computer program to assign participants to the two groups based on predefined criteria rather than subjective judgement.

A proven method of measurement was also employed, combined with the fact that the TTR was assessed and controlled by two different independent persons in every case to avoid measurement bias.

In conclusion, we would suggest that prospective studies should be done to ensure a larger sample size and to gain new insights regarding possible correlation of unexplored parameters in this context, such as ferritin and albumin.

Clinically, our findings imply that underweight pregnant women should be monitored more closely to detect potential risks for the baby. Regular check-ups could allow timely interventions. It could also be helpful to motivate future mothers to gain weight to minimize risks. Additionally, their babies might require more intensive postnatal observation and support to ensure a stable transition.

Conclusions

We found no effect of maternal underweight on the thymus size. However, the TT-ratio is an interesting parameter in perinatal medicine, as it is affected by a number of other maternal diseases, such as diabetes mellitus and obesity. Low maternal weight can have a negative impact on pregnancy, so future mothers should be encouraged to gain enough weight before and during pregnancy and monitored appropriately, depending on the cause of the underweight [39]. Additionally, both mothers and babies should be closely observed for potential risks. Prospective studies with a larger sample size should be carried out to substantiate our results.